V. V. GODOVAN HRAOOYI ITRSADSCHEMES AND PICTURES IN PHARMACOLOGY

Vladlena Vladimirovna Godovan belongs to a new generation of the Odessa school of pharmacologists and clinical pharmacolo gists headed by a Corresponding Member of the National Academy of Medical Sciences of PHARMACOLOGY Ukraine, Honoured Worker of Science and Technology of Ukraine, professor V. I. Kre syun. Vladlena Vladimirovna occupies a pro minent place in it. Doctor of medical sci IN PICTURES AND SCHEMES ences, professor of the General and Clinical Pharmacology Department, dean of the Medical faculty of the Odessa National Medical University, scientific secretary of the In 2 volumes Odessa department of the Ukrainian Pharma cologists Association, a leading research worker of the State Expert Center of the Ministry of Health of Ukraine, scientific sec retary of a specialized council. Basic direc Volume 2 tions of her scientific activity are search and creation of drugs on the basis of natural metabolites of a human organism, including coordinating compounds of germanium with bioligands; elaborations in the field of clinical pharmacology of hepatoprotectors and drug usage safety. She is an author of more than 300 scientif ic works, including 2 monographs, 35 training handbooks, manuals, dictionaries in Uk rainian, Russian and English, 18 patents of Ukraine and certificates of authorship.

The ODESSA NATIONAL 2 MEDICAL UNIVERSITY

V. V. Godovan

PHARMACÎLÎGY IN PICTURES A N D SCHEMES In 2 volumes Volume 2 Edited by a fellow of the NAMS of Ukraine, MD, professor V. I. Kresyun

Оdessа The Odessa National Medical University 2011 UDC 615.015(075.8) BBC 52.81я73

Author: V. V. Godovan Reviewers: The head of the Pharmacology Department of the Lugansk State Medical University of MH of Ukraine, Honoured Science and Technology Worker of Ukraine, MD, professor V. D. Lukyanchuk The head of the Department of Experimental and Clinical Pharmacology with Clinical Immunology and Allergology of the Higher State Educational Establishment of Ukraine “The Ukrainian Medical Stomatological Academy” of MH of Ukraine, Honoured Science and Technnology Worker of Ukraine, MD, professor V. N. Bobyryov

Translated from Russian after the edition : Годован В. В. Фармакология в рисунках и схемах : в 2-х томах / В. В. Годован. — Одесса : Одес. гос. мед. ун-т, 2009. — Т. 2. — 276 с.

У даному пораднику, що складається з двох томів, відображені питання загальної та спеціальної фармакології, стисло викладена історія створення лікарських засобів, подаються сучасні класи- фікації фармакологічних груп, узагальнені дані про фармакокіне- тику, фармакодинаміку і фармакотоксикодинаміку ліків, які засто- совуються у сучасній медичній практиці. Матеріал висвітлений в інтеграції з іншими медико-біологічними та клінічними дисципліна- ми. Особливо, унікальне місце у виданні посідає схематичний ви- клад механізмів дії лікарських засобів та їх ефектів, що розвива- ються в результаті цього.

Recommended by Scientific Council of the Odessa State Medical University (Proceedings N1 from 01.09.2008).

© В. В. Годован, 2009 © Одесcкий государственный медицинский университет, 2009 © V. V. Gоdоvan, 2011 ISBN 978-966-443-019-4 (рус.) © The Odessa National Medical ISBN 978-966-443-045-3 University, 2011 2 Part V DRUGS AFFECTING METABOLISM

Topic 18 HORMONAL DRUGS OF POLYPEPTIDE AND AMINOACID STRUCTURE. ANTIHORMONAL DRUGS

NEUROHUMORAL REGULATION

Hypothalamus inhibitor- releasing- factor factor Types of hormonal therapy: Pituitary • substitutive • stimulating hormone of • inhibiting endocrine trope pharmacodynamic gland hormone • • diagnostic

Endocrine gland

3 CLASSIFICATION OF HORMONAL DRUGS (by chemical structure)

♦ Substances of protein and polypeptide structure — drugs of hormones of hypothalamus, pituitary, epiphysis, parathyroid and pancreas ♦ Derivatives of amino acids — drugs of hormones of thyroid gland, adrenal medulla ♦ Steroidal compounds — drugs of hormones of adrenal cortex and gonadal hormones, prostaglandins

MECHANISMS OF HORMONES ACTION

Polypeptide and Steroid amino acid hydro- testo- cortisone sterone

Gs (+) adenylate cyclase Gi (-)

АТP recep- cAMP tors

Protein kinase

• membrane permeability • lipolysis • glucogenolysis DNA • secretion • ↓ or ↑ iRNA and protein • movement of iones • effects (catabolism or • synthesis of substances anabolism)

4 DRUGS OF HYPOTHALAMIC AND PITUITARY HORMONES

Statins: hypothalamus Liberins: prolactostatin corticoliberin somatostatin thyroliberin melanostatin prolactoliberin somatoliberin neuro- adeno- melanoliberin vasopressin pituitary pituitary gonadorelin oxytocin melanocyte- stimulating

adreno- somato- thyro- pro- gonadotropic: tropic tropic tropic lactin follicle-stimulating (FSH), luteinizing (LH)

cortico- somato- Т3, Т4 mammary sexual steroids medins glands glands

DRUGS OF HYPOTHALAMIC HORMONES

Hormones Drugs Stimulators of secretion Somatotropin-releasing hormone Sermorelin, somatoliberin Corticotropin-releasing- CRH hormone (CRH) Thyrotropin-releasing- Protirelin (rifatiroin) hormone Gonadotropin-releasing- Gonadorelin, leuprolid, hormone nafarelin, etc. Inhibitors of secretion Somatotropin-inhibiting- Somatostatin, octreotide, hormone lantreotide Different Danasole, bromcriptin

5 DRUGS OF HYPOTHALAMIC HORMONES

Drugs Indications Stimulators of secretion Sermorelin, Diagnosis of somatotropic hormone somatoliberin deficit Corticotropin- Diagnosis of Cushing’s syndrome; releasing hormone stimulating therapy after prolong glucocorticoids usage Protirelin Diagnosis of hyper-, hypothyroidism; (rifathyroin) Treatment of thyroid gland carcinoma Gonadorelin, 1. Diagnosis of hypogonadism leuprolid, 2. Therapy: nafarelin, etc. • stimulating: hypogonadism, cryptorchism, delay of pubescence • inhibiting: prostatic cancer, uterine fibrosis, endometriosis, polycystic ovary, premature pubescence

DRUGS OF HYPOTHALAMIC HORMONES

Drugs Indications Inhibitors of secretion Somatostatin, • Inhibiting therapy: acromegaly, tumours of the octreotide, gastroenteropancreatic endocrine system, lantreotide tumours with the hyperproduction of vasoactive intestinal peptide, glucagonom, gastrinom, tumours with hyperproduction of somatoliberin, resistant diarrhea in AIDS patients Bromcriptin • Inhibiting therapy: prolactinoms, conditions related to hyperprolactinemia (amenorhea, galactorrhea, infertility, hypogonadism, etc.); for depression of lactation in period after abortion, births • As dopaminomimetic: for treatment of parkinsonism, with cocaine abstinence

6 DRUGS OF PITUITARY HORMONES

Hormones Drugs Anterior lobe Somatotropic Somatotropin, somatrem ACTH Corticotropin and its synthetic analog — tetracosatrin (cinacten-depot, cosyntropin) Thyreotropic Thyreotropin Gonadotropic FSH (urofollitropin, follitropin-alpha and beta), FSH+LH (menopausal human gonadotropin or menotropin), similar to LH from placenta (human chorionic gonadotropin) Prolactin Lactin Medium lobe Melanotropic Intermedin Posterior lobe Oxytocin Oxytocin Vasopressin Desmopressin, terlipressin

DRUGS OF PITUITARY HORMONES

Drugs Pharmacodynamics/Indications Somatotropin, Metabolic effect (primarily insulin-like action, then somatrem insulin-antagonistic); anabolic: growth of bones and muscles, ↑ glycogen in them, etc. Replacement therapy: deficit of growth hormone in children (pituitary dwarfism) Pharmacodynamic: (?) osteoporosis, delayed wound healing, burns Corticotropin, its Formation and secretion of corticosteroids with synthetic analog adrenal cortex — tetracosatrin Stimulating therapy: hypofunction of adrenal cortex (tetracosactide, with prolong usage of glucocorticoids cinacten-depot, cosyntropin) Diagnosis: adrenal insufficiency; congenital adrenal hyperplasia, etc.

7 DRUGS OF PITUITARY HORMONES

Drugs Pharmacodynamics/Indications Thyrotropin Formation and secretion of hormones of thyroid, ↑ its sizes and vascularization; in the fatty tissue lipid release Stimulating therapy: afterwards or during application of radioactive iodide at thyroid carcinoma (for ↑ iodide capture by the organ) Diagnosis: forms of hypothyroidism From urine of FSH: in women development of follicles, menopausal women: secretion of estrogens and ovulation (with urofollitropin (mainly LH); in men — spermatogenesis FSH), gonadotropin LH: in women — ovulation, corpus luteum human menopausal stimulation, ↑ progesteron; in men — (FSH+LH) ↑ secretion of androgens From the placenta: Replacement therapy: hypothalamopituitary gonadotropin human hypogonadism with infertility; stimulating: chorionic, similar infertility with insufficiency of sexual glands, to LH polycystic ovaries, etc.; with fertilization in vitro; cryptochism (hCG) Diagnosis: cryptochism (hCG)

DRUGS OF PITUITARY HORMONES

Drugs Pharmacodynamics/Indications Lactin ↑ lactation; proliferation of corpus luteum; mitogenic activity of lymphocytes Stimulating therapy: lactation in the postpartum period Intermedin ↑ visual acuity, adaptation to darkness Pharmacodynamic therapy: degenerative changes of retina, hemeralopy, pigmental retinitis, etc. Oxytocin, Causes uterine contractions; mammary gland desamino- alveoli cells ⇒ promotes milk rejection; oxytocin weak antidiuretic and pressor activity (sandopart) Pharmacodynamic therapy: labour activity, uterine bleeding in the postpartum or postabortion periods Diagnosis: placental circulation

8 DRUGS OF PITUITARY HORMONES

Drugs Pharmacodynamics/Indications Vasopressin, ↓ diuresis; vasoconstriction; ↑ contractions of the desmopressin, myometrium and intestine; ↑ thrombocyte felipressin, aggregation, VIII factor of blood clotting pituitrin, Replacement therapy: pituitary insipidus diabetes adiurecrin Pharmacodynamic therapy: enuresis (night urine incontinence), coagulopathy at haemophilia A and von Willebrand’s disease Diagnosis: estimation of concentration ability of kidneys Problems of pharmacotherapy with hypothalamo-pituitarary hormonal drugs • Species of some hormones ⇒ there are necessary human hormonal drugs • Tissues origin drugs — danger of infections transmission • Synthetic — are expansive and have complicated synthesis, antibodies formation to them (allergy) • Precise diagnosis of disease before administration and strictly under the doctor control!

THYROID. NEUROHUMORAL REGULATION

Acute psychosis Circadian rhythms stress Cold hypothalamus ТRH somatostatin

adeno- pituitary Corticoids ТТH and dopamine

↓ dose - Т3, Т4 I ↑ Thyroid dose

9 DYSFUNCTION OF THYROID

• Euthyreoism (without thyroid dysfunction): euthyroide goiter (endemic, sporadic, medicinal, conditioned by the goitrogenic substances contained in food); thyroid neoplasia (adenoma, teratoma, papillar, follicle carcinomas, sarcoma, etc.), thyroiditis (acute, subacute, chronic — autoimmune Hashimoto’s thyroiditis, etc.) • Hyperthyroidism (thyreotoxicosis):  as a result of ↑ thyroid hormones secretion: diffuse toxic goiter (Graves’, Basedow’s disease), nodular (multinodular) toxic goiter, etc.  due to thyroid hormones secretion outside the thyroid: struma ovarii, metastases of the thyroid cancer  not associated with the thyroid hormones hypersecretion: overdosage of the thyroid hormone drugs, etc. • Hypothyroidism (mixedema):  primary: because of ↓ functioning tissue (congenital, postoperative, viral, postradiation, outcome of autoimmune thyroiditis, against a background of neoplasms); because of ↓ thyroid hormones synthesis (endemic, sporadic, medicinal, food)  central genesis: pituitary (secondary), hypothalamic (tertiary), because of disturbance of transport, metabolism and action of thyroid hormones (peripheral)

DYSFUNCTION OF THYROID

Hyperthyroidism Hypothyroidism (more frequent thyreotoxic diffuse children — cretinism: goiter (Graves’, Basedow’s disease) ↓ psychical, somatic, sexual development — ↑ basic metabolism and adult — myxedema: ↓ basic metabolism, hyperactivity of organs organ and system functions hypoactivity: and systems: • obesity, ↓ temperature of the body, dry, • cachexia, ↑ temperatures of the edematic skin, eyelids lowering; body, hyperhydrosis, exophthalm; • CNS: lethargy, neurology • CNS: ↑ excitability, hyperkinesia • CVS: ↓ ABP, HR • CVS: ↑ ABP, HR, arrhythmia • GIT: constipation • GIT: ↑ appetite, diarrhea • breathing: hypoventilation • breathing: shortness • hemopoiesis: ↓ of breath • kidneys: ↓ filtrations ↑ • hemopoesis: • reproduction: infertility, • kidneys: polyuria impotence • reproduction: ↓ fertility

10 DRUGS OF THYROID HORMONES

Levothyroxin, triiodothyronine hydrochloride (liothyronine) and combined (thyrocomb)

Amino acid Glucose Plasmatic membrane

< 5 mg 5 mg 75 mg CBP 35 mg 25 mg Mitochondrium Endo- rТ Т Т plasmic 3 4 3 reticulum

АТP iRNA АDP 15 mg Nuclear other membrane metabolites Chromatin

DRUGS OF THYROID HORMONES

Levothyroxin, triiodothyronine hydrochloride (liothyronin), combined (thyrocomb), thyroidin Indications ♦ Replacement therapy: hypothyroidism — prolong treatment (levothyroxin), coma (triiodothyronine hydrochloride) ♦ Inhibiting therapy (malignant tumours of the thyroid)

Adverse effects • Overdosage (signs of hyperthyroidism) • Action ↑ by salicylates (↓ their binding with proteins)

11 ANTITHYROID DRUGS

Iodides of Radioactive Thioamides: food iodide mercasolil, (≈150 mcg) propylthiouracil

Iodides of Iodination of plasma thyroglobulin Tissues

Peroxidase MIT Т3, Т4 I- I- I0 DIT

T3 Proteolysis of T thyroglobulin I- Тhyrosine 4

МIТ, DIТ Potassium perchlorate Iodides

ANTITHYROID DRUGS

Thioamides: mercazolil (methimazole), propylthiouracil Indications ♦ Diffuse, mixed toxic goiter ♦ Thyreotoxic crisis ♦ Postoperative relapses Adverse effects • ↓ hematosis (leukopenia, agranulocytosis, anaemia) ⇒ blood analysis once a week! • The “goitrogenic” effect and ↑ vascularization (↑ TTH by feed-back type) ⇒ impedes the surgical treatment • Allergic (in 3–6 weeks): itching, urticaria, lymphadenopathy, arthralgias • Seldom: headaches, neurites, polyneurites; dispeptic phenomena; cholestatic jaundice; fever, lupus erythematosus

12 ANTITHYROID DRUGS

Iodides: potassium and sodium iodides, Lugol solution (5% iodide solution in 10% potassium iodide solution) Indications ♦ Thyreotoxic crisis (↓ symptoms during 2–7 days) ♦ Preparation of patients to the operation on thyroid gland after or against a background thioamides (↓ size and vascularization of the thyroid) ♦ Prophylaxis of endemic goiter ♦ Prophylaxis of relapse after the surgical removing or conservative treatment Adverse effects • ↑ iodide depositing in the gland ⇒ it is possibly slowing down of effects of thioamides and radioactive iodide; is not used as mono- therapy; with “withdrawal” syndrome is possible (↑ thyrotoxicosis) • Iodism (acne rash, rhinorrhea, cough, conjunctivitis, irritation of gastric mucous, fever, etc.)

OTHER DRUGS OF THYROID HORMONES Calcitonin (polypeptide which consists of 32 amino acids, secreted also by the parathyroid glands and thymus); its drugs — calcitonin, calcitrin (of the pig’s thyroid), myacalcic (salmon’s calcitonin) Pharmacodynamics ♦ ↓ bone resorption by osteoclasts, ↓ capture Ca2+ by bone tissue ⇒ ↑ formation of bone tissue (with prolong reception ↓ osteogenesis!) ♦ ↓ Ca2+ and phosphates absorption in the small intestine ♦ ↓ Ca2+ and phosphates tubular reabsorption in kidneys, and also Na+, K+, Mg2+ ⇒ ↑ their excretion ⇒ ↓ level of Ca2+ and phosphates in the blood Indications • Hypercalcemia • Osteoporosis (at prolong immobilisation, long application of glucocorticoids, at senile age) • Nephrocalcinosis 13 DRUGS OF HORMONE OF PARATHYROID GLAND

Parathormone (parathyroidin) Pharmacodynamics ♦ ↑ bone resorption by osteoclasts, ↓ osteoblasts, ↓ Ca2+ capture by bone tissue ⇒ ↓ formation of bone tissue ♦ ↑ Ca2+ and phosphates absorption in the small intestine ♦ ↑ tubular reabsorption of Ca2+ in the kidneys ⇒ ↓ its excretion, but ↑ excretion of phosphates! ⇒ ↑ Ca2+ level, ↓ phosphate level in the blood Participation in the phosphoric-calcium exchange and interaction with vitamin D — ↑ Ca2+ and phosphates level in the blood (refer to Topic 20) Indications • Replacement therapy: hypoparathyroidism (regular control of Ca2+ in the blood!!!)

HORMONES OF PANCREAS

Types of cells % оf Products mass of secretion А-cells (α) 20 Glucagon В-cells (β) 75 Insulin, S-peptide, proinsulin, islet amyloid polypeptide D-cells (∆) 3–5 Somatostatin F-cells (PP) < 2 Pancreatic polypeptide

14 DIABETES MELLITUS

A group of metabolic diseases, characterized by hyperglycemia, which is a result of insulin secretion defects, failure of insulin action or both these factors. Chronic hyperglycemia at diabetes combines with the damage, dysfunction and development of insufficiency of different organs, especially the eyes, the kidneys, the nerves, the heart and blood vessels (WHO, 2004) There are more than 300 million of patients suffering from different forms of diabetes in the world In industrial countries prevalence of diabetes mellitus — 5–6% and there is a tendency to further growth, especially at the age groups over 40.

DIABETES MELLITUS

♦ Type I — insuline-dependent (IDDM):  severe form, leading to ketoacedosis if untreated  more frequent arises at young age (juvenile)  genetically determined autoimmune response against the β-cells antigens of pancreas: insulin is almost absent in the blood, hyperglycemia, glucosuria, hyperglucagonemia, the gland’s β-cells do not respond to all the insulinogenic stimuli  introductions of insulin preparations as life-saving indications! ♦Type II — non-insulin-dependent (NIDDM):  more mild forms of diabetes  more frequently arises over the age of 40, with obesity  resistance of tissues to insulin, ↓ an ability of pancreas β-cells to response to glucose, aggravate hyperglycemia; thus, concentration of insulin in the blood is sufficient (or ↓ a little)  needs a diet, ↓ body weight, administration of oral sugar- lowering drugs with ineffective insulin preparations therapy ♦ Other types: with genetic defects of β-cells, endocrinopathy, infections, pancreatic diseases, etc. ♦ Gestational diabetes (diabetes of pregnant women)

15 INSULIN. HISTORY OF DISCOVERY

1921 F. BANTING and J. MACLEOD together with BEST and COLLIP (Toronto) selected insulin from the calf pancreas (Nobel Prize, 1923) 1922 E. P. JOHSLIN successfully applied in clinic the first drugs of insulin; he is F. Banting considered a pioneer of clinical diabetology: “Insulin is a medicine for clever people, but not for fools, wherther they are doctors or patients” 1955 F. SENGER discovered a structure of insulin of different kinds of animals (Nobel Prize Winner, 1958) F. Senger

INSULIN

Human insulin is protein with small molecular mass of 5808, consisting of 51 amino acids, forming 2 polypeptide chain A and B, bound by 2 disulfide bridges; a predecessor — proinsulin

А-chain S S Gly Ile Val Glu Gln Cys Cys Thr Ser Tle Sys Ser Leu Tyr Gln Leu Glu Abn Tyr Cyb Abn

123456S 8 9 10 11 12 13 14 15 16 17 18 19 S 21 S B-chain S Phe Val Abn Gln Hib Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu 1 2 3 4 5 6 7 8 9 101112131415161718192021Arq 22 23 Gly Insulin В30 А8 А10 24Phe Human Thr Thr IIe 25Phe Pork Ala IIe 29 28 2726 30 Tyr Beef Thr Lys Pro Thr The drugs of insulin are distinguished according to the next criteria: • origin • method of purification and degree of purity • speed of onset and duration of action 16 DRUGS OF INSULIN

According to the origin: ♦ Animal origin (by the biosynthetic way made of animal pancreases) — badly purified; middle- (monopeak — MP) and highly- purified (monocomponent — MC): • pork (actrapid, monotard MS, semilente, etc.); differs from the human by 1 amino acid • beef (insulin lente GPP ribbon, the MC ultralente, etc.); differs from the human by 3 aminoacids — has greater antigenicity than beef ♦ Human: • by the half-synthetic method (enzymatic-chemical replacement in the pork insulin of B-30-aminoacid of alanin on treonin): chumodar R, B, etc. • by the genetic-engineering technology: recombinant (DNA gene of human proinsulin is placed in E. coli or yeast cell and hydrolyze proinsulin till the molecule of insulin): actrapid NM, humulin regular, etc. insulin analogs (replacement of natural sequence of amino ↑ acids changes pharmacokinetics — absorption, T1/2, etc.): humalog (insulin of lizpro), epaidra (insulin glulysin), lantus (insulin glargin), etc.

DRUGS OF INSULIN

• Production and usage of animal insulins in the developed countries of the world are practically stopped today • Xenotransplantations (transplantations of organs from animals to the man) and preparation of drugs from animal organs (diseases transmission, including viral, through substances from animal organs to a man) are forbidden by the public resolving organizations and committees on bioethics • Drugs of choice for patients suffering from diabetes mellitus, being on insulinotherapy, are the recombinant human insulin or its analogs • All children and teenagers suffering from IDDM, must get only human insulin from the moment of diagnosis and to the end of life

17 DRUGS OF INSULIN

According to the method of purification ♦ Badly purified — crystallized, non-chromatographic; contain admixtures of molecules of proinsulin, glucagon, С-peptide, somatostatin and other proteins; content of proinsulin > 10000 particles on a million of insulin particles; production is stopped ♦ Middle-purified — monopeak (MP): crystallized and purified by the gel chromatography method; there is one peak on the chromatogram; content of proinsulin is from 50 about 3000: actrapid, etc. ♦ Highly purified — monocomponent (MC): crystallized and purified by the method of ionic exchange chromatography; content of proinsulin < 10 particles on million of insulin particles: actrapid MC, semilente MC, monotard MC, etc.

DRUGS OF INSULIN

Substances added to insulin • For lengthening of action (depends on crystallization of insulin):  protamine (protein with alkaline properties from salmon fishes’ molt roe); in 1936 H. K. of Hagedorn created a drug containing insulin and protamin in isophane, that is equal amount ⇒ NPH-insulin (neutral protamine Hagedorn); syn. isophane-, protamine-insulin; neutral pH due to the phosphate buffer; for conjugation of the insulin crystals with protamine + some zinc, phenol and/or crezole  zinc with neutral pH lengthens insulin action ⇒ insulin-zinc- suspension amorphous: lente, monotard, etc. (up to 18 hrs) and insulin-zinc-suspension crystalline: ultralente (up to 22 hrs); buffer properties due to the acetate buffer • With the purpose of crystallization (sodium chloride) and providing buffer properties (phosphate, acetate, glycerin); at neutral pH there are less adverse effects; phosphate containing insulin is never mixed up with insulin-zinc-suspension (sediment!) • For disinfection and conservation

18 DRUGS OF INSULIN According to duration of action: Peak, Dura- Drugs Onset hrs tion, hrs Ultra-short action Analogs of insulin: humalog (the 5–10 min 0.5–2 3–4 Lilli company), epaidra (Aventis) Short action Actrapid NM (Novo-Nordisk), 15–30 min 2 5–8 insuman rapid (Aventis), humulin R (Lilli), etc. Intermediate action Insulin zinc-suspension amorphous 2–4 hrs 6–8 12–14 and protamine-insulin: insuman basal (Aventis), humulin N, ilentin II (Lilli), monotard NM, protaphane NM (Novo-Nordisk), etc. Prolong action Insulin zinc-suspension crystalline: 4–5 hrs 8–12 24–36 MC ultralente, ultratard NM (Novo- Nordisk), humulin ultralente (Lilli); analogs of insulin: lantus, etc.

DRUGS OF INSULIN

Combinations for achievement of stable average-therapeutic concentration • Mixtures of insulins in one syringe of short and intermediate action (only NPH-insulin) as ratio from 10:90 about 50:50% • Prepared combined drugs — 30% of simple and 70% NPH-insulin (novolin 70/30, actraphane-NM (Novo-Nordisc), type III (Lilli)) or 25% simple and 75% NPH-insulin (depo-N-insulin of the Hechst firm), etc. Concentrations • 40 U (U-40) and 100 U (U-100) insulin on 1 ml • The change of patients to U-100 insulins is began in the most countries • Carefulness while filling syringes with insulin with calibrating U-40 or U-100: calibrating syringes by U of insulin is calibrating by the solution volume (in U-40-insulin syringes: 4 U insulin correspond to 0.1 ml solution)

19 DRUGS OF INSULIN

Drug forms and delivery systems ♦ Powders for injections: s.c. — with daily administration, i.v. and intraperitonially — at coma ♦ Solutions for injections:  portable injector as a fountain-pen (for multiple s.c. injections at intensive insulinotherapy)  systems with the “closed circle” (infusion systems supervising the glucose level in blood; only at diabetic coma)  systems with the “open cycle” (insulin pumps — a reservoir and pump, programmed for introduction of regular insulin with calculated speed without measuring the glucose level; s.c., i.v., intraperitonially) ♦ Aerosols for the intranasal introduction ♦ The work on oral forms creation is conducted

PHARMACODYNAMICS OF INSULIN

• Stimuli (glucose, mannoza, amino acids (arginin, leicin), vagus activity) ⇒ ↑ intracellular level the ATP ⇒ closing of ATP-dependent K+-channels ⇒ depolarization of β-cells and opening of Ca- channels ⇒ ↑ intracellular level of Ca2+, starting secretion from proinsulin to insulin • Insulin → blood (in 2 fractions: unbound with proteins affects all the tissues and bound with plasma proteins — mainly on the fatty tissue) ⇒ insulin + specific receptors (consist of α- and β-subunits) on the surface of cells; by means the endocytosis the complex gets to the cell, where insulin liberates + β-subunits activate, having tyrosinkinase activity • The basic effect of hormone — facilitation of glucose transport through membranes in target tissues (the liver, muscular, fatty, lymphoid tissue) ⇒ ↑ its content 2.5 times and more; ↑ its uptake and conversion to glycogen; also ↑ these processes in the insulin- independent organs (brain, kidneys) ⇒

20 PHARMACODYNAMICS OF INSULIN

Vagus stimulation • ↓ catabolic signs of insulin deficit: Liver ↓ glycogenolysis; Insulin ↓ conversion of fatty acids and amino acids into ketoacids; ↓ ↑ triglyceride transformation depositing of amino acids into glucose Substrate • anabolic action: β depositing glucose -cytotropic Fat as glycogen; hormones ↑ triglycerides and VLDLP synthesis Muscles ↑ synthesis of protein Intestine ↑ synthesis of glycogen

PHARMACODYNAMICS OF INSULIN

♦↑ cabohydrate metabolism: • ↑ transport of glucose to cells and its phosphorylation by hexokinase and especially (at ↑ hyperglycemia) glucokinase • ⇒ ↑ usage of glucose in metabolism (in energetic exchange (tricarbonic acids cycle), in triglycerides synthesis (delivery of glycerophosphate), in re-amination (delivery of nonessential amino acids for the synthesis of protein) • as a result of ↑ glycogensynthetase — ↑ conversion of glucose into glycogen with renewal of its fund in organs • ↓ gluconeogenesis; ↓ level of sugar in blood and ↓ glycosuria ♦↑ fatty exchange to the side of lipogenesis (⇒ ↑ body weight in patients suffering from diabetes mellitus): • ↑ triglycerides formation from free fatty acids as a result of glucose income to fatty tissue and glycerophosphate formation • ↓ level of free fatty acids in the blood and ↓ their conversion into the ketone bodies in the liver (acetoacetate, acetone, oxybutirate) — ↓ ketogenesis, ketoacidosis • ↓ formation of VLDLP and cholesterol in the liver 21 PHARMACODYNAMICS OF INSULIN

♦ Protein exchange:  ↑ ribosomal synthesis of proteins  economy of fund of amino acids due to ↓ gluconeogenesis, ↑ synthesis of nonessential amino acids  ↑ RNA induced synthesis due to delivery of ribosophosphate and through cGMP  ↑ synthesis and ↓ disintergration of proteins • As a result of anabolic and anticatabolic action of insulin ↑ processes of regeneration broken at diabetes mellitus, growth of sick children is restored • The insulin (s.c.) can be used for ↑ appetite and as an anabolic with exhaustion, furunculosis, thyrotoxicosis, vomiting, chronic hepatitis; to be a part of polarizing mixture (potassium, glucose and insulin) for maintaining myocardial work at cardiac arrhythmias, overdosage by cardiac glycosides; in the psychiatric clinic has been used before for shock therapy conduction in schizophrenia patients (achievement of hypoglycemic coma)

PHARMACOKINETICS OF INSULIN

Absorption: in GIT destruction ⇒ s.c., inhalation, if necessarily i.v. and intraperitoneal introduction (but only simple insulin!) Binding with proteins: 2–25% (above mentioned function of bound and free fractions) Excretion from the bloodstream by the liver (60%) and kidneys (35–40%), in diabetics with s.c. introduction correlation is vice versa; due to hydroly- sis of disulfide bounds between chains A and B under the action of insulinase and further proteolysis (T1/2 — 3–5 min, at s.c. up to 40 min) On the part of an organism the following influences: • the drug introduction way • the introduction place: the greatest speed of absorption in the subcuta- neous fat of the absomen, less — of the trunk, shoulder, thigh • temperature of the body, massage of an introduction site, muscular work • activity of tissue enzymes destroying insulin: less doses of insulin are required at i.v. • extent of skin allergic reactions on insulin • formation of antibodies to insulin, which ↑ term of intravascular circulation of the drug • quantity of insulin receptors (↓ at acidosis, hypokaliemia, hyperinsulinemia) On the part of insulin preparations: type, pH, dose of preparation

22 ACTIVITY OF INSULIN DRUGS

• It is determined by the biological way; a biological unit of insulin is such amount of preparation which lowers sugar content in the blood down to 1.4 mmol/l (25 mg%) within 4 hrs in a day starving rabbits with the body weight of 2 kg • Unit of action (UA), or international unit (IU) is the activity of 0.04082 mg of crystalline insulin (standard) • A healthy man during a day produces from 23 to 60 IU of insulin, that makes out from 0.6 to 1.0 IU/kg of the body weight • The insulin secretion is subdivided into basal (base) and food (bolus): the base one is calculated within the limits ≈ up to 1.0 IU/hrs, that equals 24 IU per a day; stimulated by the meal — from 1.0 to 1.5 IU insulin on every 10–12 g of carbohydrates — 1 bread unit (BU) • Necessity in insulin ↑ in the morning, and sensitivity to it ↑ in the evening

INDICATIONS TO INSULIN DRUGS • IDDM (s.c.) • Ketoacidosis of different degree of severity • Comae: diabetic (hyperglycemic, ketoacidotic), lactatacidotic, hyperosmolar — i.v., intraperitonially (only simple insulin!) • Diabetes mellitus accompanied with severe somatic pathology (acute myocardial infarction, stroke, pneumonia, trauma, operation) • Resistance to the per oral hypoglycemic drugs at diabetes mellitus type 2, and also at presence of contraindications • Pregnancy in patients suffering from diabetes mellitus • Pancreatectomy • A long-term inflammatory process in any organ • Exhaustion and rapid loss of weight • Severe forms of liver defeat (hepatitis, cirrhosis), skin • Stroke and myocardial infarction (relative) • Surgical interventions (relative) 23 PRINCIPLES OF INSULINOTHERAPY

so-called intensified insulinotherapy ♦ Basal-bolus therapy, i.e. continuous replacement of insulin absence: introduction of small dose of insulin of prolonged action 1–2 times per a day (imitation of basal secretion of hormone) and injections of short action insulin (simple) 20 min before the breakfast, dinner and supper; 2/3 doses — at a day-time, 1/3 — at night ♦ Obligatory observance of dietary recommendations: planned BU quantity with each meal ♦ Self-control (monitoring of blood glucose within a day) ♦ Dosage of physical loading, to time it to the insulin action decline phase ♦ Change of insulin doses with change of necessity in it

The dose is given under blood and urine glucose level control

PRINCIPLES OF INSULINOTHERAPY

Methods of calculation 1. One of the most primitive methods of calculation: 1 IU of insulin is introduced on 1 g of glucose in urine 2. From calculation 1 IU on the 4–5 g sugar in urine; for example, at daily glucosuria 100 g, about 20 IU insulin are injected; DD is distributed into 3, 4 introductions; with a 4-fold introduction DD is distributed as follows: before breakfast — 35%, before dinner — 25%, before supper — 30% and before sleep (at 23.00) — 10% of a daily dose 3. At glycemia over 8.33 mmol/l, it is recommended 1 IU simple insulin introduction each 6–8 hrs on each subsequent 0.22 mmol/l Hypoglycemia — less than 3.3 mmol/l Healthy people — at an empty stomach 3.3–5.5 mmol/l, after the meal up to 7.8 mmol/l Hyperglycemia — at an empty stomach more than 5.5 mmol/l, after the meal more than 7.8 mmol/l

24 PRINCIPLES OF INSULINOTHERAPY

Methods of calculation 4. The daily dose depends on the patient’s body weight and the term of the disease: the patients with “fresh” DM type 1 are administered insulin in the dose of 0.5 IU/kg per a day; during remission — 0.4 IU/kg, the patients with unsatisfactory compensation — up to 0.7–0.8 IU/kg per a day 5. Insulins with the different duration of action are used in the modern insulinotherapy; calculation for basal-bolus insulinotherapy is the following:  for creation of insulin base level the insulins of prolonged action are used (approximately 1 IU/hr ⇒ ≈ 24–26 IU/day)  for regulating glycemia level before the meal they use a short action insulin in the dose of 1–1.5 IU on 1 BU (BU = 10–12 g of carbohydrates)  the basis of basal-bolus therapy conduction with insulin is in the obtained data in healthy people that 1 IU insulin ↓ level of glucose in blood by 2.22 mmol/l and 12 g of carbohydrates (1 BU) ↑ it on 2.77 mmol/l

Short insulin

40/60

30/70

20/80 Время, ч 10/90

Prolonged insulin concentration in plasma

0 3 12 24 Time, hrs

25 COMPLICATIONS OF INSULINOTHERAPY

• Immunopathologic disturbances (antibodies secretion: IgA, IgD, IgT, IgG, IgM):  insulin allergy (beef, pork insulins)  immune resistance to insulin (necessity in large doses) • Lipodystrophia at the site of injection • Hypoglycemia (20–40 ml of 40% solution of glucose, s.c. 0.5 ml 0.1% solution of adrenalin)

COMPLICATIONS OF INSULINOTHERAPY

• Hyperglycemic (diabetic) coma:  correction of dehydratation by liquids usage (i.v. droply 1–2 l of solutions salt, Ringer’s)  ↓ insulin content down to the norm (i.v. drop by drop or stream 50–100 IU simple insulin in 6–20% solution of glucose, after lowering a dose about 12 IU each 4 hrs s.c., oriented on the level of glucose in blood)  correction of acidosis at pH < 7.2 (sodium hydrocarbonate)  maintenance of potassium balance  treatment of concomitant diseases (infections) complicating diabetes

26 SYNTHETIC ANTIDIABETIC DRUGS Classification ♦ Derivatives of sulfanylurea: • I generation — butamide, bucarban • II generation — chlorpropamide, glibenclamide (maninil, glicazide) • III generation — glymepiride (amaril) ♦ Biguanides: buformin (glybutide), metformin, etc. ♦ Different chemical groups: pioglitazone, glucobai, glyfasen, etc. Indications • NIDDM (> 40 years and disease term no > than 5 years) — derivatives of sulfanylurea • NIDDM against a background of obesity — biguanides • Resistance to insulin

ANTIDIABETIC DRUGS

block, depolarize Derivatives of sulfanylurea

К+-canal ⇒ К+ closes, depolarization Trans- АТP depolarizes opens porter of Са2+-canal glucose Са2+ ⇒ ↑ metabolism  insulin libe- Glucose rating from β-cells +  ↓ glucagone in the serum +  extra-pancreatic effect (↑ action of insulin on target tissues) Insulin

27 ADVERSE EFFECTS OF ANTIDIABETIC DRUGS

Derivatives of sulfanylurea ♦ Allergic reactions (leukopenia, thrombocytopenia, jaundice, dermatites, etc.) ♦ Cardiovascular complications (↑ risk of IHD development, etc.) ♦ Gastrointestinal signs (↓ dose is necessary) Biguanides ♦ Lactacidemia up to the lactacidemic coma (especially at patients with chronic hypoxia) ♦ Metallic taste in the mouth, pain in epigastria, vomiting, diarrhea, anorexia (↓ dose or abolition) ♦ And other phenomena

28 Topic 19 HORMONAL DRUGS OF STEROID STRUCTURE, THEIR ANALOGS AND ANTAGONISTS

ADRENOCORTICOTROPIC HORMONES

Hypothalamus Corticotropin-releasing factor (corticoliberin) Stress

Adeno- pituitary

АCTH

Mineralocorticoids (external area of the Gluco- cortex) corticoids (middle area of Sex hormones the cortex) (internal area of the cortex)

29 DRUGS OF MINERALOCORTICOIDS (aldosterone, desoxycorticosterone)

Desoxycorticosterone acetate (DOCA) and trimethylacetate, fludrocortisone acetate Pharmacodynamics ♦ Metabolism of electrolytes, water, ABB (through target organs: kidneys, intestine, salivary and sweat glands) — hypercalcemia, hypokaliemia, metabolic alkalosis ↑ volume of plasma, (↑ + – - + + hypertension reabsorption of Na , Cl , HCO3, the K and H secretion) ♦ Anabolic action Indications • Adrenal failure (including Addison’s disease) • Adynamia, myasthenia

PREPARATIONS OF GLUCOCORTICOIDS

Cortisole (hydrocortisone), ♦ Natural: cortisone cortisone acetate, hydrocortisone acetate and hemisuccinate ♦ Synthetic: Receptors prednisolone, prednisone, triamcinolone, dexamethasone, betamethasone, etc. Complex hormone- receptor

• ↓ or ↑ mRNA, depression or regression of genes • ↓ or ↑ enzymes, different biological effects

30 PHARMACODYNAMICS OF GLUCOCORTICOIDS

• Carbohydrate metabolism — ↑ gluconeogenesis in the liver, antagonism to insulin • Protein metabolism — “-” nitrous balance, catabolism in the lymph nodes, thymus, spleen, skin, fatty and connective tissue, muscles (their involution, hemorrhage, worsening of healing), in the bone tissue (osteoporosis), anabolism in the liver (↑ sizes) • Lipid metabolism — ↑ FFA, redistribution of fatty tissue (in extremities — lipolysis, the breast, neck, face, humeral belt — lipogenesis) • Water-electrolyte metabolism — ↑ reabsorption of Na+, H+, + ↓ 2+ H2O; K secretion; Ca (demineralization, osteoporosis)

PHARMACODYNAMICS OF GLUCOCORTICOIDS

• CVS — “+” inotropic effect, maintinence of cell membrane stability, ↑ systole and minute volume, ↑ sensitivity of vessels to catecholamines, ↑ angiotensin effect • Blood — lymphocytopenia, monocytopenia, eosinopenia, ↑ red blood cells, thrombocytes, neutrophil granulocytes • CNS — ↑ mood, euphoria, hyposomnia • GIT — ↑ pepsin and hydrochloric acid • Endocrine system — ↓ hypothalamo-pituitary-adrenal system, TTH, FSH, sex hormones • Development of an organism — ↑ surfactant • At stress — enzymatic alteration in addition to the sympathoadrenal system

31 PHARMACODYNAMICS OF GLUCOCORTICOIDS • Anti-inflammatory (all phases): ↓ ⇒ ↓  phospholipase A2 (through lipocortin) prostaglandin (+ through COX-2) and leukotriens  ↑ neutrophils, ↓ lympho-, monocytes, eosinophils  ↓ activity of kinins and bacterial toxins, releaseof histamine, synthesis of hyaluronidase, cappilary permeability ⇒ stabilization of cellular membranes, ↓ edema  ↓ function of neutrophils and macrophages (interleukin 1, 6, 8, tumour necrosis factor, etc.) ⇒ ↓ cellular reactions of inflammation  ↓ proliferation of fibroblasts, synthesis of collagen ⇒ ↓ reparative phase, formation of scars, wound healing

PHARMACODYNAMICS OF GLUCOCORTICOIDS

• Immunosupressive:  antagonists of immune-stimulating hormones (STH, thymus factors, androgens)  ↓ proliferation of lymphoid tissues; in the large doses — involution of immune-competent organs  ↓ cellular immunity — ↓ migration in the blood of T- and B-lymphocytes stem cells from the bone marrow, thymus; ↓ activity of T- and to less degree B-lymphocytes ⇒ ↓ antibodies formation • Antiallergic: ↓ release of histamin, desensitization of H1-receptors to allergy mediators • Antishock and antitoxic: ↑ metabolic activity of the liver, ↓ BBB permeability for toxins, etc.

32 PHARMACOKINETICS OF GLUCOCORTICOIDS

Absorption:  with per oral intake — quickly and almost completely in the small intestine; Cmax in the blood in 0.5–1.5 hrs  injection: i.m. and i.v. — water soluble (hemisuccinates and phosphates); Cmax i.m. in 1–2 hrs; i.m. — suspension (acetates), absorption is slow (hrs), duration (weeks) Binding with proteins: by proteins and transcortin; natural — 90%; synthetic — 40–60% Biotransformation: by microsomal enzymes of the liver with formation of glucuronides or sulfates. T1/2 natural ones is less than synthetic. Cortisone and prednisone experience pre-systemic metabolism with formation of active metabolites (hydrocortisone, prednisolone). Fluorinated glucocorticoids (triamcinalone, dexamethasone, betamethasone) metabolize slower than others (T1/2 > 2–3 times as much) Excretion: by kidneys

DRUGS OF GLUCOCORTICOIDS

Drugs Glucocorti- Mineralocorti- Equivalent coid activity coid activity doses, mg Short action Hydrocortisone 1 1 20 Cortisone 0.8 1 25 Prednisone 4 0.8 5 Prednisolone 4 0.8 5 Methylpred- 5 0.5 4 nisolone Intermediate action Triamcinolone 5 – 4 Long action Dexamethasone 30 – 0.75 Betamethasone 30 – 0.6

33 INDICATIONS TO GLUCOCORTICOIDS

♦ Replacement therapy at adrenal cortex insufficiency (Addison disease, tumours, transplantation, etc.) — 10–25 mg of hydrocortisone or other drugs in equivalent (2/3 daily dose in the morning (!) and 1/3 — in the evening or ones in the morning) ♦ Inhibiting therapy at the adrenogenital syndrome for ACTH depression (in the therapeutic doses 3 times per a day or 1/3 — in the morning, 2/3 of dose — in the evening) ♦ Pharmacodynamic therapy (as symptomatic or pathogenetic drugs due to anti-inflammatory, anti-allergic, immunosupression and other properties)

PHARMACODYNAMIC THERAPY OF GLUCOCORTICOIDS • Collagenosis (systemic lupus erythematosus, nodular polyarthritis, etc.) • Allergies (Quincke’s edema, hay fever, urticaria, anaphylactic shock, etc.) • Diseases of the kidneys (glomerulonephritis, etc.) • Diseases of the blood (autoimmune hemolytic anaemia, thrombocytopenic purpura, etc.) • Diseases of the lungs (bronchial asthma) • Diseases of the gastrointestinal tract (Crohn’s disease, some forms of cirrhosis of the liver, etc.) • Neurological disturbances (cerebral edemas, multiple sclerosis) • Diseases of the eyes (allergic keratitis, conjunctivites, etc.) • Diseases of the skin (nodular erythema, eczema, etc.) • Malignant tumours (leukoses and lymphoproliferative diseases) • Inflammation of bones and joints (arthritis, bursitis, etc.) • Infectious diseases (tubercular pericarditis, pneumocyst pneumonia, etc.) • Severe shock conditions 34 ADVERSE EFFECTS OF GLUCOCORTICOIDS Depression of the hypothalamo-pituitary-adrenal system (jatrogenic syndrome of Itsenko — Cushing)! • Endocrine system (steroid diabetes, growth impairment in children, delay of pubescence, disturbance of menstrual cycle) • Osteomuscular system (myopathy, osteoporosis, pathological fractures, aseptic necrosis) • Gastrointestinal tract (steroid gastric and intestine ulcers, bleeding, perforations, pancreatitis) • CVS (hypertension) • Skin (hemorrhage, acne, striae, atrophy of skin and subcutaneous fat) • Regeneration (↓ wound healing)

ADVERSE EFFECTS OF GLUCOCORTICOIDS

• CNS (hyposomnia, unsteady mood, psychosis) • Water-electrolyte metabolism (edemas, hypokaliemia, hyperosmolar coma) • Eyes (glaucoma, cataract, exophthalmos) • Immunity (slurring over the clinic of infections, activation of tuberculosis and other infections) • Metabolic (hyperglycemia, hyperlipidemia, rise of appetite, redistribution of fat (a moon-like face, etc.), negative nitrous balance) • Blood (↑ clotting, etc.) • Syndrome of withdrawal

35 RULES OF GLUCOCORTICOIDS ADMINISTRATION

♦ Strictly individual dosage! ♦ A single intake in a large dose is not dangerous ♦ Short therapy (2–3 days) with the usage of not superhigh doses and without special contraindications is not dangerous ♦ Continuation of therapy over a month using the doses exceeding substitutive ones is accompanied with sharp ↑ complications, including lethal ♦ In case of prolong application the drug withdrawal must be gradual (a 9 month long rehabilitation)

METHODS OF CONTROL OF ADVERSE EFFECTS OF GLUCOCORTICOIDS

• Supervision after the dynamics of body weight • Control of diuresis • Control of arterial pressure • Blood and urine analysis for sugar • Control of electrolyte composition of plasma (potassium, sodium, calcium) • Control for the gastrointestinal tract condition • Control for the osteomuscular system condition (aseptic necrosis of bones!) • Ophthalmologic examination • Control of infectious complications development

36 FEMALE SEX HORMONES

Hypothalamus GnRH

FSH LH Growth of follicle Ovulation Growth of corpus luteum

Estrogens (estradiol, Progesterone estrone, estriol)

Development of female sex signs, endometrium, functions of the skin, Preparation to bones, vessels ↑ blood clotting, etc. pregnancy

CLASSIFICATION OF FEMALE SEX HORMONES DRUGS

♦ Estrogens (hormones of follicles): • Steroid structure — estrone, estriol, estradiol benzoate and dipropionate, ethinyl estradiol, conjugated estrogens; • Non-steroid structure — synestrol, diethylstilbestrole propionate, etc. ♦ Gestagens, progestins or progestagens (hormones of corpus luteum) — progesterone, oxyprogesterone, levonorgestrol, norcolut, pregnin, etc. ♦ Combined (estrogen-gestagenic, estrogen-gestagen-antiandrogenic) — oral contraceptives, anticlimacteric (climonorm, pregestrol), etc.

37 ESTROGENIC AND ANTI-ESTROGENIC DRUGS Indications to estrogens ♦ Primary hypogonadism ♦ Uterine bleeding ♦ Amenorrhea, dismenorrhea ♦ Breast cancer (> 60 years old) ♦ Climax, osteoporosis ♦ Cancer of prostate Adverse effects of estrogens • ↑ blood clotting, thromboembolia, edemas • Dysfunction of the liver, nausea, vomiting • Postmenopausal uterine bleeding • Hardened mammary glands, hyperpigmentation • In men feminization, ↓ libido, potentia • Carcinogenicity Anti-estrogens  Breast cancer (tamoxifen)  Infertility (clomifen)  For suppression of ovarian function (danazole)

GESTAGENIC (PROGESTINS) AND ANTIGESTAGENIC DRUGS

Indications to gestagens ♦ As contraceptives ♦ For prolong suppression of ovarian function (endometriosis, dysmenorrhea, pathological bleeding, hirsutism with contraindication of estrogens) Adverse effects of gestagens • ↑ ABP, risk of myocardial infarction possibility • Allergic reactions • Dispeptic disorders • ↓ libido, menstrual disturbances Antigestagens  For intensifying uterine contractions and abortion (mifepristone)

38 CONTRACEPTIVES

♦ Combined estrogen-gestagenic: • Monophasic — rigevidon, non-ovlon, minizistone, Diane-35, etc. • Two-phasic — anteovin, neo-eunomin • Triphasic — trisistone, triquilar, etc. ♦ One-component — microdoses of gestagens (mini-pili): continuin, norgestrel, microlut, etc.; ♦ Postcoital gestagenic: levonorgestrel (postinor); ♦ Depo-contraceptives: injection (depo-provera (medroxypro- gesterone acetate)), implantation (levonorgestrel (norplast)); ♦ Vaginal contraceptives (spermicides): benzalkonium chloride, nonoxynol, etc.

ADVERSE EFFECTS OF CONTRACEPTIVES • Insignificant (demand replacement, ↓ dose):  Nausea, tenderness of mammary glands, bleeding and edemas (estrogens)  Transient headache, migraine  Change of activity of plasma proteins, the thyroid, adrenal glands • Middle severity (requiring withdrawal)  Profuse bleeding (25% of patients, low-dosage drugs)  ↑ body weight, hirsutism, acne (containing androgen-like)  Hyperpigmentation (after a 8-year period in 40%)  Vaginal infection, urethral dilation  Amenorrhea after withdrawal

39 ADVERSE EFFECTS OF CONTRACEPTIVES

♦ Severe • Vascular:  venous thromboembolia (3 times as much) — estrogens  myocardial infarction  cerebrovascular disturbances (stroke)  hypertensions (3–6 times as much) • Disorders of gastrointestinal tract: cholestatic jaundice, cholecystitis • Depression (in 6% patients) • Carcinogenic

MALE SEXUAL HORMONES

Hypothalamus

GnRH

FSH LH

Sertoli’s cells Interstitial cells

Formation of sperm Testosterone

Development of male Growth stimulating sexual characteristics

40 ANDROGENIC AND ANTI-ANDROGENIC DRUGS Indications to androgens ♦ Androgen replacement therapy (hypogonadism, impotence) ♦ Breast tumours ♦ Climacteric syndrome ♦ Functional uterine bleeding Adverse effects of androgens • Disturbance of spermatogenesis, atrophy of testicles • ↑ temperature of the body, edemas, hepatotoxicity • In women — masculinization Anti-androgens ♦ For suppression of androgen secretion (prostatic carcinoma) — analogs of gonadotropin-releasing-hormone (goserelin, leuprolid, etc.) and anti-androgens (finasteride, ciproterone, flutamide)

ANABOLIC DRUGS

♦ Steroidal — retabolil, fenobolin, metandrostenolol, methylandrostendiol, etc. ♦ Nonsteroidal — riboxin, potassium orotate, pentoxil, methyl uracil, etc. Indications • Debilitating diseases with protein synthesis disturbance (cachexy, hypotrophy and dystrophy, after burns, operations, radiation disease, prolong infections, etc.) • Traumas, for improvement of bone defects healing, osteoporoses • IHD, myocardites and other heart diseases • Diseases of the liver, kidneys with phenomena of hypoproteinemia, gastric ulcer • Posthemorrhagic and aplastic anaemias, leukopenias • At long-term cortisone therapy (steroidal)

41 АNABOLIC STEROIDS

The derivates of male sexual hormones with reduced hormonal activity and pronounced stimulating influence on the synthesis of proteins Pharmacodynamics • Protein metabolism (antagonists of glucocorticoids):  ↑ utilization of food amino acids ⇒ ↓ their excretion, excretion of nitrous slags (especially urea), nitrous balance “+”  ↑ synthesis of proteins, including skeletal muscles, ↑ general volume, force and power of contractions; ↑ blood circulation  ↑ protein syntheses in the myocardium, kidneys  ↑ antitoxic and protein-synthesizing function of the liver  ↑ erythropoiesis, hyperplasia of the bone marrow  ↑ synthesis of protein matrix of the bone • Carbohydrate and lipid metabolism: hypoglycemia, ↓ level of lipoproteids, phospholipids • Endocrine system: refer to “Adverse effects”

ADVERSE EFFECTS OF ANABOLIC STEROIDS • Endocrine system and metabolism:  ↑ insulin, hypoglycemia, risk of diabetes mellitus development  alopecia  in men — testicle atrophy, ↓ spermatogenesis, libido, gynecomastia (rehabilitation takes place for 6 months and more, with prolong intake — irreversible changes)  in women — acne, virilisation, uterine atrophy, infertility, etc. (some of them are irreversible) • Liver: cholestatic hepatitis, oncologic processes (about 80% of those abusing the drug) • Urinogenital system: nephrolithiasis, renal tumours • CNS: irritability, ↑ excitability, hyposomnias, depressions • CVS: ↑ ABP, edemas, rhythm disturbances • Musculature, skin: ligament ruptures, degeneration of tendons, arthritis, etc.

42 NONSTEROID ANABOLIC DRUGS

Biochemical predecessors of purine and pyrimidine bases of nucleic acids and products of partial hydrolysis of the latter, facilitating nucleotide synthesis by cells • Purine derivatives — riboxin (inosin) • Pyrimidine derivatives — potassium orotate, methyluracil, pentoxil • Products of nucleic acids hydrolysis — sodium nucleinate Pharmacodynamics  Direct predecessors of purine and pyrimidine bases of DNA and RNA (riboxin, potassium orotate, sodium nucleinate) ⇒ accelerate current syntheses of DNA and RNA, cell division  Inhibit dephosphorylation of uridin monophasphate (methyluracil, pentoxil) ⇒ accelerate DNA synthesis (reduplication), DNA  Expose their action in those tissues where the syntheses occur actively, require prolong intake

43 Topic 20 VITAMIN DRUGS. ENZYMATIC DRUGS AND INHIBITORS OF ENZYMES. DIFFERENT DRUGS AFFECTING METABOLISM

VITAMIN DRUGS

Classification: ♦ Drugs of water soluble vitamins: B1* (thiamine chloride, bromide, cocarboxylase), B2* (riboflavin mononucleotide), PP or B3* (nicotinic acid, its derivatives; nicotinamide), B5 or pantothenic acid* (calcium pantothenate, pantenol), B6* (pyridoxine hydrochloride), Bc or B9* (folic acid), B12* (cianocobalamine), B15 or pangamic acid (calcium pangamate), C (ascorbic acid), R or bioflavonoids (quercetin, routine), vitamin U, lipoic acid, etc. ♦ Drugs of lipidosoluble vitamins: A (retinole acetate, etc.), E (tocoferole acetate), D or calciferols (ergocalciferol, calcitriol, etc.), K or naphthoquinones (vicasol), F or complex of PUFA (linetol)

* — coenzyme forming

44 VITAMIN DRUGS

Advantages ♦ They are used at any season ♦ Possibility of dosage ♦ Parenteral introduction in case of absorption disturbance is possible Types of disturbances of vitamin providing of an organism • Hypovitaminosis (exo- and endogenous) • Hypervitaminosis (quickly arises with inefficient usage of lipid-soluble vitamins!)

BASIC INDICATIONS TO VITAMIN DRUGS • Replacement therapy with vitamin exchange disturbances (in physiological doses): insufficient intake with food malabsorption (resection of the stomach, diseases of the intestine and liver, etc.) change of intestinal microflora (antibacterial drugs) intensive loss (polyuria, perspiration) • Adaptation therapy at ↑ need (doses 2–3 times as much as physiological): adaptation to physical loading, hypoxia, unfavorable environmental conditions pregnancy, lactation, child's age reconvalescence after traumas, operations, severe diseases chronic and diseases of hemopoiesis, liver, atherosclerosis, etc. • Pharmacodynamic (in medical doses, 5–100 times as much as physiological)

45 DRUGS OF VITAMIN B1

Thiamine chloride and bromide, coenzyme — cocarboxylase, vitamers — benfothiamine Pharmacodynamics ♦ Thiamine pyrophosphate — coenzyme of decarboxilases (oxidizing decarboxylation of α-ketoacidys, pyruvate), transketalase (pentosophosophate disintergration of glucose) ♦ Neuroprotective (anticholinesterase ⇒ ↑ neuromuscular transmission) ♦ Cardiotrophic (sinergist cardioton) ♦ Hypoglycemic action (through adenosin and ATP) ♦ Removal of metabolic acidosis, etc.

DRUGS OF VITAMIN B1

Indications • Hypovitaminosis (beri-beri) — polyneuritis, cardiovascular disturbances (daily demand (DD) — 1.5–2 mg); • Pharmacodynamic: neuritis, paresis, etc.; cardiomyopathias, endarteritis, GIT diseases; dermatitis, eczema, etc.; cocarboxylase — diabetic ketoacidosis (as a rule in children), hepatic coma, heart failure, etc. Thiamine is one of the safest water-soluble vitamins: synaptoplegia! (complexes with mediators); change of hepatic enzymes activity; with i.v. introduction — “thiamine” shock!

46 DRUGS OF VITAMIN B2

Riboflavin, riboflavin mononucleotide, etc. Pharmacodynamics ♦ In form of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) provides the second stage of electrone transport in the respiratory chain, desamination of aminoacids, oxidizing phosphorylation, etc. ♦ Neuroprotective, keratoplastic, favors erythropoietin synthesis, normal functioning of the visual organ, etc. Indications ♦ Hypovitaminosis — cheilosis, stomatitis, glossitis, dermatitis, seborrhea, hemeralopia, dysbacteriosis, depression, etc., DD = 2–4 mg ♦ Pharmacodynamic therapy: dermatitis, neuritis, conjunctivitis, hepatitis, etc.

DRUGS OF VITAMIN PP OR B3

Nicotinic acid (NA), xanthinol nicotinate (complamine), nicoshpan, nicoverin, picamilon, etc. Pharmacodynamics • NA and nicotinamide through NAD and NADP — course of glycolysis and gluconeogenesis, oxidization of susbtrates in the respiratory chain • Vasodilatating (“flushing effect”), cardiotrophic, ↑ microcirculation • Hepatoprotective and detoxicating (in ↑ doses with prolong application — lipid dystrophy of the liver) • ↓ lipolysis ⇒ anticholesterinemic • Hypoglycemic, ↑ thyroxine, hormones of adrenal cortex, fibrinolytic, etc. Indications Hypovitaminosis — pellagra: purple “varnished” tongue, “4 D” syndrome (demention, diarrhea, dermatitis, dystrophy), DD = 15–20 mg Pharmacodynamic therapy (arterial hypertension, disturbances of cerebral, peripheral circulation, atherosclerosis, etc.)

47 DRUGS OF VITAMIN B6

Pyridoxine hydrochloride, combined — milgamma, magne B6, etc. Pharmacodynamics • Pyridoxalphosphate and pyridoxaminphosphate (PALP and PAMP) — reactions of trans-, desamination, decarboxylation of amino acid, metabolism of triptophane, GABA, serotonin, lipid metabolism (↓ cholesterol) • Neuroprotective, regulating CNS excitation • Cardiotonic (synergist of cardiotonics) • Hepatoprotective action • Stimulating erythro- and leukopoiesis, etc. Indications Hypovitaminosis (DD = 2–3 mg) at chemotherapy (isonicotinic acid hydrazide derivatives), toxicosis, etc. Pharmacodynamic: neurites, neuralgias, paresis; agranulocytosis, asiderotic anemias; hepato- and cardiologic pathology; in dermatology

ASCORBIC ACID

Pharmacodynamics ↑ oxidation-reduction -2Н

AA ↑ dihydroAA reactions ↑ +2Н Especially specific • Inclusion of sulphur in mucopolysacharides — synthesis of chondroitinsulfate of cartilages, gialuronic acid, stabilization of capillaries • Hydroxylation of prolin and lysin ⇒ formation of collagen of the connective tissue, dentine and ossein of bones • ↑ synthesis of antibodies, interferon, ↑ phagocytosis, ↑ formation of prostaglandins, hormones of adrenal cortex ⇒ ↑ nonspecific immunity defence at infections, ↓ inflammatory processes • ↓ release of histamine, formation of mediators of anaphylaxis, IgE, sensitivity of tissues to histamine, acetylcholine, etc. ⇒ ↓ allergic processes of the immediate type

48 ASCORBIC ACID

Pharmacodynamics • ↑ synthesis of tyrosine, catecholamines ⇒ normal functioning of the nervous tissue • ↑ usage of glucose and pyruvic acid in the cycle of tricarbonic acids ⇒ participation in the carbohydrate metabolism • ↑ synthesis of respiratory enzymes of the liver ⇒ ↑ its synthetic and detoxicating functions ⇒ ↑ metabolism of cholesterol, biotransformation of drugs, ↓ formation of carcinogenic substances, etc. • Reduction of iron and ↑ its absorption in the intestine • Convertion of folic acid to the tetrahydrofolic one ⇒ ↑ hemopoiesis, etc.

ASCORBIC ACID

Indications ♦ Hypovitaminosis — scurvy (DD = 100–120 mg) ♦ Pharmacodynamic therapy: metabolic and respiratory acidosis, infections (scarlet fever, measles, flu, diphtheria, etc. — in increased doses), allergic reactions of immediate type, hypochromic anaemias, arthrites, psychical disturbances (a triad — hypochondria, hysteria, depression), alcoholic, nicotine intoxications (↑ excretion of vitamin C, sharp ↓ its reserve!) Adverse effects • Hypervitaminosis (irritability, sensation of heat, cold sweat, headache, tachycardia, etc.) • In the large doses (1–5 g) — hyperglycemia, ↓ synthesis and release of insulin; formation of urinary stones, microangiopathy ↑ blood clotting; ulcerogenicity; zinc and copper metabolism disturbance; ↑ sensitization of an organism to AG; “rebound” phenomenon with development of hypovitaminosis

49 VITAMIN DRUGS

Vitamin Preparation DD, mg Basic functions

B5 Calcium 5–10 In coenzyme A composition: pantothenate participation in processes of acetylation and oxidization, carbohydrate, lipid metabolism, synthesis of acetylcholin, glucocorticoids, sex hormo- nes, mineralocorticoids, ↑ tissue metabolism, cellular membranes structure, etc.

B15 Calcium 40–60 Donator of methyl groups, pangomate ↑ creatine phosphate in the muscles and glycogen in the liver, ↓ hypoxia

VITAMIN DRUGS

Vitamin Preparation DD, mg Basic functions P (biofla- Rutin, 30–50 Bioflavonoids form a vonoids) quercetin redox-system, ↑ vitamin C (antioxidant, capillary-stabilizing)

Lipoic acid Lipoic 12–25 Coenzyme of catalysis of acid piruvate and ketoglutarate decarboxylation; glycine uptake by the liver, ↑ glucose phosphorylation in it, protein synthesis, detoxica- ting, lipotropic and other actions U Methyl – Providing trophicity of the methionine GIT mucous membranes

50 PHARMACODYNAMIC THERAPY BY WATER-SOLUBLE VITAMINS • Neuritis, neuralgias (thiamine, pyridoxine, etc.) • Hepatitis, intoxications (thiamine, pyridoxine, calcium pantothenate, pangamate, lipoic acid, ascorbic acid, etc.) • Gastritis (thiamine, calcium pantothenate, pyridoxine, etc.) • Anemias (riboflavin, pyridoxine, cyanocobalamin, folic, ascorbic acid, etc.) • Bleedings, hemorrhagic diathesis (ascorbic acid, rutine, etc.) • Agranulocytosis, radiation disease (pyridoxine, folic acid) • IHD, CHF, atherosclerosis, AH (thiamine, pyridoxine, nicotinic acid) • Eye diseases (riboflavin, etc.) • Diseases of the skin (riboflavin, pyridoxine, etc.) • Infectious diseases (ascorbic acid, rutin)

INTERACTION OF VITAMINS

↑ insuf- ↓ insuf- Vitamin ficiency ficiency Incompatibility

В1 В2, В6, РР С, ЕРР, С, В12, В6, salicylicates, hydrocortisone, etc.

В2 РР В12 В12

В6 В1, В12 – В1, В12, euphyllin, caffeine

Вс В1 В12 Sulfonamides

В12 В1, В2, Вс С, В5 РР, С, В1, В6, В2, salicylila- tes, aminasin, etc.

РР В5 В1 В1, В12, В6, euphyllin, salicylates, etc.

СРРА, Вс В1, В12, euphyllin, dimedrol, dibazole, penicillins, etc.

51 DRUGS OF VITAMIN A

Retinol acetate, palmitate, vitadral, etc. Pharmacodynamics • Retinoids (retinol, retinal, retinoic acid) — combining with cytoplasmic receptor in target tissues (muscles, heart, liver), get into the nucleus, affecting genes ⇒ synthesis of mucopolysacharide, phospholipids, glycoproteids As a result of ↑ sulfate inclusions: into the components of the connective tissue (glycans, etc.) ⇒ ↑ tissue trophicity, growth of child (+ ↑ somatomedines synthesis) into heparins ⇒ maintinance of blood rheology into sulfacerebrosides ⇒ modulate nervous impulse transmission (+ ↑ myelin synthesis) provides functioning of the endoplasmic reticulum of the liver, GIT mucosa regeneration ↑ synthesis of sex hormones

DRUGS OF VITAMIN A

Pharmacodynamics ♦ Photoreception: ↑ synthesis of visual purple in rods, restoring their sensitivity to the twilight (retinal + opsin ⇒ rhodopsin) ♦ Immunogenesis: ↑ phagocytosis, immunoglobulins, antibodies and other factors of specific and nonspecific resistance ♦ Epitheliotropic: ↑ enzymes of epithelium cells, their differentiation, ↓ epithelial keratinization Indications • Hypovitaminosis: hemeralopia, keratitis, dermatitis, etc. (DD = 5000 IU) • Pharmacodynamic therapy: diseases of eyes (with vitamins B2, PP), skin, burns, infections, ricket (with vitamin D), etc. Adverse effects Hypervitaminosis: ↑ intracranial pressure (ICP), visual disorder, hepato-, nephrotoxicity, osteolysis, teratogenicity, etc.

52 DRUGS OF VITAMIN E

Tocopherol acetate Pharmacodynamics ♦ α-Tocopherol, forming a redox-system: • renders a direct antioxidant effect, anti-atherosclerotic action • stabilizes mitochondria, improving the tissue respiration • participates in construction of hem, synthesis of protein, steroids, cell proliferation Indications • Hypovitaminosis (DD = 20–30 mg) • Pharmacodynamic therapy: spontaneous abortions, climax; muscle dystrophy, arthritis, angina prectoris, etc.

DRUGS OF VITAMIN D

Provitamins Prohormones plants Ergosterin Ergocalciferol (D2) skin 7-dehydrocholesterol ultraviolet Cholecalciferol (D3) liver Chemical Preparation abbreviations Calcifediol (25- D2 Ergocalciferol, hydroxyvitamin D3) α-calcidol kidneys D3 Cholecalciferol 25(OH)D3 Calcifediol Calcitriol (1,25- 1,25(OH)2D3 Calcitriol hydroxyvitamin D3) (calcijex) and Secalcifediol Dihydro- Dihydro- (24,25-dihydroxyvitamin tachisterol tachisterol D3)

53 MECHANISMS OF MINERAL HOMEOSTASIS OF BONES

Intestine Bones D(+) Blood D(+), PTH(+), CТ(-) 2+ 2+ ↓ Са → ↑ PTH Са НРО4- → ↑ Са2+ → D(-) D(-) PTH(-) PTH(+) DD vit D = ↓ → 1,25(OH)2D CТ(+) Urine CТ(+) 500–1000 IU ↑ PTH → ↑ Са2+ Organ Parathormone Vitamin D ↑ 2+ - Intestine Са and НРО4 absorption Also due to (due to 1,25(OH)2D) 1,25(OH)2D ↓ 2+ ↑ - ↓ 2+ - Kidneys excretion Са and НРО4 Са and НРО4 output, due to 25(OH)D and 1,25(OH)2D ↑ 2+ ↑ 2+ Bone High doses Са and 1,25(OH)2D – Са and НРО - output, low ↑ оsteo- НРО- output; 4 4 ↑ genesis 24,25(OH)2D — genesis ↑ 2+ ↓ - ↑ 2+ - Result In blood Са and НРО4 In blood Са and НРО4

DRUGS AFFECTING THE BONE TISSUE ♦ ↓ bone tissue resorption: • sex hormones • biphosphonates* — etidronate, clodronate, pamidronate, alendronate • active metabolites of vitamin D* — calcitriol, alfa-calcidol • calcitonins — calcitonin, miacalcin • salts of calcium — calcium chloride, carbonate, etc. • ossein-hydroxyapatite ♦ ↑ mass of bone tissue: • fluorides — sodium fluoride (ossein), etc. • anabolic steroids • active metabolites of vitamin D — calcitriol, alfa-calcidol • fragments of human PTH* — theriparatid • growth hormone — somatotropin ♦ *Activating remodeling of physiological structure of the bone tissue

54 ENZYMATIC DRUGS

♦ With purulent necrotic processes: trypsin, chymotrypsin, chymopsin, desoxyribonuclease, collagenase, etc. ♦ For the improvement of processes of digestion: pepsin, gastric juice, pancreatin, panzynorm, festal, mezym forte, etc. ♦ Fibrinolytic: fibrinolysin, streptokinase, streptodecase, urokinase, alteplase, etc. ♦ Different: lydase, penicillinase, asparaginase, cytochrom C, etc.

INHIBITORS OF ENZYMES

• Inhibitors of proteinase — aprotinin (contrykal, gordox) • Inhibitors of fibrinolysis — aminocapronic acid • Anticholinesterase — proserin, physostigmine, galantamine • Inhibitors of MAO — nialamide • Inhibitors of carboanhydrase — diacarb • Inhibitors of xanthinoxidase — allopurinol • Inhibitors of acetaldehydrogenase — ciamide, teturam

55 DIFFERENT DRUGS AFFECTING METABOLIC PROCESSES

♦ The drugs improving energy supply — glucose, trimetazidin, ATP, riboxin, etc. ♦ Drugs of amino acids — glutamic acid, methionine, cerebrolizine, cistein, etc. ♦ Containing poison of bees, snakes, products of their vital activity — apilac, propolys, apizatron, viprosal, etc. ♦ Biogenic stimulators — carnithine, extract of aloe, fibs, etc. ♦ Cytoprotectors and chondroprotectors — actovegin, solcoseril, rumalon ♦ Antioxidants and antihypoxants — emoxypin, tocoferol, etc.

56 Раrt VI DRUGS AFFECTING BLOOD SYSTEM

Topic 21 DRUGS AFFECTING ERYTHROPOIESIS. BLOOD SUBSTITUTES

CLASSIFICATION OF DRUGS AFFECTING BLOOD ♦ Affecting hematosis • Erythropoiesis: stimulating and inhibiting • Leukopoiesis: stimulating and inhibiting ♦ Affecting blood clotting • Hemostatic: ↑ blood clotting (procoagulants) inhibitors of fibrinolysis proaggregants • Thrombolytic: ↓ blood clotting (anticoagulants) ↑ fibrinolysis (fibrinolytic) antiaggregants ♦ Affecting volume and composition of blood (blood- and plasma substituting solutions)

57 CLASSIFICATION OF DRUGS AFFECTING ERYTHROPOIESIS

♦ Stimulators of erythropoiesis: • at hypochromic anaemia — iron preparations for oral and parenteral administration • at hyperchromic anaemia — cyanocobalamin, folic acid • at anaemias of different genesis (tumours, AIDS, renal failure, chemotherapy, etc.) — drugs of hemopoietic growth factors: erythropoietin (epocomb, recormon, epomax), colony-stimulating factor of granulocytes (filgrastim) and granulocytes-macrophages (sargramostin) ♦ Depressive erythropoiesis: sodium phosphate, tagged by phosphorus-32

CLASSIFICATION OF IRON PREPARATIONS

♦ For oral application: • monocomponent — ferronal (iron gluconate), actiferrin, ferro-gradumet (iron sulfate), heferol (iron fumarate), hemofer (iron chloride), maltofer (iron hydroxide polymaltous complex), feramide • combined — tardiferon, ferroplex (+ ascorbic acid), ferrocal (+ cerebrolecitin + calcium fructosodiphosphate), hemostimulin (+ copper), maltoferfol (+ folic acid), etc. ♦ For parenteral application — ferbitol, jectofer (iron-sorbitol complex), fercoven, ferrum lec (iron saccharate), coamide (+ cobalt)

58 PHARMACOKINETICS OF IRON

With food Fe0, Fe2+, Fe3+ + ascorbic, apple, succinic (≈1–2 mg) and and other fruit acids with drugs НСl In the duodenum Fe2+ Active transport: and small + apoferritin intestine Passive “A ferritin curtain” diffusion Blood plasma Fe3+ + transferrin

Transferritin (siderofillin) Мioglobin, enzymes excretion Marrow Depot (spleen, marrow, liver) Intestine, Red blood cells as ferritin and hemosiderin kidneys, sweat

PRINCIPLES OF IRON PREPARATIONS USAGE

♦ Treatment of iron-deficient anaemia with the diet only is useless (hemic iron is better absorbed: 10–30% against 1–10% from plants) ♦ The following substances increase absorption: organic acids (ascorbic, succinic, lemon, folic, etc.), cistein, proteins; diminish absorption: intake during or immediately after the meal, milk, eggs, bread cereals, legumenous plants, calcium salts, phosphates, antacides, tetracyclines, etc. Fumarate, sulfate are better absorbed, gluconate Fe2+ — worse ♦ For haemoglobin constructing 50–100 mg of element iron (not salt!) per a day is necessary, depending on the deficit of iron, sex, age, etc. ♦ Iron preparations are prescribed 1 hr before (better absorbed) or 2 hrs after the meal (better tolerated) ♦ Effective treatment is considered at the increase of haemoglobin on 1–2 g/l a day ♦ Therapeutic effect — in 2–4 weeks, renewal of iron resources in depot — in 2–3 months

59 TOXICITY OF IRON PREPARATIONS

♦ Per oral intake: decline of appetite, nausea, vomiting, painful tenesmi, constipation (hydrogen sulfide) or diarrhoea: in the dose of 200 mg/day in 20% patients, 400 mg/day — 40%. Darkening of teeth (powder) and stool — reaction with hydrogen sulfide (H2S) ♦ Parenteral introduction: • i.m. — strong pain, infiltrates, inguinal lymphoadenopathy • i.v. — phlebitis, headache and dizziness, metallic taste in the mouth, tachycardia, generalized lymphoadenopathies, arthralgias, nephrotoxicity, encephalopathy, fever, leukocytosis, hemolysis, anaphylactic shock, urticaria, hemosiderosis ♦ With prolong and inefficient introduction: hemosiderosis The treatment must be provided by real deficit of iron!

ACUTE POISONING BY IRON PREPARATIONS

♦ 1st stage (in 30–60 min after intake) — stomach-pain, vomiting and diarrhea with blood, pallor, cyanosis, somnolence, acidosis ♦ 2nd stage (during 8–16 hrs) — period of improvement (80% of cases) ♦ 3rd stage (after 24 hrs) — collapse, seizures, coma, lethal outcome is possible ♦ 4th stage (in 1–2 months) — GIT obstruction because of scarring ♦ Level of iron > 3.5 mg/l is life-threatening Treatment • Antidote — deferoxamine i.m. 1–2 g repeatedly in 12 hrs; i.v. 15 mg/kg per an hour (DD up to 80 mg/kg) • Gastric lavage with sodium bicarbonate • Liquidation of shock, collapse, dehydratation and acidosis

60 DRUGS OF VITAMIN B12 Cyanocobalamin, oxycobalamin, cobamamide (desoxyadenosylcobalamin), vitohepat

NH2 R O O R = (CN, OH, CH2, NH2 Structure Deoxyadenosyl) A nucleotide part and chromoform part — N O H2N porfinir with 4 redu- N Co N O NH2 ced pyrrol rings and N atom of the cobalt, O connected with cyano- N group (cyanocobala- H O NH2 O O min), hydroxyl (oxyco- NH2 O balamin), methyl (me- O OH O thylcobalamin), des- oxyadenosyl (desoxy- HO O adenosylcobalamin)

It is contained in the meat and milk food, beans, synthesized by microflora of the thick intestine. DD — 2–5 mcg

CYANOCOBALAMIN

Pharmacokinetics Absorption — along the whole length of the small intestine and in the distal department of the caecum in the linked form with the specific intrinsic Castle’s factor (glycoprotein, synthesized by the parietal cells of stomach) is transported in the blood by pinocytosis through the receptor on enterocytes, the activity of which depends on the normal function of mucous, supported to Bc; at surplus — by simple diffusion Distribution — transported to the blood by transcobalamins II in the liver, marrow and spleen; transcobalamins I and III participate in depositing Depositing — the liver contains 1–10 mg (reserve for 2–5 years), daily use 0.5–8.0 mcg Excretion with bile into the intestine 3 mcg secrete daily; enterohepatic circulation (50–60% are absorbed backwards); also by kidneys (especially at surplus)

61 CYANOCOBALAMIN

Pharmacodynamics Basic reactions: 1. Desoxadenosylcobalamin (cobamamide) catalyzes methylmalonil- CoA-mutase in the reaction: methylmalonil-CoA → succinil-CoA (methylmalonil succinic acid) → metabolism of fat acids, isoleicin and valin ⇒ at deficit ↑ content of the methylmalonic acid, suppressing myelin secretion ⇒ neurological disorders 2. Methylcobalamin, participating in the reaction of demethylation of tetrahydrofolic acid, regulates: DNA synthesis: through transformation of 5CH3-H4-folate ⇒ (food and deposited) in H4-folate at deficit disturbance of hemopoiesis (DNA replication, ripening of the nucleus of erythrocytes ⇒ megaloblasts) methionine synthesis: under methyltetrahydrofolate action the cyanogroup B12 is replaced to methyl with formation of methylcobalamin, which methylizes homocystein with formation of methionine ⇒ synthesis of proteins, phospholipids, betain, choline

CYANOCOBALAMIN

Pharmacodynamics • Anabolic action: ↑ metabolism of proteins and nucleic acids • Lipotropic: ↑ metabolism of carbohydrates and lipids, ↓ content of cholesterol in blood • Activates erythropoiesis (with Bc): DNA replication, erythrocytes maturation is completed, prevention of hemolysis due to accumulation in the red blood cells of the sulfhydril compounds • ↑ immunity: ↑ phagocytic activity of leukocytes, activity of the reticuloendothelial system • ↑ blood clotting system • ↑ regeneration of tissues • Hepatoprotective function • Neuroprotection, participation in the cognitive and emotional sphere • Reproduction (↑ content of spermatozoons) Deficit at: ↓ content of Castle’s intrinsic factor (auto-antibodies to it, stomach resection, chronic gastritis), intestinal diseases, pancreatitis, diphyllobothriasis infection, etc.

62 CYANOCOBALAMIN

Indications Substitutive therapy: hypovitaminosis — anaemia megaloblastic (malignant, macrocytic, pernicious, B12-deficit, Addison—Biermer), neurological disorders (funicular myelosis: paresthesia, hypotrophy, polyneuritis); movement and visual dyscoordination, hallucinations, amnesia, dementia), atrophic glossitis (crimson lacquered tongue), etc. — treatment (with Bc) by 100 mcg daily during a week, than once a week during a month and then once a month during all the life; prophylactic (once a month) in vegetarians, with stomach resection, etc. Pharmacodynamic therapy: • anaemias (post-hemorrhagic, aplastic, etc.) • polyneurites, neuralgias, paresis, paralysis, psychical diseases • hepatitis, cirrhosis of liver • hypotrophy of prematurely born children, methylmalonic aciduria • myocardiodystrophy, myocarditis • skin diseases (psoriasis, neurodermatites) • allergic diseases (asthma, urticaria) • antidote with cyanides poisoning (overdose of sodium nitroprusside)

CYANOCOBALAMIN

Adverse effects • Nervous excitation • Pain in the heart area, tachycardia, arrhythmia (↓ K+) • ↑ blood clotting, ↑ thrombocytes, leukocytes, erythrocytes of blood • Anaphylactic shock (seldom) Interaction Malabsorption with application of potassium preparations, hypolipidemic, antitubersulosis drugs, large doses of ascorbic acid, deficit of folic acid, chronic use of alcohol Deficit during neuroleptics, glucocorticoids administration It is not recommended in one syringe with thiamine and pyridoxine ↑ ⇒ allergizing action of vitamin B1 their combination is inexpedient!

63 FOLIC ACID (Bc, B9, M)

N N Glutaminic acid H2N 8 Structure 2 1 7 γ - 3 6 COO N 4 5 9 pteroilglutaminic acid, N CH 2 CH2 consisting of pteridine OH HN heterocycle, PABA, 10 CH2 Pteridin H glutaminic acid —C—N—CH PABA O COO-            Pteroil (pteroic acid)

Yeast, liver, kidneys, cheese, green vegetables contain folic acid, it is synthesized by microflora of intestine DD — 50 mcg, at pregnancy — 400–800 mcg, children of 2–12 years old — 200 mcg

FOLIC ACID

Pharmacokinetics Absorption: folates of food are mainly polyglutamate forms of 5-CH3-tetrahydrofolate (THF); for absorption in the intestine must be hydrolyzed in monoglutamate by glutamate transferase (conjugase); ↓ its activity at alcoholism, sprue; monoglutamate-5-CH3-THF absorbs in the proxymal department of the small intestine by the active or passive transport; hot treatment ↓ content of folates by 50–95%; the best absorption — from the liver, egg yolks, brewer’s yeasts Binding with proteins — 60–70% Concentration in blood — 4–20 ng/ml Distribution — the liver, cerebrospinal fluid contain the most part of it; general content — 5–10 mg; actively transports through the pla- centa (2 and 5 times ↑ concentration in the erythrocytes and blood plasma accordingly than in a mother) Excretion by kidneys, and with the breast milk (50–60 mcg/l) as well

64 FOLIC ACID

Pharmacodynamics The basic function of tetrahydrofolic acid and its derivative — transfer (acceptor) of monocarbon groups, for example methyl and formil, from one organic compounds to other ones Coenzyme forms of tetrahydrofolate Position Radical Substance 5 N –CH3 MethylTHF N5 –CHO Folinic acid (cytroforum-factor) N10 –CHO 10-formilTHF N5-10 –CH — 5,10-methenylTHF 5-10 N –CH2 — 5,10-methylenTHF 5 N –CHNH — FormilinoTHF 10 N –CH3 OxymethylTHF

FOLIC ACID

Pharmacodynamics

1. Transformation of serin into glycine 5,10-СН2-ТHF Uridin-mono- Glycine phosphate 2. Metabolism of histidine 3. Inclusion of atoms of Serin Thymidine- carbon in the ring of monophosphate purine alkali THF Dihydrofolate 4. Transformation of homocystein into methionine with B12, as a cofactor NADP NADPN + Н+

↑ erythro-, leuko-, thrombocytosis, plastic and regenerative processes in all organs

65 FOLIC ACID

Indications ♦ Replacement therapy: hypovitaminosis — with chronic alcoholism, diseases of the liver and intestine, usage of antibiotics, sulfonamides and other drugs (see below), diseases of sprue (macrocytic anaemia, leukopenia, diarrhea, ↓ weight), as well as against a background of its deficit at B12-dependent anaemia (+ neurological disorders); medical doses — 15 mg i.m. or per os once a day, prophylactic — daily need ♦ Adaptation therapy (pregnancy, with breast feeding, prematurely born children) ♦ Pharmacodynamic therapy: • anaemias of hypochromic, hypoplastic, anaemia and leukopenia of radiation and medicinal origin • as a stimulator of regenerating processes, for healing gastric and duodenal ulcers, burns, wounds

FOLIC ACID

Adverse effects • Dyspepsia • In the large doses ↑ CNS excitability, up to seisures (↓ activity GABA), ↓ renal function • Allergic reactions Interaction Malabsorption with the usage of oral contraceptives, isoniazide, chronic alcohol addiction, antiepileptic drugs (difenine, phenobarbital, hexamidine) Metabolism disorders (↓ activity of dihydrofolate-reductase) against a background of metotrexate, sulfonamides, trimethoprim, PASA, cytostatics, etc.

It is impossible to inject in one syringe with vitamins B12, C, locally anesthetizing (destruction); together with mineral acids, alkaline substances, reducing agents (Bc inactivation) ↑ effects of cardiac glycosides; with B12 for treating megaloblastic anaemias; with Fe, vitamines B2, B6 — hypochromic anaemias

66 ERYTROPOIETINS (α, β, ω)

Recombinant human erythropoietins Epoietin-alfa — epocomb, epocrine, eprex Epoietin-beta — recormone, erythrostim Epoietin-omega — epomax Pharmacodynamics Glycoproteid hormone (synthesis in the kidneys): Hemo- and erythropoietic: ↑ erythrocytes and reticulocytes, haemoglobin, synthesis of hem, normalizes lowered hematocrit (in 4 weeks of regular intake) Indications • Anaemias of different genesis (chronic renal insufficiency, prematurity, chemotherapy of tumours) • ↑ volume of blood at autotransfusion Adverse effects Early: flu-like symptoms (at the onset of treatment), hypertension, thrombosis, myocardial infarction, embolism of lungs, sudden death Late: immune diseases, allergy, oncologic diseases of the bone marrow

CLASSIFICATION OF BLOOD SUBSTITUTES BY COMPOSITION • Protein: from the blood cells — erythrocytic, thrombocytic mass; from blood plasma — serum, antihemophilic plasma • Protein hydrolysates — hydrolysate casein, hydrolysine, infuzamine, aminotrof, alvezine, etc.; solutions of amino acid — polyamine, mariamine, friamine • Fatty emulsions — intralipid, lipofundin • Colloid: animal origin — gelatinol, plasmogel; vegetable — pectin, gummy-arabic; synthetic — dextranes (polyglucin, reopolyglucin), on the basis of polyvinylpyrrolidone (neohemodes polydes) • Crystalloid: salt — 0.9% sodium chloride solution, Ringer— Lock’s solutions, potassium chloride, quintasol, lactosol, etc.; buffer — sodium hydrocarbonate, trisamine; solutions of sugars and polyatomic alcohols — glucose, fructose, sorbitol

67 CLASSIFICATION OF BLOOD SUBSTITUTES BY INDICATION

Hemodynamic (antishock) — polyglucin (molecular mass • ≈ 60,000 ± 10,000, T1/2 3–4 days), rondex (65,000 ± 5,000), ≈ rheopolyglucin (35,000 ± 5,000, T1/2 1 day + desintoxication properties), gelatinol (about 20,000; + desintoxication properties) • Desintoxication — neohemodes (8,000 ± 2,600), polydesis, rheopolyglucin, gelatinol • Correctors of acid-base and water-salt balance — saline, buffer solutions • For the parenteral feeding — protein hydrolysates, solutions of amino acids, sugars, fatty emulsions • Drugs executing a function of oxygen transfer — perftoran • Polyfunctional — polyfer (hemodynamic, hemopoietic), rheogluman (hemodynamic, hemopoietic, desintoxicational, diuretic), polyglusol, rheosorbilact (hemodynamics and acid-base balance)

DEMANDS TO BLOOD SUBSTITUTES

♦ To have affinity by the physical-chemical properties with blood plasma ♦ Sterility and stability in the process of storage in the terms determined by documents ♦ Safety for an organism: not to have organotoxicity, pyrogenicity, with repeated introductions not to cause sensitization of an organism ♦ To be fully excreted (hemodynamic, desintoxication) or metabolized and uptaken by an organism (nourishing) ♦ Hemodynamic ones must detain in the blood stream for a long time and support ABP — to have high molecular mass (30,000–70,000) ♦ Desintoxication ones must together with bound toxins quickly excrete from an organism — to have low molecular mass (6,000–15,000)

68 COMPLICATIONS OF TRANSFUSION

♦ Immediate: • Blood volume independent — anaphylactic shock, hemolysis, fever, hyperkaliemia, infections causing acute septicemia • At massive transfusion — hypokaliemia, hyperthermia blood, ↓ blood coagulations, ↑ ABP ♦ Late: hypokaliemia, hypothermia, ↓ blood clotting

69 Topic 22 DRUGS AFFECTING LEUKOPOIESIS AND BLOOD COAGULATION

STIMULATORS OF LEUKOPOIESIS

Drugs for treating leukopenia (agranulocytosis) Agranulocytosis (extreme manifestation of leukopenia) is a clinical-immunological syndrome characterized by sharp fall (less than 0.75–109/l) or full disappearance of granulocytes and general amount of leukocytes less than 1.0–109/l Types and etiology ♦ Immune: • auto-immune: at systemic lupus erythematosus, rheumatoid arthritis • haptenic: insecticides, drugs — NSADs (derivatives of pyrazolone, ASA, indometacin), barbiturates, meprobamate, clozapine, diacarb, novocainamide, meticillin, sulfonamides, trimethoprim, chloroquine, isoniazid, levamisole, etc. ♦ Myelotoxic: radiation, benzol, drugs — cytostatics, derivatives of phenothiazine ♦ Genuine (of unclear etiology): may be caused by infections (malaria, flu, viral hepatitis, etc.)

70 STIMULATORS OF LEUKOPOIESIS

Clinical course of agranulocytosis caused by a drug ♦ Immune haptenic — acute onset, rapid infectious damage of the skin and mucous (angina, stomatitis, abscess, furuncles, etc.), chill, fever, grave general condition; with sharp ↓ granulocytes in blood, normal amount of erythrocytes and platelets ♦ Myelotoxic — gradual, unnoticeable development, weakness, frequent infections, hypodermic haematomas at injuries; ↓ granulocytes, erythrocytes, platelets in the blood, ↓ all stem cells in the marrow Treatment 1. Removal of ethiologic factors 2. Aseptic conditions for patient 3. Treatment of infectious complications (antibiotics) 4. Transfusion of leukocytic mass 5. Treatment with glucocorticoids (at immune agranulocytosis) 6. Stimulation of leukopoiesis 7. Desintoxication therapy 8. Treatment of hemorrhagic syndrome

STIMULATORS OF LEUKOPOIESIS

Classification ♦ Vitamin preparations of plastic metabolism — pyridoxine, folic acid ♦ Non-steroidal anabolic drugs — pentoxyl, methyluracil, sodium nucleinate ♦ Myelodide growth factors (coloniestimulating factors) — filgrastim (neupogen), molgramostim (leukomax), sargramostim, etc. ♦ Others — leukogen, lithium carbonate, etc. Features of treatment • Myelotoxic — stimulators of leukopoiesis • Immune haptenic — + immunosupressive therapy (glucocorticoids)

71 STIMULATORS OF LEUKOPOIESIS

Myelodide factors of growth: filgrastim (G-CSF, neupogen), sargramostim (GM-CSF), molgramostim (leukomax) Pharmacodynamics • Myeloid factors of growth: recombinant human granulocytic- macrophagal coloniestimulating factors — G-CSF and GM-CSF ⇒ affecting specific receptors, ↑ the proliferation and differentiation of proper cellular lines Indications • Leukopenia of different genesis • Transplantation of the bone marrow • AIDS Adverse effects There are a few: sargramostim — pains in the bones, convulsions, myalgias, syndrome of increased permeability of capillaries, allergic reactions, etc.

DRUGS DEPRESSING LEUKOPOIESIS

(anticancer) ♦ Alkylating compounds — sarcolysine, dopan, myelosan, cyclophosphan, etc. ♦ Antimetabolites — methotrexate, fluoruracil ♦ Anticancer antibiotics — doxorubicine, dactinomycin, bleomycin, mitomycin, etc. ♦ Alkaloids — vinblastine, vincristine, colchamine ♦ Hormonal drugs and their antagonists — phosphoestrol, prednisolone, tamoxifen, etc. ♦ Enzymes — asparaginase (crasnitine) ♦ Drugs of animal origin — propes

72 DRUGS DEPRESSING LEUKOPOIESIS

Cell-cycle specific drugs Cell-cycle nonspecific (on the tumour cells passing drugs (liquidate a capacity a cell-cycle) of cancer cells to divide) Antimetabolites; alkaloids; Alkylating; antibiotics bleomycin (dactinomycin, daunorubicin) Mitosis 2% Differentiation Synthesis of cellular components for М G0 mitosis G2 19% G1 Cell 40% DNA synthesiscycle Synthesis of the cellular components S necessary for DNA DNA genome 39% synthesis replication

DRUGS DEPRESSING LEUKOPOIESIS

Alkylating compounds — dopan, sarcolysine, cyclophosphan, myelosan Pharmacodynamics • Alkylating of DNA and RNA nucleophilic centers ⇒ disturbance of the DNA structure, synthesis of some proteins ⇒ disturbance of vital activity of cells, their division capacity • Cycle-cell nonspecific drugs, but cells are most sensitive in the late phase G1 and phase S of the cell cycle • Especially pronounced cytostatic effect to the relation of quickly proliferating cells ⇒ high doze-dependent toxicity: the bone marrow (↓ myelopoiesis) GIT (ulceration of mucosa, stomatitis, enteritis) gonads (virilization, gynecomastia, uterine bleedings) local reactions (dermal-abscessive) drug resistance

73 DRUGS DEPRESSING LEUKOPOIESIS

Antimetabolites • Analogs of folic acid — methotrexate • Analogs of purine — mercaptopurin, fopurin • Analogs of pyrimidine — fluoruracil, fluorafur Mechanism of action Concurrent antagonists of natural metabolites (are structurally similar) ⇒ substitute natural metabolites ⇒ DNA and RNA are incapable of functioning, “lethal” synthesis ⇒ ↓ division of tumor cells Anticancer antibiotics • Actinomycins — bleomycin, dactinomycin, etc. • Antracyclines — doxorubicin, rubomycin, etc. Mechanism of action ↓ DNA replication ⇒ RNA formation disturbance ⇒ enzymatic and other proteins synthesis disturbance Cytostatic, antibacterial

DRUGS DEPRESSING LEUKOPOIESIS

Аlkaloids periwinkle (vinblastine, vincristine); mandragora or podophyllin (etoposide); colchicum (colchamine); yew (paclitaxel) Mechanism of action ↓ formation of a spindle of tumoral cells division, binding with the microtubular proteins ⇒ selectively ↓ division of tumor cells at the mitosis stage (cell-cyclespecific) Hormonal drugs and their antagonists Corticosteroids (prednisolone), androgens (testosterone), estrogens (synestrol, fosfestrol), gestagens (megestrol), anti- estrogens (tamoxifen, toremifen), anti-androgens (flutamide) Mechanism of action They assist in renewal of the broken hormonal regulation of cells function ↓ division and promote their differentiation

74 GENERAL PRINCIPLES OF ANTICANCER DRUGS USAGE

♦ Rational choice of drugs depending on the type and localization of tumor ♦ Rationalization of schemes: usage of cytostatics in “pulsating” courses every 3–4 weeks ♦ Combined application (simultaneous or successive) of cytostatics of different groups ♦ Synchronization of mitotic cycles of tumor cells: after cell-cycle nonspecific drugs — drugs of the first choice are specific drugs ♦ Inclusion of immunostimulators in the combined therapy (interferons, etc.)

DRAWBACKS OF MODERN ANTICANCER DRUGS

♦ As a rule, they provide only remission (10–40%), just with some tumor diseases it is possible to achieve complete recovery ♦ Solid tumors with a relatively slow growth respond to treatment extremely badly (cancer of stomach, pancreas, liver, thick intestine, bronchi, urinary ways) ♦ Resistance of tumor cells to drugs ♦ Small selectivity of action to the tumor cells ♦ Pronounced adverse effects, deteriorating quality of life

75 ADVERSE EFFECTS OF ANTICANCER DRUGS

♦ Supression of actively proliferating tissues • bone marrow ⇒ myelotoxicity (leukopenia, agranulocytosis, thrombocytopenias, etc.) • GIT mucosa ⇒ anorexia, stomatitis, enteritis, etc. • reproductive organs ⇒ ↓ fertility, feminization in men, masculinization in women (hormonal drugs), teratogenic, embryo-, fetotoxic effect ♦ Alopecia, dermatites, skin pigmentation ♦ Cardiotoxicity (arrhythmias, hypertension) ♦ Nephro- (edemas) and hepatotoxicity (cholestasis) ♦ Fibrosis of lungs ♦ Immunosupression ♦ Anaphylactic reactions (bleomycin) ♦ Secondary malignant formations (alkylating drugs — acute leukosis)

BLOOD COAGULATION

I stage — Trauma, damage Thrombocytic hemostasis activation Destruction of tissues and vessels Adhesion and platelet Selection of Constriction aggregation vasoconstrictors of vessels Formation of a thrombocytic plug Internal way External way II stage — Plasmic Plasmic factors + catalytic Plasmic factors + tissue hemostasis surface of collagen factor (III) activation 1st phase Formation of prothrombinase

2nd phase Prothrombin Thrombin Formation of thrombin 3rd phase Fibrinogen Fibrin Formation of a fibrin clot III stage — Retractoenzyme Clot retraction Clot retraction

76 Stuck together fibrin’s polymer Polymer of fibrin Proconvertin VII + Fibrin-monomer Tissue factor Stuart—Prower’s X III XIIIa From tissues 2+ (10 sec) VIIa PL Ca Extravascular (external) way 2+ 2+ + IIa Thrombin PL Ca PL Ca XIII 2+ Xa with injury PL Ca Damage of cells II 2+ and exposed collagen I Fibrinolysis IXa Fibrinogen + factor + PL Ca BLOOD COAGULATION Fibrin stabilizing X Va Pro- VIIIa XIa thrombin (3 min) + Intravascular (internal) way IX XIIa + Kallikrein V VIII Christmas’s XI + + Collagen + XII XIIa Plasmin (fibrinolysin) HMK Highly Transferase Serine proteinase Factor kininogen molecular Plasminogen Hageman’s

Prekallicrein PL Phospholipid

Active condition Active Inactive condition Inactive

77 BLOOD COAGULATION

Clotting factors Functional role I Fibrinogen Fibrinogen → fibrin II Prothrombin (synthesizes Prothrombin → thrombin in the liver with participation Thrombin + fibrinogen = fibrin of vitamin K) III Tissue factor / thrombo- ↑ factor X during contact with VIIa, IV (external plastin (nonactive) way of prothrombinase formation — active thromboplastin) IV Са2+ It is necessary for interconnection of clotting factors with phospholipid surface of cells; ↑ pro- thrombinase and transformation of prothrom- bin into thrombin; ↑ fibrinogen-fibrin reaction V, Proaccelerin, accelerin (is ↑ factor X, prothrombinase formation VI synthesized in the liver with- оut participation of vitamin K) VII Proconvertin (form in the Participates in formation of tissue liver with participation prothrombinase of vitamin K) VIII Antihemophilic In the blood circulates as a complex factor A consisting of three subunits, from which subunit VIII-vWF — Willebrand’s factor — provides adhesion of platelets IX Antihemophilic factor B ↑ factor X, formation of prothrombinase of (Christmas) plasma X Stuart—Prower’s (is syn- It is a part of prothrombinase, activates thesized in the liver with coversion of prothrombin into thrombin participation of vitamin K) XI Predecessor of plasma Active form XIa ↑ factor IX, converting it thromboplastin into IXa XII Hageman’s factor “Initiator” of intravascular coagulation, (contact factor) ↑ prekallikreins of plasma, converting them into kallikreins, releasing kinins, ↑ fibrinolysis XIII Fibrinstabilizing Participates in reaction of final fibrin Fletcher factor Participates in formation of coagulation in (plasma prekallikrein) contact phase Fitzgerald factor Is converted by kallikrein into kinin and (BM-kininogen) participates in activating factor XI Vitamin K-dependent factors: II, VII, IX, X Sensitive factors to thrombin: I, V, VIII, XIII Factors of contact: XII, XI, BM-kininogen, prekallikrein Factors — serine protease: XII, XI, X, IX, X, VII, II, plasmin

78 PHASES OF BLOOD COAGULATION

I. Formation of prothrombinase complex or active thromboplastin: Xa, Va, phospholipids of platelets (factor III of platelets), Ca2+ ♦ External way (protection at trauma of tissue): taken from tissues or from blood leukocytes of tissue factor (III); interconnection with VII and activating X (formation of active tissue thromboplastin or prothrombinase) ♦ Internal way: • cellular mechanism ⇒ damage of endothelium ⇒ adhesive proteins of the subendothelium (collagen, fibronectin, Willebrand’s factor, etc.) + BAS, ↑ platelets (thrombin, adrenalin, serotonin, FAT, ADP, TxA , ⇒ 2 PgG2) adhesion and platelet aggregation, release of substances from them (ADP, serotonin, adrenalin, Ca2+, etc.) and synthesis of TxA2, Pg, FAT, etc., activating plasma mechanism • plasma mechanism: successively ↑ in complexes “Hageman’s factor (XII) + prekallikrein + XI factor”, and then “factor XI + factor IX + the VIII” factor with the subsequent activating X (formation of active blood thromboplastin) II. Under the action of prothrombinase prothrombin (II) → into thrombin (IIa) III. Thrombin converts fibrinogen (I) into fibrin-monomer, then polymer and ↑ factor XIII ⇒ stabilization of fibrin — a blood clot

ANTICOAGULANT FACTORS

Natural anticoagulants Functional role Inhibitor of external way of Synthesized protein in endotelium, inactivating blood coagulation (TFPI) complex the Vlla + phospholipids + factor Xa Thrombomodulin Endotelial cell’s membrane glycoprotein, binding and inactivating thrombin, in complex with which thrombin preserves an ability to activate protein C “Contact inhibitors” (phos- ↓ starter of the internal way (complex of factors pholipid, placental) Xlla-XIa and kallikrein) Antithrombin III (AT III) ↓ thrombin, factor Xa and to less extent of other proteases participating in coagulation Heparin and other sour In complex with AT III acts as strong mucopolysacharides anticoagulants Protein C Synthesized by hepatocytes vitamin K-dependent inhibitor of the Vllla and Va factors, endogenous activator of plasminogen. It is activated by thrombin and the complex “thrombin + thrombomodulin” α Protein S 2-macroglobulin Synthesized by hepatocytes vitamin K-dependent co-factor

79 INTEGRATED SCHEME OF HEMOSTASIS AND ANTIHEMOSTASIS

Endotelial damage Tissue Plasminogen collagen damage Spasm Adhesion of ХII ХIIа platelets Тhrombin Tissue factor Plasmin Stimulation ХI ХIа (III) Aggregation Тhrombin IХ IХа АDP Тhrombin VIIа VII TFPI Рlatelet VIII VIIIа Activated liberation Ca2+ Vа V protein C ХХа reaction Platelet Ca2+ coagulants Viscid meta- Prothrombinase morphoses Prothrombin (II) Тhrombin (IIa) Fibrinolysis Аntithrombin III + Fibrinogen (I) Моnоfibrin heparin Тhrombin Ca2+ ХIIIа ХIII Red stratified thrombus Polymerfibrin Fibrin-peptides Thrombin inhibition Inflammation

TYPES OF BLOOD COAGULATION DISTURBANCE

♦ ↑ blood coagulation and clot formation — hypercoagulation and development of thrombotic syndrome

♦ ↓ blood coagulation and clot formation — hypocoagulation and development of hemorrhagic syndromes

♦ Phasic disturbance of hemostasis system condition — DIC-syndrome (disseminated intravascular coagulation): phase of hypercoagulation, converting into the hypocoagulation phase; develop coagulopathy and thrombohemorrhagic syndrome

80 BLOOD COAGULATION

♦ Thrombocytic-vascular hemostasis (damage of a vessel, vasospasm, adhesion and aggregation of platelets, plasma factors accumulation) ♦ Coagulative hemostasis with forming a fibrin clot (white — as a rule in arteries; the leading role — platelet aggregation) and red (+ erythrocytes, platelets), more frequent in veins; have a “tail” ⇒ thromboembolia) ♦ Renewal of blood flow because of fibrinolysis of thrombotic masses and other factors of antihemostasis

hemostatic antithrombotic (antihemorrhagic) (thrombolytic) • proaggregants • antiaggregants • procoagulants • anticoagulants (direct and indirect) (direct and indirect) • inhibitors of • fibrinolytics fibrinolysis (direct and indirect) • Direct action drugs act in vivo and in vitro, the effect comes quickly • Indirect action drugs — act only in vivo, the effect develops slowly

HEMORRHAGES (SYNDROMES AND DIATHESES)

Classifications ♦ By the source of origin: arterial, venous, capillary, mixed ♦ By diraction: internal and external ♦ By the term of appearence: primary (traumas) and secondary ♦ By mechanism: • thrombocytic-vascular hemostasis: disturbance of platelets (quantitative — thrombocytopenias (< 3.0 G/l) and qualitative — thrombocytopathias) and vessels (vasopathias) • coagulative hemostasis (coagulopathies): 1st phases — thromboplastinopathies, 2nd phase — thrombopathies, 3rd phase — fibrinopathies ♦ By etiology: inherited (deficit of factors, etc.): haemophilias A and B, Willebrand’s disease, etc.; acquired due to hypovitaminosis K, Bc, B12, diseases of the liver, blood, tumors (leukosis), collagenosises (systemic lupus erythematosus), infectious and viral diseases (hemorrhagic fever), toxic influence (radiation, drugs, alcohol), ↑ fibrinolysis at trauma (surgery) of the lungs, uterus, pancreas; burn, shock, sepsis, etc.

81 HEMOSTATIC DRUGS

• Procoagulants: direct action: locally — thrombin, hemostatic collagen sponge, fibrin glue, etc.; systemic — drugs of blood factors (fibrinogen, concentrate of factor VIII, IX, cryoprecipitate, etc.) indirect action: vicasol (menadion), phytonadion, ethamsylate (dicinone), desmopressin • Inhibitors of fibrinolysis: synthetic: aminocapronic acid, tranexamic acid, amben animal origin: aprotinine (contrical, gordox, trasilol) • Proaggregants: calcium salts, serotonin adipinate, adroxone • Thrombolytic: decylate • Coagulants of animal and herbal origin: gelatinol, lagohilus, guelder rose, water pepper, etc. • Antagonists of heparin: protamine sulfate

PROCOAGULANTS OF INDIRECT ACTION

Thrombin, hemostatic sponge Mechanism of action: thrombin is IIa factor of coagulation system of blood; thrombin and other factors of blood coagulation are a part of different hemostatics for the local application (hemostatic sponge, fibrin glue, etc.) They are used only locally (!) on the bleeding organ in time and after the operations Fibrinogen Mechanism of action: is a factor I of coagulation system of blood (glycoprotein with the molecular weight about 340,000 dalton) It is used as a mean of the first aid with bleeding associated with its absence: acute fibrinolysis during the operations on the organs with excessive level of the tissue activators of the fibrinolytic system (lungs, pancreas, prostate, thyroid glands, etc.); in the obstetric practice (placental detachment, death of fetus, etc.); at traumatic, burn shock; radiation: severe diseases of the liver; late stages of DIC- syndrome; administered ex tempore as 1–2% solution of i.v. droply Side action — thromboses, allergy

82 PROCOAGULANTS OF INDIRECT ACTION

Preparations of vitamin K — phytonadion (K1), vicasol (menadion — water-soluble K3) Mechanism of action: liposoluble vitamin K (daily need = 100 mcg): Naphthoquinone K1–C7 (K1 — phytonadion in food, for example, green leaves of vegetables; K2 — menaquinone is synthesized by the flora of intestine of a man; K3 — menadion, synthetic water soluble); in the the liver participates in gamma-carboxylation glutaminic residue of prothrombin (II), proconvertin (VII), factor IX and X, as well as anticoagulant endogenous proteins S and C. These residues (domains) are necessary for transition of these factors into the active condition (to bind calcium and stick to phospholipids) Тhrom- Predecessor of clotting Active clotting Ха II bin ІІа factor factor K EGF2 2 СН2 СН2 EGF Carboxylase 1 K1 Va СН2 СН vitamin К, СО2 Gla- COOH HOOC COOH Ca2+Ca2+Ca2+Ca2+ domain Glutaminic Gamma-carboxy- residue glutaminic residue (Gla)

PREPARATIONS OF VITAMIN K

Phytonadion (K1), vicasol (menadion) (K3) Kinetics: K1 is absorbed in the small intestine, K2 — in the large intestine (bile acids are necessary!); diseases of GIT and the liver ↓ absorption ⇒ hypovitaminosis (hypoprothrombinemia, hemorrhages); an ability to accumulate is limited; distribution depends on lipophility; 20–30% of vitamin K with per oral introduction are not absorbed and are excreted. Indications: with a prophylactic purpose (120 mcg, during a pregnancy period, in newborns, in elderly people, preparation to the operation, prolong chemotherapy, etc.) and medical (10–15 mg, at pathology with the hemorrhagic syndrome and hypoprothrombinemia: dysfunction of the liver (hepatitis, cirrhosis) and GIT, tuberculosis, thyreotoxicosis, hyper- thermia, etc.; overdosage of indirect anticoagulants (antagonists!), usage of NSAID, antibacterial drugs). The medical effect develops by 24 hrs. Vicasol is uneffective with diseases of the liver and overdosage by indirect anti- coagulants. Phytonadion is effective with all the K-hypovitaminosis conditions Adverse action: ↑ hyperhydrosis, face reddening, at i.v. — dyspnea, pain in the breast, in the back, allergy ⇒ very slow introduction!; vicasol causes methemoglobinemia, hemolysis of erythrocytes, hemoglobinuria

83 INDIRECT PROCOAGULANTS

Ethamsylate (dicinone) Mechanism of action: hemostatic (moderate ↑ formation of tissue thromboplastin, also effects the thrombocytic link of hemostasis + ↑ formation of platelets, their exit from the marrow); angioprotective (possessing antihialuronidase activity and stabilizing ascorbic acid, ↑ resistance of capillaries, ↓ their permeability) Indications: parenchymatose and capillary bleeding, thrombocytopenia and thrombocytopathies, prophylaxis of intra- and postoperating bleeding, diabetic microangiopathy Adverse effects: sometimes heartburn, discomfort in the epigastric region, hyperemia of the face, parasthesia of the lower extremities, ↓ ABP Desmopressin (ADH synthetic analog) Mechanism of hemostatic action: ↑ formation of the Willebrand’s and VIII factors

INHIBITORS OF FIBRINOLYSIS

Synthetic — aminocaproic acid, tranexamic acid, amben Animal origin — aprotinin (contrykal, gordox, trasilol) Causes of generalized fibrinolysis • Hyperreactivity of the protective fibrinolytic system as inadequate to the reaction on ↑ blood coagulation • Release of tissue proteinases with extensive injuries of the lungs, kidneys, pancreas, thyroid gland, prostate, uterus, ovaries, veins • Septicemia with ↑ toxins and enzymes of streptokinase type External mechanism of activating Internal mechanism of activating (tissue activators) (plasma activators) Plasminogen Tissue activator of + + Complex of “factor plasminogen (t-PA), (profibrinolysin) XIIa + kallikrein urokinase of kidneys, from + VMC”, activated the cells of blood, bacteria proteins C + S (streptokinase) Plasmin – (fibrinolysin) Aminocapronic α-аntiplasmin and – acid – other inhibitors Aprotinin Products of Тhrombin (IIa) Fibrinogen Fibrin Fibrinopeptides disintergration (secretion of proteolysis)

84 INHIBITORS OF FIBRINOLYSIS

Synthetic inhibitors of fibrinolysis (amino- and carbonic acids, they are structurally close to amino acid lysin) — aminocaproic acid, tranexamic acid, amben Mechanism of action • ↓ fibrinolysis due to ↓ transformation of profibrinolysin (plasminogen) in fibrinolysin (plasmin) by the concurrent blocking (because of affinity with lysin) of active center of profibrinolysin activator + ↓ fibrinolysin itself • Inhibitors of kinins (bradykinin, callidin) and some factors of the complement system, appearing at hypoxia, acidosis, damage of tissues, inflammation, allergy • Antishock activity (↓ proteolytic enzymes and ↑ treatment function of the liver)

INHIBITORS OF FIBRINOLYSIS

Synthetic • Indications: conditions, characterized by excessive fibrinolysis, that leads to life-threatening bleedings: overdose of fibrinolytics, massive blood transfusions traumas (operations) of the organs rich in plasminogen activators (lungs, brain, uterus, prostate, thyroid gland, pancreas) placental detachment, antenatal death of the fetus, sepsis extracorporal circulation pulmonary, gastric bleeding subarachnoidal bleeding, traumas of the skull of the DIC-syndrome hypocoagulation stages severe hepatitis, pneumonia, etc. radiation disease • Adverse effects: low-toxic; dizziness, nausea, diarrhea, mild catarrh of the respiratory tracts are possible

85 INHIBITORS OF FIBRINOLYSIS

Animal origin (polypeptide from tissues (lungs’) of cattle) — aprotinin (contrykal, gordox, tracilole) Mechanism of action: inactivate proteinases of the blood and tissues (plasmin, kallikrein, kininogenase, trypsin, chymotrypsin), forming nonactive complexes with them, as well as ↓ their formation from proactivators ⇒ ↓ blood fibrinolysis and proteolysis in tissues at inflammation, extensive damage Indications (treatment and prophylaxis): • bleedings caused by hyperfibrinolysis (after the operations on the prostate, lungs, lung embolism and amniotic fluids, lipid embolism at polytraumas; posttraumatic; after the extracorporal circulation; before, during and after the births; at the thrombolytic therapy, etc.) • acute pancreatitis, pancreonecrosis, chronic recurrent pancreatitis • angioneurotic edema • severe forms of shock (endotoxic, traumatic, burn, hemorrhagic) • extensive and deep damages of tissues (pneumonias, lung destruction, burns) • diseases of the joints (intra-articularly) Dosage: individually, depending on indications and clinical situation; i.v. by bolus or droply (lying on the back!). On the average the initial medical dose = 500,000 KIU/hr, maintaining = 50,000 KIU/hr. The activity can be expressed in U, kallikrein-inactivating units (KIU), in trypsin inactivating units (TIU) and in the antitrypsin units (ATU) Adverse effect: CVS: arterial hypotension and/or tachycardia allergic reactions: skin rash, urticaria, rhinitis, conjunctivitis, bronchospasm, symptoms of anaphylactic reactions up to development of anaphylactic shock CNS: psychotic reactions, hallucinations, mental confusion GIT: with rapid introduction — nausea, vomiting local reactions: at prolong infusion — thrombophlebitis embryotoxicity

86 PROAGGREGANTS

Calcium chloride and gluconate Mechanism of action: calcium participates in aggregation and adhesion of platelets, and also assists in thrombin and fibrin formation (↑ formation of thrombocytic and fibrin blood clots) Indications: • as an agent decreasing vascular permeability, at hemorrhagic vasculitis • as a hemostatic with pulmonary, gastric, nasal, uterine bleedings, and before the operation • with bleedings associated with ↓ Ca2+ in the blood plasma (after citrate blood massive transfusion, plasma substitutes) Adverse effects: with rapid i.v. introduction there is heat sensation (“a hot injection”); cardiac arrest, ↓ ABP is possible; at subcutaneous administration of calcium chloride — necrosis of tissues

PROAGGREGANTS

Serotonin adipinate, adroxone (product of adrenalin oxidization) Mechanism of action: serotonin, adrenalin ↑ aggregation of platelets, cause vasoconstriction, which stimulates appearance of thrombocytic blood clots; ↑ strength of capillaries; serotonin also ↑ formation of thrombin Indications: • parenchymatous and capillary bleeding with operations and traumas • thrombocytopenia and thrombocytopathies • hypo- and aplastic anaemias, Willebrand’s type I disease, Werlhof’s disease, hemorrhagic vasculitis Adverse effects: serotonin adipinate — with rapid introduction pain along the vein rout; stomach pain, heart pain, ↑ ABP, nausea, diarrhea, ↓ diuresis

87 -antiplasmin) ) 2 Antiactivators α ( protease, System of urokinase fibrinolysis XIIa, thrombin, Plasmin (fibrinolysin Plasminogen (profibrinolysin) a ІІІ Heparin X (heparin cofactor II, antithrombin fibrin Stabile Fibrinogen Endothelium Fibrin-polymer Fibrin-monomer ntithrombin III + А а ANTIHEMOSTASIS hrombin Hirudin Т 2+ Xa Са Va Antithrombotic factors III, activators of plasminogen, antitrypsin, C-inhibitor, protease-nexin, etc.) PL , 2 issue factor VII (blood flow Т hrombin т Protein S 2+ Prothrombin hrombomodulin + Т Са IXa VIIIa XIa PL XIIa Activated protein C К

Contact activation XII PK HMK Indirect Витамин Protein C anticoagulants thrombomodulin, protein C, S) Thromboresistance of vessels and hemodilution, smoothness of endothelium, fibrin monolayer, heparinoids, RgI

88 ANTITHROMBOTIC DRUGS

♦ Anticoagulants: direct action: heparin and it low-molecular fractions (fraxiparin, enoxaparin, dalheparin, etc.), sulodexide, hirudin and its drugs, sodium citrate indirect action: cumarin derivatives (neodicumarin, sincumar (acenocumarol), warfarin, fenprocumarol), indandion derivatives (phenilin) ♦ Fibrinolytic: direct action: fibrinolysine, heparin, trнpsin indirect action (activating profibrinolysin): streptokinase, streptodecase, urokinase, alteplase ♦ Antiaggregants: ACA, dipyridamol, pentoxyfyllin, ticlopidin, clopidogrel (plavix), reopro, lamifiban, thyrofiban

ANTICOAGULANTS OF DIRECT ACTION

Heparin and its low-molecular fractions (fraxiparin (nadroparin), enoxaparin, dalheparin, etc.), sulodexide; hirudin (desulfatohirudin) and its preparations (hiruten, hirulog); sodium citrate, etc. Classification by the mechanism of action Inhibitors of thrombin (factor IIa): • direct (specific), i.e. acting independently on antithrombin III (selectively and reversibly binding with the active center of thrombin, remove all its effects: transformation of fibrinogen into fibrin, ↑ factors V, VIII, XIII, aggregation of platelets): hirudin (polypeptide of leech saliva) and its drugs • indirect (in complex with antithrombin III): heparin nonfraction and drugs of its low-molecular fractions

89 HEPARIN

Glycosaminoglycan is a mixture of fractions of sulfatated mucopolysaccharides with the different length of polymeric chain from 3,000 dalton (low molecular) to 40,000 (highly molecular); is released in 1916 from the liver (hepar), is in the secretory granules of mast cells 1 2 345 6 7

iduronic glucuronic glucosamine acid acid Only 30% of heparin has the biological action and affinity to antithrombin, which have a pentasaccharide active center (glucoronic, iduronic acids, glucosamine). The strong organic acid (because of residues of sulphuric acid and presence of carboxyl groups) ⇒ very strong negative charge ⇒ it is anionic polyelectrolyte Sources of origin • Preparation of nonfraction heparin (NH) from the mucous membrane of intestine of pork and lungs of the cattle (dose in U); pork is more active; sodium and calcium salts are identical by activity (the sodium one causes less adverse reactions — haematomas at the site of injection) • Drugs of low molecular weight heparin (LMH) by depolymerization from NH Pharmacodynamics • Binding with antithrombin III (AT III), sharply ↑ its activity (1,000 times as much) ⇒ inactivation of thrombin (IIa), prothrombinase (Xa), IXa, XIa, XIIa, plasmin and kallikrein ↓ proteolytic activity of thrombin and other enzymes (factor XIII), stabilizing fibrin (especially in veins) • Due to strong negative charge it binds with receptors on intimae of vessels and platelets (+ ↓ thrombin) ⇒ ↓ platelet aggregation • Heparin only catalyzes the antithrombin-protease reaction, remaining intact: after completion of the reaction releases from the complex IIa + ATIII + heparin and may be used again, and the complex IIa + ATIII is deleted by the endotelial system • In ATIII absence — resistance to heparin • For ↓ thrombin high molecular fractions are necessary — at NH antithrombotic and anticoagulant action; for ↓ of the factor Xa — low-molecular fractions ⇒ LMH drugs have the antithrombotic action and do not practically influence coagulation

90 PHARMACODYNAMICS OF HEPARIN

A variety of effects is conditioned by its high reaction ability as polyanion: ↓ many enzymes (plasmin, trypsin, kallikrein, phosphatase, pepsin, etc.), stabilization of endothelium, etc. • Antiatherosclerotic — “clarifying effect”, i.e. ↓ atherogenic substances: ↑ lipoproteinic lipase (hydrolysis of triglycerides with the complement of chylomicrons and VLDLP); ↓ proliferation and migration of endothelial and smooth cells of vascular wall • Hypoglycemic, antitoxic • Immunosupressive (disturbances of T- and B-lymphocytes cooperation, ↓ system of complement) • Anti-inflammatory, analgesic, wound-healing, antiallergic (↓ hyaluronidase, ↓ vascular permeability, antagonist of histamin, serotonin, adrenalin) • Diuretic potassium-saving (↓ excessive synthesis of aldosterone) • Vasodilating, coronarodilating (↓ tonus of resistive and coronary vessels) • Angioprotective

PHARMACOKINETICS OF HEPARIN

Introduction: i.v. (bolus and infusion — with the medical purpose), s.c. (in to the area of the abdomen — prophylactics), and also inhalation, transdermal; in the GIT inactivates Bioavailability: at s.c. NH — 15–20%; LMH — 90% Beginning of the action: at i.v. — immediately, at s.c. — in 30 min; the effect lasts for 4–5 hrs; LMH — 8–12 hrs Distribution: in blood it binds with the heparin-neutralizing proteins; rapidly (especially at i.v.) is uptaken by endothelial vessels, by macrophages, from where releases gradually; at s.c. binds more firmly + by other cells ⇒ level in the blood is more stable; LMH binds to proteins of blood, endothelium, cells to less degree Biotransformation: in the cells of endothelium and macrophage, and then and in the liver by heparinase depolymerizes Excretion: unchanged and depolymerized by the kidneys, ≈ ≈ Tel1/2 1 hr (LMH 1.5–4.5 hrs)

91 HEPARIN APPLICATION

• Treatment of acute thrombosis (especially venous) and embolia (acute myocardial infarction, preinfarction angina, thrombosis of pulmonary artery, cerebral arteries, renal veins, ileocecal vessels, thromboembolia at pregnant woman, stage of hypercoagulation of DIC- syndrome, etc.) — bolus i.v. 5,000–10,000 IU, then droply 900 IU/hr or factiously — each 4 hrs 75–100 IU/kg (at the beginning the daily dose = 60–90 thousand IU, then — 30–35 thousand IU) • Prophylaxis of thrombosis (operations, diagnostic procedures on vessels, heart, pelvic organs, lower extremities; hemodialysis, pulmonary circulation; IHD, heart failure; after births, burns, frost-bites, sepsis, at traumatic shock, etc.) — s.c. by 5,000– 10,000 IU each 8 or 12 hrs • Locally: thrombophlebitis of superficial veins, chronic varicosis, aseptic infiltrates, etc. (lioton, heparin ointment) • In the complex therapy of patients suffering from bronchial asthma, rheumatic fever, hyperaldosteronism, glomeruloneph- ritis, atherosclerosis, etc.

HEPARIN APPLICATION Optimum therapy ♦ Activated partial thromboplastin time (APTT) — ↑ of the normal (27–35 sec) 1.5–2 times as much is possible ♦ Time of blood coagulation — ↑ of the normal (5–7 min) 2–2.5 times as much Peculiarities of LMH drugs • They have antithrombotic action (do not effect coagulation); provide local thrombolysis (↑ elasticity of erythrocytes, ↓ migration of leukocytes, ↑ tissue activators of plasminogen); do not influence platelet aggregation • ⇒ prophylaxis of venous thrombosis in orthopedic, surgical, neurological, therapeutic patients and the first aid at acute pulmonary thromboembolism • Advantages of pharmacokinetics (is more predictable ↑ bioavailability, prolongation of action) ⇒ are administered s.c. 1–2 times a day without blood coagulation indices control • Rarer cause bleeding and thrombocytopenia

92 ADVERSE EFFECTS OF HEPARIN

♦ Hemorrhage (in 10–30% patients, often from operation wounds and retroperitoneal haematomas, haematomas at the site of injections), thrombocytopenias (in 6–16% patients; in connection with immunogenicity of NH; sometimes severe so-called “syndrome of white blood clots” — intravascular platelet aggregation and arterial thrombosis) ♦ At ↑ sensitivity allergic reactions (anaphylactic shock, hyperthermia) ♦ In case of prolong intake (over 5 months) alopecia, osteoporosis (↑ parathyroidin, osteoclasts), nausea, vomiting, diarrhea At severe bleedings i.v. slow introduction of heparin antidote — protamine sulfate (protein obtained from sperm of salmon and other types of fishes); 1 mg neutralizes 100 IU heparin

INDIRECT ANTICOAGULANTS

♦ Derivatives of coumarin — neodicumarin, syncumar (acenocumarol, thrombostop), warfarin, fenprocumarol ♦ Derivatives of indandione — phenylin Pharmacodynamics • Antagonists of vitamin K (antivitamins): disturb the vitamin K epoxide renewal in hepatic microsomes ⇒ ↓ carboxylation of factors II VII, IX, X, and also proteins C and S, i.e. indirectly ↓ coagulative hemostasis • ⇒ act only in vivo, they are effective at the venous thrombosis Phylloquinone- monooxygenase

Vitamin K Hepatic microsomes Vitamin K epoxide Vitamin K epoxide reductase Indirect anticoagulants

93 INDIRECT ANTICOAGULANTS

Pharmacokinetics Absorption: in the small intestine is good (80–90%) — oral introduction Binding with proteins: 90%! Beginning of the action: half-elimination of supressed blood coagulation oppressed factors is prolong — the action of drugs develops in 8–72 hrs, is long-term and lasts for 24–72 hrs after withdrawal! Biotransformation: in the liver due to the microsomal oxidizing (R450); enterohepatic circulation is common to some of them Excretion: by kidneys, T1/2 is different: 2 hrs (neodicumarin), 42 hrs (warfarin) Cumulation: in majority is pronounced The indirect anticoagulants often interact (pharmacokinetically and pharmacodynamically) with other drugs and change their effect at different diseases

INDIRECT ANTICOAGULANTS

Interactions causing ↑ effect ↓ effect Pharmacokinetic Pharmacokinetic ↓ elimination: amiodaron, ↑ elimination: adsorbents, cimetidine, disulfiram, inductors of microsomal metronidazole, myconazole, oxidation of the liver trimethoprim/sulfametoxazole (barbiturates, rifampicine) ↓ binding with albumen: ↓ absorption: cholestiramine phenylbutazone Pharmacodynamic Pharmacodynamic ↑ vitamin K synthesis inhibition: Diuretics, vitamin K cephalosporins of the III and Factors of an organism: IV generations — additional inherited resistance, hypothyroidism, influence on hemostasis: hyperlipidemia aspirin, heparin; diseases of the liver, thrombocytopenia, deficit of vitamin K ↑ need in vitamin K: clofibrate, thyreotoxicosis

94 INDIRECT ANTICOAGULANTS

Indications Prolong therapy for preventing and treatment of venous thromboses ♦ Prevention of systemic embolization at presence of: thrombophlebites of deep veins of extremities, phlebothromboses; valve replacement; IHD, atrial flutter fibrillation; severe heart failure; schemic strokes; rheumatic defeat of the heart; atherosclerosis of coronary and other vessels ♦ Treatment of acute pulmonary thromboembolism or its relapses ♦ Prevention of idiopathic thrombosis and hereditary predisposition to it ♦ Congenital and acquired coagulation factors deficit

INDIRECT ANTICOAGULANTS

Adverse effects Treatment by indirect anticoagulants is a difficult task for a doctor (prothrombin index = 40–50, 2 times a week!). Treatment is strictly individual! ♦ Bleedings (0.9–2.7%), hemorrhage ♦ More seldom — diarrhea, hepatitis, vasculitis, eczema, necrosis of the skin, alopecia, syndrome of “blue fingers of feet” ♦ Idiosyncrasy to coumarins ♦ Teratogenicity Antidote — drugs of vitamin K, if necessary — blood transfusion Principles of administration ♦ Immediate result — anticoagulants of direct action ♦ Prolong treatment — anticoagulants of indirect action ♦ Combination: direct anticoagulants, in 2–4 days — of indirect action

95 FIBRINOLYTICS

• Direct — fibrinolysin, heparin, trypsin • Indirect (activating profibrinolysin) — streptokinase, streptodecase, urokinase, alteplase Pharmacodynamics It helps dissolute fibrin blood clots — thrombolysis (venous ones lyze better than arterial ones) External mechanism of Internal mechanism of activation activation (tissue activators) (plasma activators) Plasminogen Tissue activator of plasmino- + + (profibrinolysin) Complex “factor XIIa + gen (t-PA), renal urokinase, from kallikrein + HMK”, bacteria (streptokinase) activated proteins C + S

Indirect fibrinolytics Plasmin (drugs on the basis of (fibrinolysin) activators) Thrombin (IIa) Fibrinopeptides Products of Fibrinogen Fibrin disintergration (products of proteolysis)

FIBRINOLYTICS

Drug SourceMolecular Affinity Note weight to fibrin Fibrino- Blood of a man 75,000– + Liquidates only fresh lysin 120,000 fibrin blood clots in veins, is rarely used Strepto- Beta-hemolytic 47,000 – Antigen properties kinase streptococci ⇒ allergy, tolerance to a drug

Anistre- Acylated complex 139,000 + The same plasa of streptokinase and plasminogen

Uro- Renal tubules cell 33,000 + It lacks antigen kinase epithelium cultures properties

Alte- Recombinant 70,000 + The same plasa tissue plasminogen activator

96 FIBRINOLYTICS

Indications ♦Acute myocardial infarction (first 4–6 hrs) ♦Pulmonary thromboembolism (5–14 days) ♦Peripheral arterial thromboses ♦Thrombosis of the central vein of the retina, hepatic, renal and other veins, except for the lower extremities ♦Thrombosis of additional vascular shunts, valve prostheses Adverse effects • Bleedings ⇒ control of prothrombin time, APTT (↑ twice), level of fibrinogen, platelet number; combine with heparin, ASA • Allergic reactions: nonspecific reactions on protein (hyperemia of the face, pain along the vein route, as well as retrosternal and stomach pain), fever, urticaria • Arterial hypotension

ANTIAGGREGANTS

Initiators and activators Platelet aggregation of platelet aggregation inhibitors Collagen – АDP Adenosin and its stabilizators α α Noradrenalin (through 2) 2-Adrenolytics Serotonin Antiserotonin drugs Histamin Antihistamin drugs Thrombin Heparin Calcium ions Calcium channel blockers cGMP and its inductors cAMP and its inductors (through β-adrenoreceptors and PDE inhibitors) Arachidonic acid Dextranes, protein

Thromboxane A2 Prostacycline I2 97 ANTIAGGREGANTS

♦ ↓ synthesis of thromboxane A2: COX inhibitors (ASA (small doses!), aspirin-cardio (325 mg); inhibitors of thromboxanthine synthetase (dasoxyben) ♦ Blockers of receptors on platelets: ADP (ticlopidine, clopidogrel (plavix)); FTA (ketotifen, drug of Ginkgo biloba — tanacan); serotonin (ketanserin), glycoprotein type IIb/IIIa (reopro, lamifiban, thyrofiban, xemilofiban, etc.) ♦ Inhibitors PDE + adenosine desaminase (↑ contents of cAMP and adenosin in platelets): dipyridamol, pentoxyphyllin ♦ ↑ activity of the prostacyclin system (↑ prostacyclin receptors): epoprostenol

ANTIAGGREGANTS

Collagen Endothelium Vascular wall

Defect Vaso- Blood constriction PGI2 Prostacycline АSA

Platelets at the stage of ТХА2 viscid metamorphosis 5-НТ Tanacan АDP IIa/IIIb Platelet FTA activation Fibrino- ТХА2 gen 5-НТ Thrombin АDP

Lamifiban Ticlopidil Dipyridamol

98 ANTIAGGREGANTS

Indications ♦ Prophylaxis of clot formation ♦ Valve replacement, vascular shunting ♦ IHD, disturbances of cerebral, peripheral circulation, Raynaud’s disease ♦ For DIC-syndrome prophylaxis at infectious toxicosis, septicemia (shock) ♦ Dehydration, hemodialysis Adverse effects • Bleedings, thrombocytopenia • Leukopenia, anaemia, erythrocyte hemolysis • Dyspepsia, ulcerogenicity, hepatitis (ASA, cyclopidin, pentoxyphyllin) • Reddening of the face, dizziness, headache, tachycardia • Allergy, etc.

99 Раrt VII DRUGS AFFECTING IMMUNITY

Topic 23 IMMUNOTROPIC AND ANTIALLERGIC DRUGS

IMMUNITY

Delivery of AG ⇒ subsequently join: ♦ Unspecific (congenital, natural): • mechanical barriers (skin, mucous, secrets) and physiological factors (sneezing, vomiting, etc.) • chemical and biochemical reactions, that supress development of infection in organism (lysozyme, lactoperoxidase, low acidity of secrets, etc.) • cellular component: mononuclear phagocytes (monocytes, tissue macrophages), granulocytes (neutrophils, eosinophils, basophils), killer cells — natural (NK-cells), just killer (C-cells), lymphokin-activated killer (LAK-cells) • humoral component: natural antibodies (AB), system of complement (group of serum proteins for deleting extracellular forms of pathogen, mediating the reactions of humoral immunity and fagocytosis), protein (properdin, β-lysin, lactoferin, interferons, etc.) ♦ Specific (acquired, adaptation): • cellular component (system): T-lymphocytes • humoral component (system): B-lymphocytes, plasmic cells (plasmocytes) and produced by them specific AB (immunoglobulins)

100 SPECIFIC IMMUNE RESPONSE

• Cellular — T-system — cytotoxic (killer) destruction of genetically different cells and tissues (foreign grafts, cancer, virustransformed cells): T-system includes thymus (site of differentiation of T-cells’ medullar predecessors), subpopulations of T-cells (T-helpers/inductors (CD4), T-killers/ supressors (CD8), a group of cytokines produced by them basic functions: cytotoxic reaction (cytotoxic T-lymphocytes (CTL; CD8 T-cells); reaction of hypersensitivity of slow type (CD4 T-cells of inflammation — Th1); reaction “the graft against the host” (CD8, CD4); graft rejection reaction; and also immuno- logical memory, supression or B-cells stimulating • Humoral response as the AB (immunoglobulins) secretion — by B-system — protection against bacteria and their toxins: B-lymphocytes (generation in the marrow) transform into plasmocytes — active AB producers, executing the following functions: AG neutralization, opsonization (joining AG ligands, facilitating its phagocytosis) of bacteria, ↑ system of complement

THE SCHEME OF CELLULAR AND HUMORAL IMMUNITY

AG recog- Clonal Differentia- Immune  nition proliferation tion effects  Native Small  AG lymphocyte  Аntigenreactive  T-cell from Accumula-  thymus tion of cells at the site of  response  -lymphocytes  Т Мitosis 

Мitosis T-helper effects Binding  with AG  T-supres-  sor effects  A predecessor Macro- of antibody-  phage forming cell  Antibody- Plasmic forming cell Immuno- 

cell -lymphocytes globulins  В Superficial AG Specific AB  A memory cell secretion 

101 CYTOKINES

Cytokines Properties Interferons α (leukocytic) and Antivirus and antiproliferative (anticancer) β (fibroblast) Interferon-γ Immunomodulating (↑ macrophages, all types of (lymphocytic) cytotoxicity; ↑ cellular and autoimmuny, ↓ humoral); synergist of tumor necrosis factors (TNF); weak antiviral Interleukin-1 Stimulates endogenous pyrogen and growth of the marrow; a mediator of inflammation Interleukin-2 Stimulates T-cells proliferation and their activating to the “killer cells” Interleukin-3 Stimulates early predecessors in the marrow; “multi CSF” Interleukin-4 Stimulates proliferation of AG-activated B- and T-cells Interleukin-5 Stimulates proliferation of eosinophils Interleukin-6 Stimulates plasmocytes and early predecessors of the marrow Interleukin-7 Stimulates differentiation of early cellular predeces- sors Interleukin-8 Neutrophil hemotaxis factor Interleukin-9 Mast cell growth factor Interleukin-10 Suppression of immune response Tumor necrosis factors Stimulators of cytotoxicity, interleukins, (TNF) α and β granulocytes, endogenous oxidants, apoptosis of tumor and other cells; endogenous pirogens; ↑ adhesins, collagenase, procoagulants, factor of platelet activation, fibrogenesis; ↑ granulematosis, angiogenesis; contrinsular; hypercatabolism; cachexy; α — a mediator of pre-immune response and septic shock; β — a mediator of cytotoxic lymphocytes and granulocytes

Colony-stimulating factor of Stimulates proliferation, differentiation of granulocytes-macrophages granulocytes, neutrophil monocytes-macrophages, (GM-CSF)) eosinophils Colony-stimulating factor of Stimulates proliferation and differentiation of granulocytes granulocytes (G-CSF) Colony-stimulating factor of Stimulates proliferation and differentiation of macrophages (M-CSF)) monocytes-macrophages

102 EFFECTORS OF IMMUNE RESPONSE

Effectors Secreted products T-lymphocytes Interleukin-4 (IL-4) in T-helpers; (do not stick on the glass; γ-interferon in T-supressors spontaneously form “rosett” with sheep erythrocytes) В-lymphocytes (stick on the Specific the AB of class M (IgM); glass; form “rosett” ? interferon with sheep erythrocytes, covered with AB and complement) Plasmic cell Specific AB of classes IgG, IgA, IgM, (from B-cells) IgD or IgE; interferon

H2-histamin- AG-histocompatibility Receptor of complement receptor

tеtа-АG AG binding receptors receptor AG T-lymphocyte B-lymphocyte Plasmocyte

IMMUNOPHARMACOLOGY

A medicobiologic discipline, studying relationship of medicinal drugs with the immune system of an organism of a man and animals (the III International Congress of Pharmacologists, 1968) Types of immunocorrection Specific and unspecific

stimulating replacement suppressive

infections, immuno- allergy tumors deficits

103 IMMUNOMODULATORS

Immunocorrecting drugs, agents of chemical or biological nature which modulate (stimulate or supress) the reactions of immunity due to influence on the immunocompetent cells, processes of their migration or on interrelation of these cells and their products (lymphokins, AB) with the proper targets

Mainly immunostimulators Mainly immunosupressants Phenomenon of “pendulum” is an opposite influence on immunity of the same preparation (azathioprine, mercaptopurine, cyclophosphamide, dactinomycin, etc.) On the final effect influence the following things: dose and scheme of drug introduction initial immune status genetic features of an organism biological type (a human, an experimental animal)

CLASSIFICATION OF IMMUNOSUPRESSANTS • Antimetabolites: mercaptopurine*, azathioprine*, methotrexate*, brecvinar, allopurinol*, etc. • Alkylating substances*: cyclophosphamide, chlorbutin, etc. • Antibiotics: cyclosporin A*, tacrolymus (FK 506), rapamycin, chloramfenicol, anticancer* (mitomycin, bleomycin, actinomycins: dactinomycin, daunorubicin) • Alkaloids*: vincristin, vinblastin • Glucocorticosteroids: hydrocortisone, prednisolone, dexamethasone, etc. • Glucocorticoids: hydrocortisone, prednisolone, dexamithasone • Antibodies: antilymphocytic globulin (ALG), antithymocytic globulin (ATG), monoclonal antibodies (OCT-3, zenapax), etc. • Derivatives of different chemical groups: NSAIDs (ASA, para- cetamol, voltaren, naproxen, etc.), enzymatic drugs (asparagi- nase*), derivatives of 4-aminocholine (chloroquine), salazopyridazine*, heparin, aminocapronic acid, drugs of aurum, penicilamine, etc. * — used as anticancer drugs too

104 SITES OF IMMUNOSUPRESSANTS APPLICATION

AG recognition 12345 Antimetabolites

12345

Antilymphocytic 12345

12345

globulin and 12345 12345 12345Prolifer- monoclonal AB 12345 12345 12345 12345 ation 12345 12345

12345 12345         Differentiation Alkylating Antibiotics and synthesis T-cells or AB Interaction + complement Gluco- AG corticoids NB! Pharmacology of some groups is presented in the Topic 22 Tissue rejection NSAIDs

INDICATIONS TO IMMUNOSUPRESSANTS

Disease Drugs Autoimmune Idiopathic thrombocytopenic Prednisolone, vincristin, sometimes mercaptopu- purpura rine or azathioprine, high doses of gamma- globulin Autoimmune hemolytic Prednisolone, cyclophosphamide, mercaptopu- аnemia rine, azathioprine Acute glomerulonephritis The same Different “autoreactive” Prednisolone, cyclophosphamide, azathioprine, disorders cyclosporine Isoimmune Hemolytic anaemia of Rh0(D)-immunoglobulin newborns Transplantation of organs Kidneys Cyclosporine, azathioprine, OCT-3, ALG Heart OCT-3, dactinomycin, cyclophosphamide Liver Cyclosporine, prednisolone Bone marrow ALG, irradiation, marrow of the donor, etc.

105 ADVERSE EFFECTS OF IMMUNOSUPRESSANTS

Early ♦ Dysfunction of the marrow ♦ Dysfunction of the GIT ♦ Predisposition to infections ♦ Allergic reactions Late ♦ Carcinogenic (cytostatics) ♦ Disturbance of the reproductive function (10–70%) and teratogenicity ♦ Growth inhibition in children ♦ Others: syndrome of hyperpigmentation, lung fibrosis, hemorrhagic cystitis, alopecia; hepatotoxicity (antimetabolites), neurotoxicity (alkaloids of periwinkle)

CLASSIFICATION OF IMMUNOSTIMULATORS

By origin • Endogenous and their synthetic analogs: drugs of thymus (thymalin, thymogen, tactivin, thymactide, vilozen, imunofan), red marrow (myelopide), placenta (extract of placenta) immunoglobulins: immunoglobulin human normal (intraglobin, sandoglobin, oktagam, immunovenin, vigam, etc.), immunoglobulin human antistaphylococcal (cytotect) interferons: recombinant interferon-gamma (gammaferon, imukin, immunoferon) interleukins: recombinant interleukin 1-β (betaleukin), recombinant interleukin-2 (proleukin, roncoleukin), recombinant interleukin 1-beta (betaleukin) growth factors: recombinant human granulocyte-macrophageal colony-stimulating factor (molgramostim) regulator peptides: taftsin, dalargin

106 CLASSIFICATION OF IMMUNOSTIMULATORS

By origin (continuation) • Bacterial origin and their analogs: vaccins (BCG, etc.), extracts (biostim), lysates (bronchomunal, imudon, rinovac, respivax), lipopolysaccharides of the cellular wall (pirogenal, prodigiosan, licopide), combination of ribosomes and fractions of the cellular wall (ribomunil), fungal (bestatin, etc.) and yeast polysaccharides (zimozane, sodium nucleinate), probiotics (linex, blasten) • Synthetic: purine and pirimidine (methyluracil, pentoxil, isoprinozine, diucifon, etc.), derivatives of imidazole (dibazole), inductors of interferon (cycloferon, amyxin, neovir), polyoxidonium, etc. • Vegetable origin and their analogs: adaptogens (drugs of echinacea (immunal), eleuterococcus, ginseng, rhodiola rosea), others (aloe, garlic, kidney beans, onion, cayenne, etc.) • Other classes: drugs of vitamins C, A, E; metals (zinc, copper, etc.)

CLASSIFICATION OF IMMUNOSTIMULATORS By the mechanism of action Group Drugs Mainly stimulating Anabolic of nonsteroid (methyluracil, unspecific factors pentoxil, etc.) and steroid structure, of defence drugs of vitamins A, E, C; vegetable

Mainly stimulating mono- Sodium nucleinate, zymozan, cytes (macrophages) vaccins (BCG, etc.), pyrogenal, prodigiozan, biostim Mainly stimulating Dibazole, thymalin, tactivin, T-lymphocytes thymogen, drugs of zinc, interleukins (IL-2) Mainly stimulating Myelopid, taftsin, dalargin, B-lymphocytes bestatin, amastatin, etc. Mainly stimulating Interferons, antiviral drugs NK and K-cells (isoprinozine), extract of placenta

107 INDICATIONS TO IMMUNOSTIMULATORS

♦ Primary (hereditary) immunodeficiency ♦ Secondary immunodeficiencies (more frequent of T-system): • at viral (measles, rubella, flu, epidemic parotitis, viral hepatitis, AIDS), bacterial (leprosy, cholera, syphilis, tuberculosis), mycotic, protozoal (malaria, toxoplasmosis, tripanosomosis, leishmaniosis) diseases, helminths • at tumors of lymphoreticular origin (reticulosarcoma, lymphogranulematosis, myeloma, lymphosarcoma, chronic lympholeukosis, etc.) • as a result of pathological processes accompanied by hypoproteinemia (renal disease, burn disease, diabetes mellitus, chronic hepatitis, severe traumas, chronic stress, etc.) • as a result of drug usage (immunosupressants depressing CNS, anticoagulants, etc.), alcohol, ionizing radiation, pesticides • in newborn children and children of first years of life (immaturity of the system); as a reault of aging

PRINCIPLES OF IMMUNOCORRECTION

• They are used in complex with ethiotropic and pathogenetic pharmacotherapy • In case of absolute expedience in immunotherapy it is necessary to estimate the character and degree of immunological disturbances • Choice of a drug or drug combination with taking into account the direction of their action (activation, supression, modulation), degree of selectivity in vitro to immunocytes of a definite patient and mechanisms (a “pendulum” effect) • Definition of optimum dose of drug, intake rate, ways of introduction, duration of course with taking into account the age of a patient, sex, neuroendocrinic, genetic features, biological rhythms, concomitant pathology, etc. • They combine immunotropic drugs, affecting only different components of the immune system

108 PRINCIPLES OF IMMUNOCORRECTION

• Taking into account immunotropic effects of accompanying therapy • Providing for adverse effects, as well as a possibility of change of immunomodulators’ spectrum of action in a definite patient • Manifestation of clinical effect ↑ in patients at the acute period of disease or in severe condition and with multiple introduction • To remember that the removal of deficit of one component of immune system compensates stimulating the other • One should not draw hasty conclusions about efficiency of immuno- therapy (it is necessary from 30 days to half-year and more) • For the complete recovery, ↓ relapses rate and chronization process a timely repeated immunological inspection is necessary, and if necessary — treatment • Efficiency of immunotherapy ↑ with the usage of vitamins, microelements, adaptogens, enterosorbents

ALLERGY

1906 Clemens PIRQUET gave definition of allergy for the first time: “Vaccinated in relation to the vaccine, syphilitic — to the causative agent of syphilis, tuberculous — to the tuberculin react differently than individual which does not meet with this antigen. However, it is very far from the condition of insensitivity. Its reactivity is changed. For this general notion of changed reactivity I propose a term allergy” C. Pirquet

109 ALLERGY

Manifestation in an organism of increased perverted sensitivity caused by reaction of antigens and antibodies interaction Allergy — is a hand-made illness! About 10% of population of developed countries suffer from pronounced allergic diseases; 50% — have transient symptoms of allergy

A fantasy writer V. Yefremov predicts at our days, “...that even when all the diseases will be defeated, still unconquered allergy will life-threaten to a handful of the mankind survived in a hard struggle”

CLASSIFICATION OF ALLERGIES

• IMMEDIATE type reactions — immediate hypersensitivity (IH) (in 20–25 min or some hours (postponed) after influence of a specific antigen): anaphylactic shock, Quincke’s edema, urticaria, some types of bronchial asthma, serum sickness, pollinoses (hay fever), etc.

• DELAYED type reactions — delayed-type hypersensitivity (DTH) (in 24–72 hrs): allergic reactions at infectious diseases (tuberculosis, brucellosis, toxoplasmosis); transplantation of organs and tissues (blood transfusion); contact influence on the skin and mucous chemical substances (contact allergic dermatites); food and medicinal allergy, bites of insects

110 TYPES OF HYPERSENSITIVITY REACTIONS

Type I — reactive (immediate) — acute allergic reactions caus- ed by IgE (on bites, pollen, meal, drugs): anaphylactic shock, Quin- cke’s edema, urticaria, pollinosis, IgE bronchial asthma Ag Mast cell Histamine Type II — cytotoxic — complement-dependent reaction IH, caused by IgG, sorbed on the cellular surface (bacteria, viru- + comple- ses, drugs — penicillins, etc.): ment autoimmune thrombocytopenia, hemolytic anaemia, hemolytic disease of newborns at rhesus- conflict Тissue cell Lysis

TYPES OF HYPERSENSITIVITY REACTIONS

Type III — immunocomplex — IH Immune complex reaction caused by the damage of tissues Endothelium by the immune complexes (IgG + exogenous AG) with participation of complement and lysosomal enzymes + comple- (viruses, bacteria, drugs — sulfon- ment amides, etc.): serum sickness, Arthus reaction (at the site of injection), glome- Reaction of rulonephritis, rheumatoid arthritis, inflammation systemic lupus erythematosus, etc. Type IV — cellular — DTH reaction mediated by cytotoxins of sensitized T- lymphocytes (bacteria, viruses, etc.): con- tact dermatitis, graft reaction, tubercu- IFN-γ losis, infectious rhinitis, pharyngo- laryngobronchitis, infectious-allergic Тh1 diseases (myocarditis, nephritis), etc. Macrophage Cyto- toxins

111 ROLE OF ALLERGY MEDIATORS

SRS-A Prosta- Reaction Hist- (leukо- Sero- Bradi- glandin amine tonin kinin triens) Е2

Bronchospasm ++ +++ + ++ ++

Intestinal spasm ++ + + ++ +

↑ vascular perme- +++ + ++ ++ + ability

Secretion of glands ++ 0 0 + 0 (bronchial, naso- pharynx)

Dilation of smal +++ 0 Const- +++ Const- vessels, ↓ ABP riction riction

STAGES OF ALLERGY DEVELOPMENT

♦ Immunological stage corresponds to the process of sensitization of an organism at the moment of the primary contact with allergen ♦ Pathochemical stage is a result of repeated contact of immune system with allergen cell “activation” takes place ⇒ its metabolism disorder with ↑ mediators of allergy (histamine, serotonin, bradikinin, heparin, SRS-A and other BAS; totally about 20) ⇒

♦ Pathophysiological stage corresponds to dysfunctions of an ` organism, peculiar to the allergic reaction with its pathomorphologic (↑ permeability of vessels, histohematogenous barriers, inflammatory edema appears) and clinical manifestations

112 PRINCIPLES OF IMMIDIATE HYPERSENSITIVITY TREATMENT

1. Prevention of getting in Antigen 2. Hyposensitization 3. ↓ antibody-formation Аntibody

4. ↓ activity of cell Mast cell (↓ allergy factors activation release) ↑ mediators of inflammation

5. Receptors blocking Receptor

Manifestations 6. Struggle with manifestations of allergy of allergy

ANTI-ALLERGIC DRUGS

♦ For treatment of IMMEDIATE type reactions: • Glucocorticoids • H1-histamine blockers: dimedrol, suprastine (chloropyramine), tavegil, diazoline (mebhydroline), etc. • Stabilizers of mast cells — ketotifen, sodium cromolyn, etc. • Antileukotrienic drugs: leukotriene receptor blockers — zafirlukast, montelukast 5-lipoxygenase inhibitors — zileuton • ↓ damage of tissues — steroid and nonsteroid AIDs • ↓ allergy manifestations (functional antagonists of allergy) — adrenomimetics, spasmolytics (euphyllin), M-cholinergic blockers ♦ For treating of DELAYED-type reactions: • Immunosupressants • ↓ damage of tissues — anti-inflammatory steroid drugs, nonste roid and slow action drugs (chingamine, drugs of gold, dalson, etc.)

113 ANTI-ALLERGIC DRUGS

АG Predecessors  (allergens)   В Lymphocytes Т   Sensitized  lymphocyte Immuno-

 supressants Plasmocyte Macrophage   Humoral Cellular immunity АТ immunity

IН Mast DTH cell Glucocorticoids      Cromolyn, adrena-       line, theophylline,      Gluco- heparin Mediators of  corti-      allergy  Glucocorticoids       coids Histamine blockers             Adrenomimet-      NSAIDs ics, theophylline      Local damage of  General reactions tissues (inflammation) (anaphylactic shock)

ANTI-ALLERGIC DRUGS

Glucocorticoids Mechanism of anti-allergic action • ↓ release of histamine, leukotrienes and other allergy mediators • + immunosupressive and anti-inflammatory actions (refer to Topic 19) Indications • Urgent therapy of severe allergic reactions (anaphylactic shock, Quincke’s edema, angioneurotic edema, urticaria, serum sickness, status asthmaticus, etc.) — a few days in large doses! • Systemic treatment of diseases with an allergic component (bronchial asthma, etc.)

114 HISTAMINE BLOCKERS

Recep- Localization Effects of Blockers tors excitation ↑ Н1 Smooth muscles tonus I generation of bronchial tree (dimedrol Intestine ↑ tonus diprazine, diazoline, Heart ↓ АV ↓ ↑ suprastine, Vessels arteries, veins tavegil, Capillaries ↑ permeability fencarol), Reception of pain ↑ II and III genera- and itching tions (loratadine, СNS Different ceterizine, telfast)

Н2 Gastric glands ↑ secretion Cimetidine, Heart + ino- and chrono- ranitidine, famotidine, Arteries ↓ tonus nizatidine Myometrium Relaxation CNS ↑ emetic, ↓ vasomotor center

HISTORY OF H1-HISTAMINE BLOCKERS CREATION

1907 Histamine was synthesized 1937 Daniele BOVET synthesized the first histamine substance thymoxidiethylamine (The Nobel Prize in 1957)

1940 The first H1-histamine receptor blocker was applied for the first time in clinic D. Bovet 1966 Inheterogenicity of histamine receptors was established

1977 H1-histamine blocker of the II generation terfenidine was introduced into clinical practice 1990-ies The first drug of the III generation fexofenadine (an active metabolite of terfenadine)

115 CHEMICAL STRUCTURE OF H1-HISTAMINE BLOCKERS

Depending on the X-bond there are divied into the derivatives of General formula ethanolamine, ethylenediamine, phenothiasine, quinuclidine, N—X—C—N tetrahydrocarboline, alkilamine, piperazine, piperidine

O COOH N

Dimedrol N Cetirizine CH3

CH —O — CH2 — CH2 — N CH3 Cl

H1-HISTAMINE BLOCKERS CREATION I generation Lipophilic, affect the peripheral and central H1-histamine recep- tors, as well as other types of receptors (M-cholino-, serotonono-, dopamine-) do not have the additional anti-allergic action • Ethanolamine: dimedrol (diphenhydramine, benadril), tavegil (clemastin) • Ethylendiamine: suprastine (chloropiramine) • Phenothiasine: diprazine, promethazine (pipolfen) • Alcylamine: fenastil (dimetinden), feniramine • Quinuclidine: fencarol (hifenadin) • Tetrahydrocarboline: diazoline (mebhydroline, omeril) • Piperidine: ciproheptadine (peritol) Pharmacodynamics ♦ Anti-allergic: concurrent and reversible blockade of H1-receptors (in total ≈ 30%) ⇒ ↓ tonus of smooth muscles of bronchial tubes, uterus, intestine, partly vessels; ↓ permeability of capillaries, hyperemia, itching

116 H1-HISTAMINE BLOCKERS

Pharmacodynamics of I generation ♦ Additional effects: blockade of peripheral M-cholinoreceptors (derivatives of ethanolamine and ethilendiamine) Ю atropin-like effects ⇒ effectiveness at nonallergic bronchites (see below)

blockade of the central H1-receptors and M-cholinoreceptors ⇒ sedative and hypnotic effect; antiemetic, antiparkinsonic action antiserotonin and antidopamin activity (peritol) ⇒ anti-itching action; mental depression α-adrenoreceptors blockade ⇒ ↓ ABP sodium channels blockade ⇒ local anesthetic action (dimedrol, diprazine) blockade of histamine- and serotoninergic links of nociceptive reflexes ⇒ analgetic effect and potentiation of analgetics

Н1-HISTAMINE BLOCKERS

Indications to I generation • Allergic reactions (acute; especially those with histamine as a basic mediator; at the early stages, when histamine receptors are free): anaphylactic shock, Quincke’s edema (parenterally, as an additional mean); allergic rhinitis (episodic symptoms; duration of exacerbations < 2 weeks); urticaria; allergic and pseudoallergic reactions at drugs (prophylaxis and treatment); foodstuffs; serum sickness • Acute respirator viral infection (ARVI), rhinitis (“drying” effect on the mucous membranes): suprastine, dimedrol, pheniramine (+ paracetamol + ascorbic acid = fervex), chlorpheniramine (+ paracetamol + ascorbic acid = antigrippin), etc. • Correction of sleep disorders (↑ falling asleep, depth and quality of sleep, effect no > 7–8 days): doxylamine! • For stimulating appetite: peritol • Air, sea disease: dimedrol, diprazine • Potentiation of analgetics and local anesthetics action (premedication, component of lytic mixtures): dimedrol, diprazine

117 Н1-HISTAMINE BLOCKERS Adverse effects of I generation • Sedative and hypnotic effect ⇒ co-ordination disoders, ↓ attention, stimulation of alcohol and CNS depressants action; toxic doses cause excitement, cramps • Depressive complications • Atropin-like effects: dryness of mucosa, constipation, accommodation disorders, transient tachycardia, etc.) • Arrhythmogenic action (quinidine-like action on the heart), ↓ ABP • ↑ appetite, gastrointestinal disorders (diprazine, dimedrol) • Tolerance (by the 7th–12th day) • Allergic reactions with their usage for more than 7–10 days

Н1-HISTAMINE BLOCKERS II generation

Affect the peripheral H1-histamine receptors, do not cause central effects, have an additional anti-allergic action, cardiotoxic as well • Azatidine: loratadin (claritin, rhinoral) • Piperazine: cetirizine (zirtec, citrin) • Triprolidine: acrivastin (semprex) • Oxypiperidine: ebastin (kestin), levocabastin (gistimet) • Benzymidazole: mizolastine* • Piperidine: terfenadine (seldan)* • Imidazole: astemizole (gismanal)* III generation • Active metabolites of II generation: fexofenadine (telfast, altiva, alegra), desloratadine (erius), norastemizol (sepracor), carebastine, levocetirizine (xizal) * — they are forbidden in some countries

118 Н1-HISTAMINE BLOCKERS

Advantages of II and III generations • Anti-allergic action: high selectivity, non-competitive and more stable bound with H1-receptors + additional effects: stabilization of mast cells; ↓ expression of adhesion molecules and eosinophil induced release of IL-8, GM-CSF and sICAM-1 from the epithelial cells, ↓ pronounced allergen-induce bronchospasm, ↓ symptoms of bronchial hyperreactivity possibility of high doses usage, sufficient for removing daily and nightly symptoms in patients during the blossoming period • Absence of blockade of other receptors types, especially cholinergic ones • Absence of tolerance

Н1-HISTAMINE BLOCKERS

Pharmacokinetics

Absorption: the meal influences the absorption in the GIT (astemi- zole ↓ by 60%, ebastine and loratadine ↑, acrivastine, azelastine and cetirizine does not change); I generation better at pH > 8.0 ⇒ an hour before the meal or 2–3 hrs after the meal; drugs rendering irritating action (diprasen, dimedrol) after the meal; the effect onset with oral intake takes place in 15–30 min; peak of concentration in blood occurs in 1–3 hrs Binding with proteins: 60–90% and more ⇒ 1) at combination a possibility to replace the other drugs; 2) at hypoproteinemia ordi- nary doses can be toxic Distribution: I generation — well pass through the BBB ⇒ central effects (sedative, hypnotic) and placenta — embryo-, phetotoxicity

119 Н1-HISTAMINE BLOCKERS

Pharmacokinetics

Biotransformation: by P450 enzymes in the liver; “first pass elimination” ⇒ with urgent states i.v. or i.m. introduction; dimedrol, suprastine — microsomal oxidation inducers; some II generation drugs form active metabolites ⇒ prolonged action; some of them are prodrugs ⇒ variability of effects of II generation in different people (especially of metabolism) Excretion: by the kidneys and liver as metabolites, ≈ get to the breast milk; T1/2 of I generation 4–8 hrs; II and III generations — 12–48 hrs, the effect can persist about 2 days (diazoline), ↑ 10 days (astimizole); T1/2 with the age, at diseases of the liver and kidneys

Н1-HISTAMINE BLOCKERS

Advantages of II and III generations • Improvement of pharmacokinetics: rapid onset of action (the meal influence on absorption is absent in some drugs) sufficient duration of effect (about 24 hrs and more) more lipofobic ⇒ badly penetrate through the BBB ⇒ central effects are absent Drawbacks of II generation • A possibility of overdose because of inhibition of metabolism; factors of risk — diseases of the liver, hyperkaliemia; simultaneous application with macrolides, antimycotic azoles, anti-arrhythmics, antidepressants, calcium channel blockers, fluoroquinolones, etc.; juice of grapefruit • Cardiotoxicity — fatal arrhythmias (terfenadine, astemizole)

120 Н1-HISTAMINE BLOCKERS

Characteristics of II and III generations • Potentially sedative — cetirizine, loratadine • Potentially cardiotoxic — terfenadine, astemizole, ebastin • Nonsedative and noncardiotoxic — fexofenadine Indications ♦ Long-term therapy of allergic diseases, in genesis of which the mediators of late phase of allergic inflammation play a considerable part: all-the-year-round allergic rhinitis seasonal allergic rhinitis (conjunctivitis) with duration of seasonal exacerbations > 2 weeks chronic urticaria atopic dermatitis allergic contact dermatitis early atopic syndrome at children

Н1-HISTAMINE BLOCKERS

Antihistaminic activity M-cho- Drugs Sedative linolytic Irritating Rate Force Duration, effect hrs effect action Dimedrol Rapid ++ 3–5 ++ ++ + (s.c.) Diprazine Тhe same ++++ 6–8 +++ +++ + (s.c.) Tavegil « +++ 8–12 + + + (s.c.) Suprastine « ++ 4–6 + + + (s.c.) Diazoline Slowly ++ >24 - - + (per oral) Fencarol Тhe same ++ 6–8 + + + (per oral) Loratadine 30 min ++ 24 + - - Fexofenadine 30 min +++ 24 - - -

121 ANTI-ALLERGIC DRUGS

Stabilizers of mast cells Cromolyn-sodium (intal) and on its basis drugs: sodium nedocromil (tailed), opticorm, lomuzole; ketotifen (zidaten) Mechanism of antiallergic action •↓ synthesis and release of histamine and other mediators of allergy from the mast cells Indications • Cromolyn-sodium: effect in 2–4 weeks of intake ⇒ for ↓ of bronchial asthma attacks rate; prevention of bronchospasm at bronchial asthma, asthmatic bronchitis, pneumosclerosis, etc.; Nedocromyl sodium: bronchial asthma of different genesis (bronchodilating + anti-inflammatory); opticom: allergic diseases of eyes; lomuzole: allergic diseases of the nose • Ketotifen: for treatment of bronchial asthma in adults and prophylaxis of its attacks in children (+ histamine blocking + sedative effect)

FUNCTIONAL ANTAGONISTS

Adrenomimetics Mechanism of anti-allergic action • Activation of adenylate cyclase and ↑ level of cAMP in the mast cell and basophils ⇒ calcium channels do not open ⇒ depress the rise of intracellular concentration and subsequent reactions development • ↓ IH systemis manifestations (↓ bronchial spasm, ↑ vascular tonus, ↑ cardiac activity) Indications Adrenaline: anaphylactic shock Ephedrine, beta-adrenomimetics: removal and prophylaxis of bronchial asthma attacks

122 FUNCTIONAL ANTAGONISTS Xanthines Theophylline, its watersoluble preparation aminophylline, and its prolonged drugs bamiphylline, theophylline-retard, theotard, durophylline, theo-dur, theonova, euphylong, etc. Mechanism of anti-allergic action • Prevent from the outflux of histamine and other IH mediators from the mast cells • ↓ systemic manifestations of IH (a myotropic spasmolytic), refer to Topic 16 • A long-term intake promotes T-supressors formation, inhibiting IgE synthesis Indications Theophylline: injection for removing status asthmaticus, bronchial asthma attacks; in tablets for the prophylaxis of bronchial asthma attacks Prolonged forms: prophylaxis of night attacks of bronchial asthma

TREATMENT OF IMMEDIATE TYPE HYPERSENSITIVITY

Macrophage Glucocorticoids

Proliferation and AT production АB differentiation АG Interaction of cells IgE B-lymphocyte Plasmocyte T-lymphocyte H -histamine blockers 1 AB fixation on β -adrenoreceptor receptors of 2 high affinity Interaction of cAMP histamine and other relaxation mediators with receptors spasm A sensitized mast cell

Bronchiole Mediators of allergy α β β , - and 2-adrenomimetics Cromolyn-sodium, glucocorticoids (symptomatic glucocorticoids, therapy) aminophylline, adrenaline

123 TREATMENT OF DELAYED-TYPE HYPERSENSITIVITY

Macrophage Glucocorticoids Cyclosporin Antimeta- Production Production The T-lym- bolites IL-1 IL-2 phocytes activation AH recognition Proliferation

T-helper

Тс-lymphocyte

АG Interaction Cyclo- sporin Release of with AB cytokines Differentiation

NSAIDs

Тс-lymphocyte Inflammation Glucocorticoids

ANAPHYLACTIC SHOCK

A systemic generalized allergic reaction of immediate type on the repeated introduction of an allergen as a result of rapid massive IgE mediated release of mediators from tissue basophils (mast cells) and basophils of the peripheral blood

Drugs causing shock ♦ Often: vaccines, serums, penicillins (bicillins — 10%, benzylpenicillin — 7%), cephalosporins, streptomycin (6%), organopreparations, local anesthetics (novocaine — 6%), thiamine (3%), contrical, neohemodesis, rheopolyglucin, polyglucin, protamine sulfate, roentgen contrast substances ♦ Rarer: sulfonamides, tetracyclines, polyvitamins, cocarboxylase, folic acid, cyanocobalamine, calcium chloride, dimedrol, heparin, PASA, omnopon, promedol, etc.

124 ANAPHYLACTIC SHOCK

Types • Hemodynamic (critical ↓ ABP) • Asphyxic (bronchospasm, lung emphysema, lung edema) • Abdominal (pain syndrome by acute abdomen type, collapse) • Cerebral (cerebral hemorrhage) • Thromboembolic (thromboses of the heart, brain)

Treatment Symptomatic, directed at removal of cardiovascular collapse, disorders of breathing, internal deficit of blood volume (BV), cramps

ANAPHYLACTIC SHOCK

Treatment • Adrenaline hydrochloride 0.3–0.5 ml of 0.1% solution s.c. at the site of allergen introduction with interval 5–15 min under the ABP control, the total dose — 2 ml • Glucocorticoids in large doses!: if possible i.v. streamly, then droply prednisolone up to 100 mg, dexamethasone 40–80 mg, hydrocortisone 1,000 mg by 300–500 ml of 5% glucose solution or physiological solution + adrenaline (0.1% solution 0.5–1 ml) or mezatone (1% solution 1 ml) • Calcium chloride i.v. 10 ml of 10% solution • Antihistaminic drugs (diprazine 2.5% solution 2–4 ml, suprastine 2% solution 2–4 ml, dimedrol 1% solution 5 ml) • With the presence of indications: Bronchospasm — aminophylline 24% solution 1–2 ml i.v. or 2.4% 10 ml i.m. cardiac glycosides (digoxin i.v. 0.025% 1 ml in 20 ml of physiological solution) pulmonary edema — furosemide i.v. or i.m. 4% solution 2 ml

125 DRUG DISEASE

1824 A. P. NELUBIN published a treatise “Formation of drugs theory”, for the first time he suggested a possibility of drug complexes “drug-protein” formation, called later “haptene” 1834 A. M. FILOMAFITSKY proposed the first classification of adverse effect of drugs, which was the basis for “idiosyncrasy” discovery:

1. Antipathy — when an “ordinary drug has an extremely strong action” 2. Heteropathy — when “external manifestations are unnatural in rilation A. M. Filomafitsky to the general rule of excitability” 3. Apathy — when “excitability is not set into motion by the usual influence”

DRUG DISEASE

1891 Charles RICHET described serum sickness, where the protein allergy became the basis for understanding all other allergies. For the works on anaphylaxia he is awarded with the Nobel Prize (1913)

1901 Ye. A. ARKIN introduced the term “drug disease” and affirmed that it is a complicated set of manifestations but not just medicinal rash

1934 N. V. LAZARYEV published the work “The drug is not poison but a medical preparation”

An academician Ye. M. TARYEYEV gave a nosologic form to the term “drug disease” Ye. М. Таryeyev

126 DRUG DISEASE

We should not be deceived by gaining victories over nature. For every such victory it takes vengeance on us. Each of these victories has, in the first place, those consequences we meant, but in the second and third place, the consequences are quite different, unforeseen, and destroy the value of the first ones very often. F. Engels “Dialectics of nature” Drug disease (DDs) is an original stable reaction, in most cases associated with the specific immunological reaction of an organism on introduction of therapeutic or allowed (small) doses of drugs and manifested by a variety of clinical syndromes

DRUG DISEASE

DDs rate makes 15–50% Annually 2.2 mln of people fall ill, 100,000 die Per se any medicinal preparation can result in drug allergy • 1st place is occupied by antibiotics (33%): penicillins, cephalosporins — 59%, streptomycin — 15% • 2nd place — serums and vaccines (23%) • 3rd place — tranquilizers (14%) • 4th place — hormonal drugs (10%) • 5th place — NSAIDs, sulfonamides • Others — roentgen contrast substances, vitaminic drugs (especially of B group), spasmolytics, quinines, drugs of aurum, local anesthetics, etc.

127 DRUG DISEASE

Causes of development • Conditions of drug application — overdose (absolute, relative, cumulative); excessive local concentration; duration of application; wrong management; self-treatment and administration without taking into account contraindications; polypragmasy, pharmacological incompatibility; toxic admixtures in preparation • Extratherapeutic manifestations of DDs — sensitization (exo-, auto-); acute and chronic intoxication; carcinogenicity; mutagenicity; teratogenicity; complications of corticosteroid therapy (“cushingoidism”, withdrawal syndrome); tropicity of some drugs; ulcerogenicity; disbacteriosis; reflex reactions; tolerance; dependence, etc. • Condition of object of influence (susceptibility): allergic anamnesis: allergic constitution; burdened heredity; specific medicinal sensitization; sensitization by other allergens (drugs is the “main” factor) nonallergic manifestations: genetic enzymopathies; “perverted” metabolism of drugs; diseases of internal organs (liver, kidneys); endocrine diseases; dermatites; tumors; psychoneurotic disorders; alcoholic, narcotic intoxication; pregnancy, etc.

PATHOMORPHOLOGIC MANIFESTATIONS

♦ Allergic: • immediate type: disturbances of vessels (change of tonus, disturbance of permeability, overfilling of organs with blood, hemorrhage, blood clots); spasm and dilatation of bronchiols; infiltration of cells (lymphocytes, eosinophils, plasmic); dystrophic changes of internal organs (turbid swelling, fatty dystrophy) • delayed type: vasculitis, reticuloplasmocytic infiltration of lymphoid apparatus; defeat of the skin (exfoliative dermatitis); the bone marrow (agranulocytosis, hemolytic and aplastic anaemias); viscerites (necrosis of the liver, GIT, etc.); the secondary defeats of organs (medicinal caverns, fistula, scars, etc.) ♦ Infectious defeats: dysbacteriosis; superinfection (candidomycosis, staphylococcosis, hypovitaminosis) ♦ Isolated ulcerous defeats of the GIT: steroidal, aspirinic, butadionic ♦ Other disturbances: adrenal atrophy; manifestation of acute or chronic intoxication; stimulation of tumor growth, etc.

128 CLINICAL FORMS OF DRUG DISEASE

• According to the clinical course: acute and prolong • According to severity: mild, middle, severe • According to outcome: reconvalescence, chronization, death • According to manifestations: allergic complications (local or systemic) nonallergic complications conditioned by the direct pharmacological action of drug (antibioticotherapy, corticosteroid therapy) nonallergic complications conditioned by the adverse action of the drug (nearest, remote) withdrawal syndrome (corticosteroids, insulin, anticoagulants)

TREATMENT OF DRUG DISEASE

• Is based on common principles, but with taking into account the peculiarities of the clinical picture of DDs Bed rest Nonirritating diet with the sufficient liquid Cessation of all the drugs Desensitizing therapy: calcium chloride, antihistaminic drugs, glucocorticoids Specific hyposensitization (however, it is ineffective and is not conducted at pancytopenias) Symptomatic therapy

129 MYTHES AND REALITIES

Myth: During the antibiotics intake it is necessary to administer antihistaminic drugs for reduction of allergic reaction The antihistaminic drugs (except for III generation) have pronounced adverse effects. Besides, they can “slur over” the clinical manifestations of allergy Myth: The children which take antibiotics should be administered diazoline Myth: Diazoline is the safest of drug for children Diazoline is one of the eldest antihistaminic drugs. Its medical effect is not the strongest, but it has a number of side effects, especially for a child’s organism (neurotoxicity). Though there is a child’s form of diazoline (granulate for solution preparing), it is more expedient to choose a more modern and safe drug Myth: It is possible to accept antihistamineic drugs without recommendation of doctor Practically all drugs of I generation render a sedative effect, inhibit the physical and psychical reaction, II generation — cardiotoxic action; they should be taken under the control of doctor. Many antihistaminic drugs strengthen action of some drugs, alcohol Myth: It is possible to take dimedrol at insomnia Dimedrol is an antihistaminic drug depressing CNS and having a number of other side effects; it is impossible to use it as a hypnotic drug Myth: Histamine blockers of II generation are safer and stronger than I generation drugs II generation of histamine blockers has no pronounced sedative effect, but renders strong cardiotoxic action. The medical effect comes slower, but is continuing for a long time. “Claritine” can be considered a safer drug, because it has no cardiotoxic action

130 Part VIII ANTIMICROBIAL AND ANTIPARASITOGENIC DRUGS

Topic 24 DISINFECTANTS AND ANTISEPTICS

GENERALLY ACCEPTED TERMINOLOGY

♦ Disinfectants are drugs applied for removal of causative agents of infectious diseases in the external environment

♦ Antiseptics are drugs applied for removal of causative agents of infectious diseases externally on the surface of body

♦ Chemotherapeutic means are drugs which inhibit vital functions of causative agents in a macroorganism, i. e. those having common (resorptive) action

131 CLASSIFICATION OF ANTIMICROBIAL, ANTIPARASITOGENIC AGENTS

Disinfectant and antiseptic Chemotherapeutic: • antibiotics • sulfonamides • of different chemical structure (derivative of nitrofurane, 8-oxyquinoline, imidazole, quinoxaline, naftiridine, fluorquinolones) • by special indications: antituberculous antihelminthic antisyphilitic antiviral antiprotozoal anticancer antimycotic

CLASSIFICATION OF DISINFECTANT AND ANTISEPTIC DRUGS

• Halogen-containing compounds: preparations of chlorine (chloramine, chlorhexidine, pantocide and etc.) and iodine (alcohol solution of iodine, Lugol’s iodine solution, iodinol, polividone-iodine and etc.) • Oxidants: hydrogen peroxide, potassium permanganate, sodium hypochlorite (amukin) • Acids and alkalines: salicylic acid, ammonia solution, benzoilperoxide, etc. • Phenoles: resorcin, polycresulen (vagotil), etc. • Tars, resins, mineral oils, petroleum processing products: birch tar, ichthammol, naphthalene petroleum, medical ozokerite, vinisol, citral, sulsen, etc. • Aldehydes and alcohols: formaldehyde, cidipol, hexamethilenetetramine (urotropin), ethanol • Compounds of metals: silver nitrate, protargol, copper sulfate, zinc oxide, zinc sulfate, etc. • Dyes: diamond green, ethacridine lactate, methylene dark blue • Detergents and soaps: cerigel, roccal, ethonium, decametoxine, miramistin, green and potassium soap, etc. • Different chemical groups derivatives: nitrofurane (furacilin), thyosemicarbazone (pharingosept), etc. • Drugs of natural origin: garden sage, calendula, camomile, novoimanine, chlorofillipt, ectericide, lisozyme, etc.

132 LAID CLAIMS

Disinfectants ♦ Bactericidal action ♦ Safety for the persons contacting with them ♦ Not to damage processed objects ♦ To be chemically stable ♦ Available for wide application Antiseptic drugs ♦ Bactericidal and bacteriostatic action ♦ Not to cause damage and irritation of tissues ♦ Not to have allergic properties ♦ Not to render the resorptive action ♦ Not to supress the processes of regeneration Chemotherapeutic drugs ♦ Bactericidal and bacteriostatic action ♦ Not to supress basic functions of an organism

COMPARATIVE DESCRIPTION OF ANTISEPTIC (DISINFECTANT) AND CHEMOTHERAPEUTIC DRUGS

Indicator Antiseptic Chemotherapeutic (disinfectant) drugs drugs Basic mechanism Unspecific — microbial Selective of action cell proteins coagulation Antimicrobial Relatively low Relatively high activity Spectrum of anti- Very wide Narrow (on some microbial action species) Character of action Mainly bactericidal Bacteriostatic and bactericidal Toxicity for As a rule, high As a rule, low macroorganism Methods of application Local Resorptive, local Acquired tolerance of Rarely, has no Quickly and to the microorganisms practical value most preparations

133 THE CONDITIONS DETERMINING ANTIMICROBIAL ACTIVITY

Chemical structure, physical and chemical properties Concentration, degree of dissociation pH of the medium Time (exposition) Temperature Type of microorganism, an ability to spore formation Number of microbial bodies Properties of a substrate (protein, pus, etc.), in which the drug action takes place

GENERAL INDICATIONS

Disinfection Treatment and prophylaxis of purulent-inflammatory diseases of the skin and mucous membranes Conservants in the food and medical industry Antidote therapy (potassium permanganate, methylene dark blue)

134 HALOGENS (Cl-, I-)

Chlorine drugs: Iodine drugs: alcohol solu- chloramine, chlorhexidine, tion of iodine, Lugol’s iodine pantocide solution, iodopolymers (iodi- nol, polyvidone-iodine and etc.) Mechanism of action Bactericidal: Bactericidal: Chlorine substitutes the atom of The active molecular iodine hydrogen, as a result the secondary interacts with NH-groups of structure of protein is damaged protein molecules, causing –NH–CH–CO–NH–CH–CO– protein denaturation protein R R Depending on concentration –NCl–CH–CO–NCl–CH–CO– irritating, tanning, cauterizing R R action While interacting with water the atomic oxygen, which oxidizes Also renders fungicidal, substrate of microbial cell releases antiviral, distracting action → Cl2 + H2O HCl + HClO; HClO → HCl + O

OXIDANTS (H2O2, KMnO4)

Hydrogen peroxide Potassium permanganate diluta (3%) и concentrata (33%) Mechanism of action Bactericidal: releasing of atomic oxygen, oxidization of substrate of microbial cell provides the death of microorganisms Under catalase influencing it is Under influencing peroxidases degraded with formation of molecular it is degraded with formation of O2 (wound-cleansing) atomic oxygen katalase ↑ 2KMnO + H O → 2KOH + 2H2O2 2H2O + O2 4 2 + 2MnO + 3O· Under peroxidase influencing some 2 quantity of atomic oxygen forms Also has a deodorating action. (antiseptic) Due to MnO2 albuminates formation depending on peroxidase · concentration has an 2H2O2 2H2O + O astringent, irritating and Also has hemostatic, desodorating, cauterizing effect. discolouring action It is alkaloid antidote

135 ACIDS AND ALKALINES (HCl, NH4OH) Salicylic acid, ammonia solution, benzoilperoxide, etc. Mechanism of action Bactericidal: non-dissociated molecules, penetrating through the cellular walls of microorganism, cause protein denaturation With the rise of concentration ↑ of action takes place: keratoplastic → keratolytic astringent → irritating → cauterizating The conditions determining antiseptic properties of acids: degree of dissociation properties of substrate, properties of anion with which they interact solubility in lipids temperature of the body acidity of the medium change of tissue proteins The salicylic acid also has fungicidal properties The water solution of ammonia (liquid ammonia) also reflexly stimulates a respiratory center

PHENOLS (C6H5OH)

Resorcin, polycresulen (vagotil), tricresol, etc.

Mechanism of action

Bactericidal: block enzymatic activity of dehydrogenase; in large doses cause microbial cell’s protoplasm denaturation

With the rise of concentration ↑ action takes place resorcin 2% resorcin < 20% keratoplastic keratolytic

Also have antimycotic, deodorating, hichomonadocidal (vagotil) activity Phenol is the first antiseptic, a standard (phenolic coefficient). It is not used because of high neurotoxicity

136 TARS AND RESINS (C6H5OH)

Birch tar, ichthammol, vinisol, citral, sulsen, etc. Mechanism of action Bactericidal: depends on contents of phenols Also have keratoplastic, keratolytic, local irritating, insecticide activity They are part of Vishnevsky’s liniment, Wilkinson’s ointment

ALDEHYDES AND ALCOHOLS (HCHО, C2H5OH)

Formaldehyde, cidipol, Ethanol hexamethylenetetramine (urotropin), etc. Mechanism of action Bactericidal: formaldehyde binds to Bactericidal: dehydrates the aminogroups of proteins, causing and denaturates cell proteins their denaturation and microorganisms’ walls (20–70%) Formaldehyde and its Also has superficial activity, derivatives have a desodorating irritating (20–40%), action too tanning (>70%) effect

Hexamethylentetramine is It is not used as an antisep- a cavital antiseptic: in urine tic in concentrations >70%! (acid reaction!) decomposes on formaldehyde and ammonia

137 METAL COMPOUNDS (Ag, Cu, Zn)

Protargol, silver nitrate, copper sulfate, zinc oxide, zinc sulfate, etc. Mechanism of action Bactericidal: with interaction of metal ions with proteins the albuminates form, that results in denaturation of microorganisms’ protein → R–COOH + AgNO3 R–COOAg + HNO3 Schmiedberg’s row Al, Pb, … Fe, Cu, Zn, Ag, … Hg dense albuminates friable albuminates astringent irritating cauterizing Depending on concentration ↑ of action takes place keratoplastic keratolytic

DYES

Brilliant green, methylene dark blue, ethacridin lactate

Mechanism of action

Bactericidal: inhibit enzymatic processes, create hard-soluble complexes, affect permeability of cellular membranes, cause lysis Brilliant green is active to goldish staphylococcus, a causative agent of diphtheria and other grampositive (Gr+) microorganisms Methylene dark blue has also oxidation-reduction properties and is an antidote with cyanide, aniline (1% water solution v.v., preparation “Chromosmon”)

138 DETERGENTS

The synthetic substances with a high superficial activity and having antiseptic, washing, foam-forming properties Cationic — cerigel, Anionic — potassium, roccal, decametoxin, green and other soaps, miramistin, etc. detergents Mechanism of action Bactericidal: lower down the surface tension on the border of phase division ⇒ the structure and permeability of the microbial cell’s membrane, osmotic balance, nitric and phosphoric metabolism derange, lysis and death of bacteria take place Gr+ and Gr– bacteria, yeasts, fungi are sensitive to cationic detergents They have anti-itching, regenerative, deodorating action as well Cationic and anionic detergents — antagonists!

NITROFURANE DERIVATIVES

Furacillin (nitrofural), furaplast, lifuzol

Mechanism of action They contain a nitrogroup in its structure, which restores into aminogroup, and as a result DNA function deranges, the cellular breathing inhibits; citric acid formation is depressed, Crebs’ cycle is disturbed In the therapeutic concentrations render bacteriostatic, in high — bactericidal action Gr+ and Gr– bacteria (staphylococci, streptococci, dysentery, gas gangrene agents), protozoa, large viruses, fungi are sensitive They have also wound-healing activity

139 CHEMOTHERAPEUTIC DRUGS

Topic 25 ANTIBIOTICS

CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS

♦ Antibiotics ♦ Sulfonamides ♦ Different chemical structure — derivatives of: • naphthiridin. Quinolones (nalidixic acid, etc.). Fluoroquinolones (ciprofloxacin, etc.) • imidazole (metronidazol, tinidazol) • 8-oxyquinoline (chlorquinaldol, nitroxoline, etc.) • nitrofurane (furasolidone, furadonine and etc.) • quinoxaline (dioxidin, quinoxidin) ♦ By special indications: • antituberculosis • antisyphilytic • antiprotozoal • antimycotic • antihelmintic • antiviral • antitumoural

140 GENERAL PRINCIPLES OF CHEMOTHERAPY

• Rational choice of a drug (depending on the sensitivity of disease agent, concomitant diseases, anamnesis, etc.) • Early beginning of treatment • Way of introduction (depending on localization, severity of a pathological process, concomitant diseases) • Choice of a dose for creation of therapeutic concentration (depending on weight, age, sex, concomitant pathology, etc.) • Interval of introduction (depending on the pharmacokinetic properties of preparation) • Duration of treatment (“train” principle — continuation of treatment up to clinical and bacteriological recovery) • Combined treatment • Rise of immunological reactivity of an organism (probiotics, vitaminic drugs, immunomodulators)

HISTORY OF ANTIBIOTICS DISCOVERY

1877 L. PASTEUR and J. JOUBERT established the principle of microorganisms’ antagonism

I. I. MECHNICOV suggested its practical application

1928 A. FLEMING discovered penicillin

141 HISTORY OF ANTIBIOTICS DISCOVERY

1940 H. FLOREY and E. B. CHAIN obtained cleared penicillin (Nobel Prize)

1942 Z. V. YERMOLYEVA launched the industrial output of penicillin in the USSR

1944 Z. VAKSMAN separated streptomycin

ANTIBIOTICS

The substances of mainly biological origin (biosynthetic), their half-synthetic and synthetic analogs, causing damaging or destroying effect on the microorganisms which are sensitive to them

By origin • Mould fungi — penicillins, cephalosporins, etc. • Radiant fungi — streptomycin, levomicetin (chloramphnicol), tetracycline • Bacteria — gramicidin • Synthetic analogs and derivatives of natural antibiotics

142 CLASSIFICATION OF ANTIBIOTICS

By chemical structure ♦ Beta-lactam — beta-lactam ring (penicillins, cephalosporins, carbepenemes, monobactams) ♦ Macrolides — lactonic ring (erythromycin) and azalides (azithromycin) ♦ Tetracyclines — 4 rings (tetracycline, doxycycline, etc.) ♦ Aminoglycosides — containing aminosugars (streptomycin, gentamicin, etc.) ♦ Lincosamides (lincomycin, etc.) ♦ Derivatives of dioxyaminophenilpropan — (levomycetin) ♦ Polymixins — cyclic polypeptids (polymixin B) ♦ Polyenes (amphotericin B, nystatin, etc.) and others

CLASSIFICATION OF ANTIBIOTICS

By antimicrobial spectrum With the primary action on Gr+ microflora: • beta-lactam antibiotics (penicillins, cephalosporins, beta-lactam-like) • macrolides and azalides • by special indications (rifampicins, lincosamines, etc.) With the primary action on Gr- microflora: • aminoglycosides • polymixins Affecting Gr + and Gr- microflora: • tetracyclines • levomycetin Affecting Gr + and Gr- microflora and applied externally Antimycotic (polyenes, etc.) Antitumoral

143 CLASSIFICATIONАНТИБИОТИКИ OF ANTIBIOTICS — это

By mechanism of action Inhibition of the cellular wall’s Disturbance of cellular wall protein synthesis: permeability: penicillins, cephalosporins, polymixins, polyenes ristomycin, etc.

DNA

Ribosomes

Inhibition of cell Inhibition of nucleic protein synthesis: acids synthesis: macrolides, aminoglycosides, rifampicin, griseofulvin, tetracyclines, levomicetin, antitumoral drugs, etc. lincomycin, etc.

CLASSIFICATIONАНТИБИОТИКИ OF ANTIBIOTICS — это

By the type of action ♦ Mainly bactericidal — penicillins, cephalosporins, aminoglycosides and fungicide action — polyenes ♦ Mainly bacteriostatic — tetracyclines, levomycetin, macrolides Minimal inhibitory concentration (MIC) — the least concentration of antibiotic (mcg/l or mg/ml), which fully inhibits the visible growth of bacteria in vitro Minimal bactericidal concentration (MBC) — the least concentration of antibiotic (mg/l or mcg/ml), which while examining in vitro causes the death of 99.9% microorganisms from the initial level during a definite period of time

144 GENERAL PRINCIPLES OF ANTIBIOTIC THERAPY

• Rational choice of antibiotic (depending on disease causative agent sensitivity, concomitant diseases, allergologic, medicinal anamnesis, etc.) disk-diffuse method Е-tеst

There is no zone A zone of of microorganism bacteria growth 1 growth depression 3 around the disk МЕ with antibiotic (3 — Ellipsoid-like 64 zone of 2 microorganisms 48 24 growth are resistant to 16 12 depression antibiotic) 8 6 4 MIC A zone of microorganism growth 3 depression around the disk with 2 2 mcg/ml 1,5 antibiotic (1 — the microorganisms 1,0 (mg/l) 0,75 are resistant to antibiotic or 2 — the 0,50 microorganisms are moderately resistant to antibiotic)

GENERALАНТИБИОТИКИ PRINCIPLES — это OF ANTIBIOTIC THERAPY • Rational choice of antibiotic Category of sensitivity Clinical characteristics Sensitive Therapy is successful in usual doses With intermediate Therapy is successful with resistance maximal doses or localization of infection in antibiotic accumulated tissues Resistant Maximal doses are ineffective

145 GENERALАНТИБИОТИКИ PRINCIPLES — это OF ANTIBIOTIC THERAPY

• Early onset of treatment • Way of introduction (depending on localization and severity of process, concomitant diseases) • Choice of dose for creation of therapeutic concentration (depending on the body weight, age, concomitant diseases) • Interval of introduction (depending on pharmacokinetic parameters)

GENERALАНТИБИОТИКИ PRINCIPLES — это OF ANTIBIOTIC THERAPY • Duration of treatment: In accordance with recommendations of the World Health Organization (WHO), 1 drug for no more than 5–7 days long; the “train” principle Postantibiotic effect (PAE) — depression of vital function of microorganisms, proceeding after stopping a contact with antibiotic (minutes, hours) • Combined treatment: Makes sense with mixed infection, threat to life more frequent — bactericidal with bactericidal, bacteriostatic with bacteriostatic • Rise of immunological reactivity of an organism (probiotics, vitaminic drugs, immunomodulators)

146 ADVERSE EFFECTS OF ANTIBIOTIC THERAPY

♦ Development of polyresistance in microorganisms (biological, specific, secondary, persistent, cross) ♦ Development of allergic reactions (immediate type — beta- lactam, etc.; delayed type) ♦ Direct organotoxic effects (neuro-, hepato-, myelo-, nephrotoxicity, gastrointestinal disturbances, etc.) ♦ Development of exacerbation reaction (endotoxic) ♦ Development of superinfection (candidomycosis, staphylococcosis, hypovitaminosis) ♦ Mutagenic, teratogenic, embryo- and fetotoxic action

GENERAL DEMANDS AND CRITERIA OF ANTIBIOTICS DISTINCTION

• Resistance to microorganisms, mutated during the process of antibacterial drugs application • Range of antibacterial action spectrum • The minimal toxicity for macroorganism • Prolongation of action • Acid stability • If necessary — penetration through the blood brain barrier

147 MECHANISM OF BETA-LACTAM ANTIBIOTICS ACTION

PENICILLINS CEPHALOSPORINS

External membrane  porins Bactericidal: Cellular  wall  irreversible inhibition of  transpeptidase  (enzyme of peptidoglycan transpeptidizing reaction) because of β-lactamase similarity of their PBP structure with the D-alanyl-D-alanine- PBP peptide chain of Cytoplasmic membrane peptidoglycan

CLASSIFICATION OF PENICILLINS

• Biosynthetic: short action — benzylpenicillin sodium and potassium salts, phenoxymethylpenicillin; depo-preparations — benzathine benzylpenicillin (extencillin), bicillin-1), bicillin-5 • Semi-synthetic: izoxazolilpenicillins — oxacillin, cloxacillin, flucloxacillin aminopenicillins — ampicillin, amoxicillin antipyocyanic — carboxypenicillins (carbenicillin, ticarcillin) and ureidopenicillins (azlocillin, piperacillin) combined and inhibitor-protected — ampiox, helicocide (amoxicillin + metronidazol), amoxiclav (amoxicillin + clavulanate), ampicillin + sulbactam, ticarcillin+ clavulanate, piperacillin + tazobactam, etc.

148 PHARMACOKINETICS OF PENICILLINS

• Absorption: parenterally and per oral (on an empty stomach or in an hour after the meal!); bioavailability 30–50% • Binding with proteins: different (biosynthetic — about 80%, oxacillin — 90%, ampicillin — 20%) • Distribution: high concentration in the liver, lungs, kidneys, reproductive organs, lower in tissues of the eyes, prostate gland, CNS, penetrate well to the mucous membranes, badly to the bone tissue • Time of therapeutic concentration (ThC) is different: benzypenicillin — 3–4 hrs, depo preparations — up to 2–4 weeks, semi-synthetic — 6–8 hrs • Biotransformation: in the liver practically does not metabolize, except for oxacillin, etc. • Excretion: excrete mainly by the kidneys, and also by the liver, saliva, breast milk

CHARACTERISTICS OF SOME GROUPS OF PENICILLINS

Distinctions: ♦ Pharmacokinetic parameters (acid stability, T1/2, etc.)

♦ Resistance to beta-lactamase (penicillinase)

♦ Range of antibacterial spectrum

Natural: cocci which do not produce penicillinase (streptococci, pneumococci, staphylococci, gonococci, meningococci), anaerobes (peptostreptococci, clostridia), spirochetes, actinomycetes.

All of them are not acid stable, except phenoxymethylpenicillin!

149 CHARACTERISTICS OF SOME GROUPS OF PENICILLINS

♦ Aminopenicillins: more broad spectrum (+ escherichia, shigellae, salmonellae, protea, Helicobacter), but are not stable to beta-lactamase. All of them are acid stable! ♦ Oxacillin, cloxacillin: the same spectrum like in natural ones, but stability to beta-lactamases (antistaphylococcal). All are acid stable! Resistance! ♦ Carboxy- and ureidopenicillins: majority of enterobacteria and Pseudomonas aeruginosa, but are less active to the Gr+ flora. Are not stable to beta-lactamase. All of them are not acid stable! ♦ Combined: spreading of the spectrum (+ klebsiella, proteus, bacteroidi) due to combination with inhibitors of penicillinase — clavulanic acid, sulbactam

CHEMOTHERAPEUTIC SPECTRUM OF PENICILLINS

With diseases caused by causative agents sensitive to penicillins • Purulent infections • Pneumonia • Rheumatism (rheumatic fever) • Bacterial meningitis • Gonorrhoea • Spirochetoses (Syphilis) • Actinomycoses • Anthrax • Diphtheria • Gas gangrene • Pseudomonal infection, etc.

150 ADVERSE EFFECT OF PENICILLINS

♦ Allergic reactions (immediate! and delaed type). Cross allergic reaction with cephalosporins! ♦ Endotoxic reaction (reaction of exacerbation) — benzylpenicillin at syphilis ♦ Superinfection ♦ Neurotoxicity (high doses) ♦ Local-irritating action (phlebites, infiltrates, dyspepsia)

CLASSIFICATION OF CEPHALOSPORINS

I generation: cephaloridine, cefazoline (cephzol), cephalotin; acid stable — cephalexin, cephradin II generation: cefoxitin, cephamandol, cephprosil; acid stable — cefuroxim, cephaclor III generation: cefotaxime (claforan), cephtriaxone, cephtizoxim, cephtasedim, etc.; acid stable — cefixim, cephtibuten IV generation: cefepime, cefpirom Distinctions • Pharmacokinetic parameters (acid stability, T1/2, etc.) • Resistance to cephalosporinase • Range of spectrum of antibacterial action • Penetration through the BBB

151 PHARMACOKINETICS OF CEPHALOSPORINS

Introduction: parenteral and oral (depending of the type) Bioavailability: 50–90%, does not depend on the meal Binding with proteins: 20–90% (depends on generations) ThC in blood: for the I generation — 3–4 hrs, for the II generation — 6–8 hrs, III and IV generations — 8–12 hrs Distribution: in many tissues, organs (except for the prostate gland) and secretes (including the intraocular liquid). The III and IV generations get to the tissues better (especially to the CNS, the bone) Biotransformation: mainly do not metabolize, except for cephalothin and cefotaxime (deacetylated in the liver, kidneys) Excretion: by kidneys and liver

CHARACTERISTICS OF SOME GROUPS OF CEPHALOSPORINS

♦ I generation — Gr+ cocci (except for enterococci), some Gr- bacteria. They are not resistant to beta-lactamases and do not penetrate through BBB ♦ II generation — like in the previous generation, but activity to the Gr- flora is more expressed (+ Escherechia coli, hemophilic bacillus). Stable to cephalosporins of Gr- microorganisms. Only cefuroxime penetrates through BBB. ♦ III generation — are more active to Gr- microflora than to Gr+ (+ enterobacteria), also blue pus bacillus (cefoperazone, ceftazedim). Are resistant to the beta-lactamases of Gr--bacteria and get to CNS ♦ IV generation — broad spectrum (Gr+ and Gr– microflora, anaerobes, etc.). They are resistant to beta-lactamases and penetrate to CNS

152 CHEMOTHERAPEUTIC SPECTRUM OF CEPHALOSPORINS

♦ Infections caused by Gr+ microflora (I generation) and Gr– microflora (II–IV generation), osteojoint system, soft tissues, urogenital tracts, pneumonias, otites, etc.

♦ Septicemia (III–IV generation)

♦ Meningitis (III–IV generation)

♦ Pseudomonal infection, etc.

ADVERSE EFFECTS OF CEPHALOSPORINS

• Allergic reactions of immediate and delayed type, including cross ones with penicillins! • Superinfection • Hepato- and nephrotoxicity • Haematological reactions (leukopenia, hypothrombopenia, etc.), especially III generation • Local irritating action (phlebites, infiltrates, dyspepsia)

153 OTHER BETA-LACTAMS

CARBAPENEMS — imipenem, meropenem • Spectrum of action — Gr+ cocci, meningo- and gonococci, Shigella, Salmonella, E. coli and Pseudomonas, clostridis, Proteus, Enterobacteris, hemophilic bacillus, Serracia • They are used as reserve antibiotics during severe infections caused by resistant strains, with mixed infections • Side action — allergic reactions, neuro- and hepatotoxicity, pseudomembranous colitis, local irritating action MONOBACTAMS — aztreonam • Spectrum of action — aerobic Gr- microflora • Is used as a reserve antibiotic with infections caused by Gr- strains resistant to cephalosporins, aminoglycosides • Side action — skin allergic reactions, dyspepsia, diarrhea, disbacteriosis, eosinophilia, etc.

MACROLIDES AND AZALIDES

I generation: erythromycin, oleandomycin II and III generations: roxythromycin, spiramycin, claritromycin, jozamycin; azalides — azithromycin Mechanism of action — bacteriostatic (in large concentrations bactericidal); disturbance of synthesis of bacterial cell protein by the way of binding with 50S-subunit of ribosomes and translocation process inhibition

Antimicrobial spectrum — Gr+ microflora (staphylo-, pneumo-, streptococci), causative agents of whooping-cough and diphtherias, listeria, spirochetes, some mycobacteria, legionellae, chlamydia, mycoplasmas, ureaplasms, amoebae, anaerobes and large viruses

154 MACROLIDES AND AZALIDES

Indices I generation II and III generation Antimicro- Appearance of resistent Broader, more expressed bial spectrum strains (staphylo- to enterobacteria, pseudo- cocci, etc.) monades, anaerobes, Неlicobacter Pharmaco- Bad acid stability (in the More acid stable; kinetics membranes); do not bioavailability is higher pass through the BBB, T1/2 — 2–4 days but penetrate through the placenta; T1/2 — 2–5 hrs Adverse Allergic reactions, hepatotoxicity, superinfection, effects dispeptic signs, photodermatitis, embryotoxicity

Resistance Cross-resistance within the group They have antiviral, immunomodulating and anti-inflammatory activity

AMINOGLYCOSIDES

I generation — streptomycin, monomycin, kanamycin, neomycin II and III generations — gentamicin, tobramycin, sisomycin, amicacin, framicetine, etc.

Mechanism of action — bactericidal; irreversible inhibition of synthesis of bacterial cell’s protein — binding with 30S-subunit of ribosomes results in disturbance of amino acid inbuilding into proteins and formation of the nonfunctional protein

Antimicrobial spectrum — mainly Gr- microflora: Escherechia, Clebsiellae, E. coli, causative agents of dysentery, brucellosis, tularemia, tuberculosis, plague, lepra. They have postantibiotic effect

155 AMINOGLYCOSIDES

Indices I generation II and III generation Antimicro- Appearance of resistent Broader (+ staphylo- and bial spect- strains (micobacteria, etc.) streptococci, Proteae, rum Salmonellae, Shigellae, Pseudomonas)

Chemo- Tuberculosis, tularemia, Infections of intestinal and therapeutic brucellosis, plague, lepra, urinary tracts, peritonitis, spectrum endocarditis, peritonitis meningitis, sepsis, pneumo- nia, pleuritis, empyema

Pharmaco- They are nor absorbed in GIT (only parenteral); kinetics do not get to CNS and eye tissues; T1/2 — 6–8 hrs and more; excretion mainly by kidneys

ADVERSE EFFECT OF AMINOGLYCOSIDES

♦ Ototoxicity (especially I generation) ♦ Nephrotoxicity ♦ Myorelaxant action ♦ Allergic reactions ♦ Superinfection ♦ Local irritating action ♦ Embryotoxicity ♦ Rapid growth of resistance (up to appearance of dependent strains (streptomycin-dependent)

156 POLYMIXINS B and E

Mechanism of action — bactericidal; disturb permeability of cellular wall and transport mechanisms, binding with the bacteria’s cell membrane Antimicrobial spectrum — Gr– microflora Pharmacokinetics — do not absorb into the GIT, with parenteral introduction badly penetrate the tissues, do not get to alive cells; excretion by kidneys Adverse effects — high nephro- and neurotoxicity (parestesia, dizziness, discoordination of movements), respiratory paralysis, etc. The usage — locally (the skin, mucosa, in the pleura, joint cavity, etc.)

TETRACYCLINES

• Biosynthetic — tetracycline, oxytetracycline • Semi-synthetic — metacycline, doxycycline (vibramycin) • Combined — oletetrine, ericycline Mechanism of action — bacteriostatic; disturbance of synthesis of bacterial cell’s protein — binding with 30S-subunit of ribosomeses results in disturbance of peptide chain; the formation of the chelate compounds with metals causes depression of the enzymic systems

Antimicrobial spectrum — broad: Gr+ and Gr- microflora, causative agents of plague, cholera, dysenteries, brucellosis, tularemia, malarias, rickettsial infection, spirochetes, actinomycetes, some protozoa, etc.

157 TETRACYCLINES

Chemotherapeutic spectrum • Preparations of choice with infections caused by Mycoplasmae, Chlamydia, Ricketsia, some Spirochetes • They are effective with dysentery, brucellosis, tularemia, plague, cholera, meningitis, malaria, intestinal infections and biliary ducts Pharmacokinetics Absorption in the small intestine — from 30 to 100%; binding with proteins — 40–80%; well penetrate (except for the cerebrospinal fluid), can deposit in the osteal and dental tissues, easily penetrate through the placenta; T1/2 — 6–12 hrs and more, excretion by the kidneys, intestine, milk, saliva. The enterohepatic cycle of metabolism is peculiar to semi-synthetic ones

ADVERSE EFFECT OF TETRACYCLINES

♦ Superinfection ♦ Gastrointestinal disorders (glossitis, stomatitis, diarrhea, proctitis, etc.) ♦ Hepato- and nephrotoxicity ♦ Haematological deviations (trombocyto-, neutropenia, eosinophilia) ♦ Catabolic effect on macroorganism ♦ Allergic reactions ♦ Disturbance of the osteal and dental tissue formation (chelate compounds). Contraindicated before 12 years old! ♦ Teratogenicity ♦ Photosensitization ♦ Cross resistance

158 LEVOMYCETINE (CHLORAMPHENICOL)

Mechanism of action — bacteriostatic; disturbance of bacterial cell’s protein synthesis — binding with 50S-subunit of ribosomes and the blockade of peptidyltransferase results in peptide chain disturbance

Antimicrobial spectrum — broad: Gr+ and Gr- microflora, rickettsia, spirochetes, large viruses, bacteroids, etc. Resistance arises seldom

The usage — with the threat of life and severe conditions at salmonellosis infections (typhoid fever), meningitis, sepsis, microflora resistance to other antibiotics

Pharmacokinetics — is well absorbed, binding with proteins — 30%, well penetrates all the tissues, T1/2 — 6–8 hrs; biotransformation — conjugation and reduction; excretion by kidneys

ADVERSE EFFECT OF LEVOMYCETINE

• Myelotoxicity (leukopenia, agranulocytosis, reticulocytopenia, aplastic anaemia up to the lethal outcome!). Control of blood on every 2nd day! • “Grey baby syndrome” • Superinfection • Gastrointestinal disorders (glossitis, stomatitis, diarrhea, etc.) • Hepato- and nephrotoxicity • Reaction of exacerbation (with typhoid fever) • Allergic reactions • Neurotoxicity (ophthalmic nerve neuritis)

159 ANTIBIOTICS OF OTHER GROUPS

Antimycotic antibiotics • Polyenes: for the system usage: amphotericin B, mycoheptin per os and locally: nystatin, levorin • Others: griseofulvin Antitumoral antibiotics Anthracyclins: doxorubicin, daunorubicin, rubomycin, etc. Actinomycins: bleomycin, dactinomycin Others

Р. S. Description of antimycotic antibiotics is given in Topic 27 “Antituberculous, antisyphilitic... antimycotic ... drugs”, antitumoral — in Topic 22 “The drugs affecting leukopoiesis and blood coagulation”

160 Topic 26 SULFONAMIDES. ANTIMICROBIAL DRUGS OF DIFFERENT CHEMICAL STRUCTURE

HISTORY OF SULFONAMIDES CREATION

1932 I. KLARER and F. MIETSCH (Germany) synthesized and tested in vitro antibacterial activity of prontozil (red streptocide)

1935 G. DOMAGK for the first time showed in vivo its activity against the hemolytic streptococcus and causative agents of other infections

G. Dоmаgk

161 CHEMICAL STRUCTURE OF SULFONAMIDES

Derivatives of sulfonilic acids (as a rule, white, without an odour, bitter crystalline weak acids, badly water-soluble)

Modification through the H2N — — SO2 — NH2 aminogroup causes change of physical, sulfonamide (streptocide) chemical, pharmacological properties

A majority of sulfonamides are produced as sodium H2N — — COOH salts p-aminobenzoic acid (PABA)

CLASSIFICATION OF SULFONAMIDE DRUGS

♦ Well absorbed in GIT and have resorptive action: • short — streptocide, ethazole, norsulfazole, sulfadimezine • long — sulfapyridazine, sulfadimethoxin • ultra long — sulfalen ♦ Badly absorbed in GIT: phthalazole ♦ Combined: • with salicylic acid — salazopyridazine, etc. • with trimethoprim — co-trimoxazole (bactrim, biseptol), sulfaton, lidaprim, etc. ♦ For the local application — streptocide, sulphacyl-sodium and other sodium salts

162 PHARMACOKINETICS OF SULFONAMIDES • Absorption (well absorbed drugs) Mainly in the small intestine • Binding with proteins: 20–90% • Distribution: the greates concentrations — in the liver, kidneys, lungs, skin; less — in the fatty tisue. They penetrate well the liquid mediums of an organism, including through the BBB, placenta • Biotransformation: acetylated, oxidized, form nonactive glucuronides or are not changed. Acetylating forms (especially in the acidic medium!) precipitate in the renal tubules, resulting in crystalluria • Excretion: by kidneys, mainly, by the way of gromerular filtration. The preparations of prolong action undergo repeated reabsorption In children and elderly people pharmacokinetics changes!

MECHANISM OF SULFONAMIDES ACTION Concurrent antagonism with PABA

p-aminobenzoic acid SULFONAMIDES Dihydropteroatsynthetase

Dihydrofolic acid

Dihydrofolate reductase TRIMETHOPRIM

Tetrahydrofolic acid

Purines

DNA and RNA

163 THE CONDITIONS DETERMINING ANTIMICROBIAL ACTIVITY

The concentration of sulfonamide should exceed PABA concentration in substrate on average 100–1,000 times as much

The antibacterial activity lowers down at presence of pus, blood, products of disintergration of organism tissues, where the greater PABA quantity is

ANTIMICROBIAL SPECTRUM

Bacteriostatic action ♦ Highly sensitive causative agents: Cocci (pneumococci, gonococci, meningococci, streptococci), intestinal (E. coli, salmonellas, Vibrio cholera), large viruses (of trachoma, inguinal lymphogranulematosis), Protozoa (malaria, toxoplasmosis), Chlamydia, causative agents of gas gangrene, diphtherias, etc. ♦ Moderately sensitive: Staphylococci, Enterococci, Klebsiellas, causative agents of leprosy, tularemia, micobacteria, leishmaniosis, actinomycetes

In combination with trimethoprim — bactericidal action, antibacterial spectrum is broader

164 RESISTANCE TO SULFONAMIDES

Only those microorganisms are sensitive which need PABA for the vital activity

Because of frequent and inefficient administration a number of Staphylococci, Meningococci, Streptococci, Gonococci, E. coli have mutated, which made them resistant

Cross resistance is peculiar to sulfonamides

INDICATIONS TO SULFONAMIDES

• Acute cocci infections (pneumonias, sore throat, bronchitis, sinusites, otites, cholecystitis, meningites, etc.) — resorptive long and ultra long action (sulfadimethoxine, sulfalen), co-trimoxazole • Acute infections of urinary tract and genital organs (cystites, prostatites, etc.) — resorptive short action (urosulfane), co-trimoxazole • Acute intestinal infections (dysentery, enterocolites, colitis, etc.) — badly absorbed (phthalazole); non-specific ulcerous colitis — salasosulfonamides • Eye infections (ulcerative conjunctivites, blepharitis, etc.) — sulphacyl-sodium • For treatment of trachoma, malaria, clamidiosis, toxoplasmosis, actinomycosis, leprosy, etc.

165 ADVERSE EFFECTS OF SULFONAMIDES

• Disturbance of urine excretion: crystalluria, hematuria, urine retention ⇒ abundant alkaline drink, control of diuresis! • Disturbance of hematosis: leukopenia, agranulocytosis, sulmethemoglobinemia, anaemias ⇒ control of blood! • Hepatotoxicity: hepatitis, in children — icterus (insufficiency of glucuronyltransferase) • Allergic reactions: dermatitis, Stevens—Johnson’s syndrome, etc. • Neurotoxicity (dizziness, headache, depressions) • Immunosupression (co-trimoxazole)

GENERAL PRINCIPLES OF SULFONAMIDE THERAPY • Rational choice of sulfonamide taking into account anamnesis of a patient! (whether administered before, sulfonamide resistance, diseases) • Early onset of treatment • Principle of loading dose! • Interval of introduction • Duration of treatment — 6–8 days (with acute infections and especially in children and elderlies) • Combined treatment (sulfonamides do not combine with each other!), careful usage with other drugs (novocaine, diphenine, NSAIDs, synthetic hypoglycemic drugs, diuretics, anticoagulants, etc.) • Rise of immunological reactivity and decline of therapy complications (vitaminic drugs, immunomodulators)

166 ANTIMICROBIAL DRUGS OF DIFFERENT CHEMICAL STRUCTURE

• Derivatives of naftiridin: Quinolones (nalidixic, oxolinic acids, etc.) Fluoroquinolones (ciprofloxacin, ofloxacin, etc.) • Derivatives of imidazole: metronidazole, tinidazole • Derivatives of 8-oxyquinoline: chlorquinaldol, nitroxoline, oxolinic acid, etc. • Derivatives of nitrofurane: furazolidone, furadonine, furagin, etc. • Derivatives of quinoxaline: dioxydine, chinoxydin

QUINOLONES. FLUOROQUINOLONES

By the chemical structure: • Non-fluorinated quinolones: nalidixic acids (nevigramon, negram), oxolinic, pipemidic (palin) • I generation — monofluoroquinolones: norfloxacin, ciprofloxacin, ofloxacin, pefloxacin • II generation — difluoroquinolones: lomefloxacin, sparfloxacin • III generation — trifluoroquinolones: fleroxacin, trovafloxacin, moxyfloxacin

O O R O

F 5 4 6 1 3 COOH 7 1 8 1 2 N N N R X N X = С R R R R or N nucleus of quinolone nucleus of naftiridine fluoroquinolone

167 QUINOLONES. FLUOROQUINOLONES

Mechanism of action • Inhibits DNA-gyrase (bactericidal) • Also affect the RNA bacteria and bacterial proteins synthesis, on stability of membranes and other vital processes of bacterial cells • They have a post-antibiotic effect (~2 hrs) Antibacterial spectrum They are highly active to aerobic Gr– bacteria (E. coli, Shigella, Salmonella, Vibrio cholerae, Yersinia enlerocolytica, Legionella, Brucella, Listeria monocytesgenes, Haemophilus, Neisseria gonorrhoeae, N. meningitidis, P. aeruginosa, etc.), the Gr+ series: majority of staphylococci (Streptococci are more stable), Chlamydia, Mycoplasmas, Ureaplasmas, and also Mycobacteria tuberculosis, Rickettsia, Leishmania, Plazmodia, etc. They are active to the bacteria which are resistant to other antimicrobial drugs! Resistant stains appear

QUINOLONES. FLUOROQUINOLONES

Generation Drugs Spectrum of activity Non-fluorinated Nalidixic acid As a rule Gr– microflora quinolones (Enterobacteriaceae family)

I — “gram- Ciprofloxacin Gr- microflora, S. aureus, negative” fluoro- Pefloxacin low activity against quinolones Ofloxacin Streptococcus pneumoniae, Lomeflotxacin Mycoplasma, Chlamydophila - II — “respira- Levofloxacin Gr microflora, S. aureus + high tory” fluoro- Sparfloxacin activity of Streptococcus quinolones pneumoniae, Mycoplasma pneumo- niae, Chlamydophila pneumoniae III — “respira- Moxyfloxacin The same + anaerobes, atypical tory” + “antian- causative agents aerobial” fluoro- quinolones

168 QUINOLONES. FLUOROQUINOLONES

Pharmacokinetics • Absorption: fluoroquinolones are well absorbed with oral intake (Tmax = 1–3 hrs); meal, antacides slow up absorption • Binding with proteins: no more than 30% • Distribution: fluoroquinolones (unlike quinolones!) create high concentrations in organs and tissues (higher than in the blood!), penetrate into the cells. Ciprofloxacin, ofloxacin, pefloxacin penetrate through the BBB, placenta, breast milk • Biotransformation: quinolone quickly metabolized, fluoroquinolones with different degree, some metabolites are active • Excretion: by kidneys, with bile too; T1/2 norfloxacin — 3–4 hrs, pefloxacin — 13 hrs

QUINOLONES. FLUOROQUINOLONES

Indications Non-fluorinated quinolones and norfloxacin: chronic infections of the urinary system and intestinal infections Fluoroquinolones: • ENT-infections: malignant otitis and sinusitis caused by polyresistent strains • Infections of the lower respiratory tracts: chronic bronchitis, nosocomial pneumonia, legionellosis • Intestinal infections: shigellosis, typhoid fever, generalized salmonellosis, plague, cholera • Anthrax • Intra-abdominal infections

169 QUINOLONES. FLUOROQUINOLONES

Indications Fluorquinolones: ♦ Infections of pelvic organs, urinary system, prostatitis, gonorrhoea ♦ Infection of the skin, soft tisues, bones and joints ♦ Infections of eyes ♦ Meningitis caused by gram-negative microflora (ciprofloxacin) ♦ Sepsis ♦ Infections in patients suffering from mucoviscidosis and neutropenia (treatment and prophylaxis) ♦ Tuberculosis (ciprofloxacin, ofloxacin, lomefloxacin as drugs of II series)

QUINOLONES. FLUOROQUINOLONES

Adverse effects

General for all quinolones: GIT: heartburn, pains in the epigastral region, appetite disorders, nausea, vomiting, diarrhea CNS: ototoxicity, drowsiness, insomnia, headache, dizziness, visual disorders, paresthesia, tremor, seizures Allergic reactions: rash, itching, angioneurotic edema; photosensitization Typical for non-fluorinated quinolones: Haematological reactions: thrombocytopenia, leukopenia; with deficit of glucoso-6-phosphate dehydrogenase — hemolytic anaemia Liver: cholestatic icterus, hepatitis

170 QUINOLONES. FLUOROQUINOLONES

Adverse effects Typical for quinolones: Locomotor apparatus: arthropathies, arthralgias, mialgias, tendinitis, tendovaginitis, raptures of tendons (are not recommended before 18 years old and pregnant women!) Kidneys: crystalluria, transitory nephritis Heart: the QT interval lengthening on ECG Others: most often — candidiasis of the mucous membrane of oral cavity and/or vaginal candidiasis

DERIVATIVES OF IMIDAZOLE

Metronidazole (metrogil, trichopol), tinidazole Mechanism of action: bactericidal — a recovered nitro group of the drug disturbs replication and transcription of the microbial cell’s DNA

Antimicrobial spectrum: Adverse effects: • Anaerobic bacteria Anorexia, diarrhea • Trichomonades Dryness, metallic taste • Lamblia in the mouth • Amoebae Allergy • Balantidia Leukopenia • Helicobacter Candidomycosis • They are ineffective to fungi Disulfiram-like effect and aerobes (incompatibility with alcohol)

171 DERIVATIVES OF 8-OXYQUINOLINE

Nitroxoline (5-NOX), chlorquinaldol, intetrix, oxolinic acid Mechanism of action: bactericidal — inhibit the synthesis of protein, form chelates, increasing oxidizing processes in protoplasm Antibacterial spectrum: broad — Gr+ and Gr– bacteria (Staphylococci, Enterobacteria, etc.), Protozoa (Amoebae, Lamblia, Balantidia), pathogenic fungi Indications: are effective against resistant microflora to other antibacterial drugs — intestinal infection and disbacteriosis (chlorquinaldol, intetrix); — infections of the ureniferous system (nitroxoline) Adverse effects: peripheral neuro- and myelopathies, defeat of the visual nerve, allergic reactions, stomach pain, nausea

DERIVATIVES OF NITROFURANE

Furadonine, furazolidone, nifuroxaside, furagin; locally — furacilin, etc. Mechanism of action: bacteriostatic and bactericidal (on concentration). A nitrogroup containing in the structure restores in the aminogroup, which inhibits the DNA function, cellular respiration, Krebs cycle; pH < 5.5 increase action! Antibacterial spectrum: Gr+ and Gr– bacteria, Protozoa (Amoebae, Lamblia, Trichomonades), large viruses, fungi Indications: are effective against microflora resistant to antibiotics and sulfonamides — intestinal infections (furazolidone, nifuroxaside); — infections of the urinary system (furadonine, furagin) Adverse effects: allergic reactions, neurites, bleeding, methhemoglobinemia, nephrotoxicity, dispeptic disorders, embryotoxicity

172 QUINOXALINES

Dioxidine, quinoxidine, dioxycol

Mechanism of action: bactericidal — block bacteria’s DNA synthesis Antibacterial spectrum: Gr+ and Gr– bacteria, Proteus vulgaris, Pseudomonas, pathogenic anaerobes, etc. They are active to bacteria which are stable to other chemotherapeutic drugs Indications: arthritis, severe pyo-visceral processes, sepsis, etc. Adverse effects: mutagenic, teratogenic, embryotoxic action, seizures, allergic reactions, hyperthermia

They are administered only for adults and strictly under the supervision of a doctor!

173 Topic 27 ANTITUBERCULOSIS, ANTISYPHILITIC, ANTIPROTOZOAL, ANTIHELMINTHIC, ANTIMYCOTIC ANTIVIRAL DRUGS

CLASSIFICATION OF ANTITUBERSULOSIS DRUGS

Group A — the most effective drugs: • antibiotics: rifampicin, mycobutin • synthetic drugs: derivatives of hydrazid of isonicotinic acid (HINA) (isoniazid) Group B — drugs of middle efficiency: • antibiotics: streptomycin, kanamycin, florimycin, capreomycin, cycloserin • synthetic drugs: etambutol, etionamide, protionamide, pirasenamide, ofloxacin Group C — drugs of low efficiency: • synthetic drugs: para-aminosalicylic acid (PASA), thioacetazone (tibon)

174 COMPARATIVE CHARACTERISTICS OF ANTITUBERSULOSIS DRUGS

Preparation, Mechanism Adverse daily dose of action effects Rifampicin, Inhibits RNA Hepato-, nephrotoxicity, 0.45–0.9 g synthesis (bactericidal) leukopenia, allergy, turn sputum urine and other secrets into red color

Isoniazid, Forming the chelate Hypovitaminosis B, 10–15 mg/kg compounds with metals, neuro- (peripheral neuritis, depresses respiratory euphoria, hyposomnia), enzymes as well as syn- hepatotoxicity, anaemias, thesis of mycolic acids allergy, dyspepsia (bacteriostatic) Streptomycin, Inhibits synthesis of Nephro- and ototoxicity, 1–2 g cell protein (bacterio- myorelaxing effect, static) allergy, etc. Rifampicin and isoniazid affect intracellular mycobacteria as well! To all these drugs resistance develops quickly!

COMPARATIVE CHARACTERISTICS OF ANTITUBERSULOSIS DRUGS

Preparation, Mechanism Adverse daily dose of action effects Cycloserin, Inhibits the synthesis Nueropsychic disorders, about 1 g of protein of the cellular allergy, dyspepsia; resis- wall (bactericidal) tance seldom Ofloxacin, Inhibits DNA-gyrase Dyspepsia, disturbances 0.8 g (bactericidal) on the part of the liver, blood, allergy, etc. Ethambutol, Inhibits RNA Defeat of visual nerve 25 mg/kg synthesis (bacteriostatic) (disturbance of color vision), neuritis, dyspepsia, resistance (quickly) PASA, Concurrent antagonism Hypothyroidism, allergy, 12–16 g with PABA (bacteriostatic) crystalluria, agranulo- cytosis, hepatitis, resistance (slowly)

175 SPECTRUM OF ACTION OF ANTITUBERCULOSIS DRUGS

Isoniazid Mycobacteria tuberculosis PASA Ethambutol Causative agent of plague Ethionamide Causative agent of tularemia Causative agent of brucellosis E. coli Rifampicin Cycloserin Shigellae Salmonellae Proteus Cocci Causative agent of diphtheria

COMPARATIVE EFFICIENCY OF ANTITUBERCULOSIS DRUGS

Isoniazid > rifampicin > streptomycin >

kanamycin > pyrazinamide > protionamide >

ethambutol > cycloserin > florimycin >

PASA > thioacetazone

176 GENERAL PRINCIPLES OF TUBERCULOSIS TREATMENT

♦ Rational choice of drugs according to mycobacteria sensitiveness ♦ Early diagnosis and beginning of treatment ♦ Way of introduction ♦ Dose ♦ Interval of introduction ♦ Duration of treatment (6–12 months and more) ♦ Combined treatment (the first 2–3 months combination of 3 drugs, then — 2 drugs) ♦ Rise of immunological reactivity of an organism and decline of complications number (isoniazid — vitamin B6, streptomycin — calcium pantothenate, PASA — abundant alkaline drink, etc.)

CLASSIFICATION OF ANTISYPHILITIC DRUGS

♦ Antibiotics: • of first choice — penicillins: extencillin (bicillin-1), bicillin-5 • alternative (at intolerance or resistance to penicillins) — cephalosporins, macrolids, tetracyclins ♦ Drugs of bismuth: • biioquinole (8% meal of quinine iodine bismuthate in the neutralized peachy oil) • bismoverole (meal of the basic bismuth salt of monobismuth acid in the neutralized peachy oil)

177 DRUGS OF BISMUTH

Biioquinole, bismoverol Mechanism of action: inhibition of SH-groups of the spirochete enzymal systems

Effects: bacteriostatic, anti-inflammatory

Application: treatment of different forms of syphilis (in combination with antibiotics), non-syphilitic disease of CNS

Adverse effects: gingivitis, stomatitis, colitis, diarrhea, appearance of dark border on the edge of gums (bismuth edge), hepato- and nephrotoxicity, etc.

ANTIPROTOZOAL DRUGS

For treating: Malarias Amebiasis Lambliasis Toxoplasmosis Trichomoniasis Chlamydiasis Leishmaniasis Balantidiasis

178 MALARIA

Acute protozoal disease characterized by the fever attacks, anaemia, enlargement of the liver and spleen Causative agents: Plasmodium vivax — 3-day malaria Plasmodium ovale — 3-day malaria Plasmodium malariae — 4-day malaria Plasmodium falciparum — tropical malaria

Source: Transmitter: a sick man or gametocarrier Anopheles female

CLASSIFICATION OF ANTIMALARIAL DRUGS

According to the origin and chemical structure: ♦ Synthetic: • derivatives of 4-aminoquinoline — chloroquine (quingamin, delagil), hydroxychloroquine (plaqvenil) • derivatives of 8-aminoquinoline — primaquine, quinocide • derivatives of diaminopyrimidine — chloridine (pyrimethamine), trimethoprim • derivatives of 9-aminoacridine — acriquine • sulfonamides — sulfadimetoxin, sulfalen • sulfones — dapsone • tetracyclines — tetracycline, doxycycline combined — fansidar, metakelphine, etc. ♦ Natural: • quinine of hydrochloride, quinine sulfate and its derivatives — kinemax, kineform

179 ANTIMALARIAL DRUGS

Life cycle of Anopheles erythrocytic development: female corpuscles Gamontotropic gamonts→ schizonts, drugs ookinet→ gametocytes (chloridin) oocyst→ sporozoits capillary sporozoits Hemato- tissue schizotropic schizonts drugs (chloro- Histoschi- quine, zotropic 15–16th рrе- chloridin, drugs day mefloquine, (primaquine, quinine) chloridin) para- merozoites ery- thro- months, Acute Relapses cytar attack years BLOOD (erythrocytic LIVER (tissue stage) stage)

CLASSIFICATION OF ANTIMALARIAL DRUGS

According to the type of action ♦ Hematoschizotropic: • chloroquine, chloridin, quinine, mefloquine, kinemax, sulfonamides, acriquine ♦ Histoschizotropic: • pre-erythrocytic (primary tissue) forms — primaquine, chloridin, tetracycline • para-erythrocytic (late tissue) forms — primaquine, quinocide ♦ Gamontotropic: • acting gamontocide — primaquine, quinocide • acting sporontocide — chloridin ♦ Combined action: • fansidar, metakelfine, fanzimef

180 PRINCIPLES OF ANTIMALARIAL DRUGS USAGE

I. Sporontocidic drugs application, that is influencing on sporozoits which got into the blood of a healthy man with the bite of infected mosquito (individual chemoprophylaxis — prevention of malaria development in a healthy man drugs) — chloridin II. Treatment of a sick man: 1) hematoschizotropic drugs application — chloroquine, chloridin, fansidar, sulfones and sulfonamides; quinine and mefloquine (especially with chloroquine-stable malaria), with acute attack, malarial coma parenteral — chloroquine, quinine, in large doses of kinemax, kinform 2) histoschizotropic drugs application: treatment and prophylaxis of early and late relapses (interseasonal, pre-epidemic) — primaquine, etc. III. Gamontocidic drugs application, that is prevention of mosquito infection from a sick man (collective or public epidemic, chemoprophylaxis) — fansidar, fanzimef, chloridin

STAGES OF ANTIMALARIAL DRUGS APPLICATION

oocyst sporozoits

infected zygota zygote infection mosquito of mosquito

gametocytes Individual pro- erythrocytar phylaxis: Collective cycle sporontocidic prophylaxis: hepatic gamontocidic malaria attack cycle

Rapid relief of symptomes, Treatment of tissue influence on erythrocytic forms and prophylaxis of schizonts: relapses: hematoschizotropic histoschizotropic

181 CLASSIFICATION OF ANTIAMEBIAL DRUGS

Acting with any localization of amoebae — metronidazole, tinidazole

Affecting amoebae in the intestinal lumen — quiniofone, intetrix, chlorquinaldon

Affecting amoebae in the intestinal lumen and wall — tetracyclines

Affecting the tissue amoebae in the wall of the intestine and in the liver — emetine hydrochloride

Affecting the tissue amoebae in liver — chloroquine

DERIVATIVES OF IMIDAZOLE

Metronidazole (metrogil, trichopol), tinidazole Mechanism of action: bactericidal — a reduced nitrogroup of drug disturbs replication and transcription of microbial cell’s DNA

Antimicrobial spectrum: Adverse effects: Anaerobial bacteria Anorexia, diarrhea Trichomonades Dryness, metallic taste Lambliae in the mouth Amoebae Allergy Balantidiae Leukopenia Helicobacter Candidomycosis They are ineffective to Disulfiram-like effect fungi and aerobes (incompatibility with alcohol)

182 BASIC INDICATIONS TO ANTIPROTOZOAL DRUGS APPLICATION

Tetracyclines Balantidiasis Quiniofon

Toxoplasmosis Macrolides Chloridin

Chlamydiasis Metronidazole Sulfalen

Monomycin Trichomoniasis Furazolidone

Lambliosis Solusurmin Acriquine

Leishmaniasis

CLASSIFICATION OF ANTIHELMINTHIC DRUGS

♦ With intestinal nematoses (ascaridiasis, enterobiasis, trichocephaliasis, ancylostomiasis): • breaking metabolic processes of helminths — mebendazole (vermox), levamisole (decaris), medamin, naphthammon • paralysing action — piperasine adipinate, pyrantel (combantrin) ♦ With intestinal cestodoses (diphyllobotriasis, teniasis, teniarynchiasis): • breaking metabolic processes of helminths — aminoacriquine, acriquine • paralysing action — praziquantel, phenasal, seed of pumpkin ♦ With extra-intestinal helminthiasis: opisthorchiasis, fasciolosis — prasiquantel, chloxyl, bithionol; vucheriasis, onchocercosis — ditrazine citrate; schistosomiasis — antimonyl sodium tartrate, stibofen

183 CLASSIFICATION OF ANTIFUNGAL DRUGS

♦ For treating dermatomycosis: azoles (for the local application — clotrimazole, miconazole; for the system one — ketoconazole, etc.) antibiotics — griseofulvin acids — salicylic, benzoic dyes — brilliant green, etc. drugs of iodine — solution of iodine, potassium iodide drugs of different chemical groups — undecin, terbinafin, naphthifin, mycoseptin, etc. ♦ For treating candidomycosis: polyene antibiotics — nystatin, mycoheptin azoles — clotrimazole, myconazole representatives of other groups — decamin, cyclopirox, etc. ♦ For treating systemic mycosis: polyene antibiotics — amphotericin B, amphoglucamin, mycoheptin azoles — ketoconazole, fluconazole, itraconazole

POLYENE ANTIBIOTICS

Amphotericin B, mycoheptin; locally and per os — nystatin, levorin Mechanism of action: fungicide — because of binding with fungal membrane’s ergosterole Pharmacokinetics: they do not practically absorb in GIT and with local application as well. With i.v. amphotericin B introduction is distributed to many organs and tissues. It hardly passes through BBB, excreted by the kidneys slowly. The half-life is 24–48 hrs, but with prolong application it can increase up to 2 weeks due to cumulating Adverse effects: nystatin — allergy, gastrointestinal disorders; amphotericin B — + on i.v. introduction fever, chill, nausea, vomit- ing, headache, hypotension, phlebites, and also nephro-, hepato-, neurotoxicity, haematological reactions, electrolyte metabolism disorder, etc.

184 CLASSIFICATION OF ANTIFUNGAL AZOLES

♦ Derivatives of imidazole: the I generation (only locally 2–3 time per a day, the course — 2–6 weeks): clotrimazole, mIconazole, isoconazole, amicazole, bifonazole the II generation (locally, the course — 3–4 days): econazole, thioconazole the III generation (both for local and for the systemic therapy, once a day): ketoconazole (nizoral), sulconazole, oxyconazole

♦ Derivatives of triazole: fluconazole (diflucan), itraconazole, fluorconazole, terconazole (fungistat)

ADVERSE EFFECT OF ANTIFUNGAL AZOLES

• Gastrointestinal: nausea, regurgitation, vomiting, diarrhea • Hepatotoxicity: ↑ hepatic transaminases, up to toxic hepatitis • Nephrotoxicity: edemas • Allergic and dermatological reactions (alopecia, skin itching) • Neurotoxicity: headache, dizziness, drowsiness, neuropathy, photophobia • Endocrine: ↓ testosterone and cortisole, gynecomastia, oligospermia and ↓ libido (ketoconazole)

185 ADVERSE EFFECT OF ANTIFUNGAL AZOLES

• Haematological: thrombocytopenia, anaemia (ketoconazole, miconazole) • Biochemical shifts: hyponatriemia and hypokaliemia, hyperlipidemia • Cardiovascular system: arrhythmias (miconazole, i.v.) • Locally irritating, i.v.: thrombophlebitis • Individual intolerance • Increase action of cumarine anticoagulants, oral hypoglycemic drugs

CLASSIFICATION OF ANTIVIRAL DRUGS

♦ Interferons (interferon human leucocyte, reaferon, laferon, betaferon) and inductors of interferon (poludan, amixin)

♦ Synthetic drugs: • derivatives of amantadine — remantadine, midantane • analogs of nucleosides — ribavirin, idoxuridin, citarabin, vidarabin, acyclovir, gancyclovir; azidothymidine (zidovudin), lamivudin, etc. • different chemical groups — bonaphthon, oxoline, florenal, tebrofen, etc.

186 MECHANISMS OF ANTIVIRAL DRUGS ACTION

At all the stages of viruses replication they cause inhibition of: ♦ Adsorption and penetration to the cell — amantadine, gamma-globulin ♦ Synthesis of early non-structural proteins (polymerases of nucleic acids) — analogs of nucleosides (under action of intracellular kinase turn into active phosphorylated forms (nucleotides), which ↓ DNA, RNA synthesis and replication of virus), interferons ♦ Synthesis of final structural proteins — some antibiotics ♦ Gathering of viral parts and their exit from the cell — rifampicin

INDICATIONS TO ANTIVIRAL DRUGS

♦ Respiratory viral infections (para- and orthomixoviruses): amantadine, remantadine (influenza A), ribavarin, amixin ♦ Herpes and cytomegaloviral infection (herpesviruses): idoxuridin, citarabin, vidarabin, influenza acyclovir, gancyclovir ♦ HIV (retroviruses): azidothymidine (zidovudin), lamivudin, etc. ♦ Viral hepatitis (hepadnavirdae): interferons (+ prophylaxis, treatment of mentioned above AIDS infections + papillomae, leukemia, etc.), amixin ♦ Rabies, polyomyelitis (prophylaxis): gamma-globulin

hepatitis С

187 INTERFERONS

A group of biologically active proteins or glycoproteides (cytokines), synthesized by the cell in the process of protective reaction against alient agents (viral infection, antigenic or mitogenic influence) Types ♦ I type (mainly antiviral and antitumoral effects) — α-interferons (more than 20 proteins, produced by leukocytes, macrophages, B-lymphocytes, etc. ⇒ leukocytar; inductors — viruses) and β-interferons (synthesized by fibroblasts, epithelial cells, etc. ⇒ fibroblastic; inductors — viruses) ♦ II type (mainly immunomodulating action) — γ-interferons (by T-lymphocytes and NK-cells ⇒ lymphocytar; inductors — antigens)

INTERFERONS

♦ Natural (of the culture of human leukocyte cells, stimulated by viruses): α-ferons (human leukocytar interferon, egiferon, velferon) β-ferons (toraiferon) ♦ Recombinant (produced by bacteria with a built-in interferon gene in their genome): α-2A (reaferon, viferon, roferon) α-2B (laferon, intron-A, inrec) α-2C (berofer) β-ferons (betaferon, fron) γ-ferons (gammaferon, immukin, immunoferon) Pharmacodynamics ♦ Antiviral action — depression of replication of virus: • ↑ latent endoribonuclease ⇒ viral RNA destruction • ↑ specific proteins ⇒ ↓ viral RNA synthesis • ↓ synthesis of viral membrane proteins

188 INTERFERONS

Pharmacodynamics ♦ Antiproliferating (antitumor) action: • ↑ cytotoxic cells • ↑ expression of tumor-associated antigens, modulation of antibodies production • ↓ action of tumor factors of growth • ↓ RNA synthesis and tumor cells’ proteins • ↓ cellular cycle with transition to the “rest” phase, renewal of control after proliferation • inhibition of formation of new vessels in tumors • ↓ tumor spreading • cytostatics activity biomodulation • overcoming of drug resistance (DR) due to ↓ genes of multiple DR

INTERFERONS

Pharmacodynamic ♦ Immunomodulating action (gamma-inteferons): • ↑ macrofages and all types of cytotoxicity • ↑ expression of antigens of histocompatibility • ↑ regulation of sensitivity to cytokines • ↑ cellular and autoimmunity (factor synergist of necrosis of tumour, IL-2) • ↓ humoral immunity ♦ Antibacterial action: • ↑ indolamino-desoxygenase ⇒ ↓ intracellular tryptophan contents ⇒ metabolism of bacterial cell ⇒ its death • ↑ NO-synthetase ⇒ NO production (a powerful bactericidal factor) ⇒ destruction of bacterium cell

189 INTERFERONS

Indications ♦ Infections (treatment and prophylaxis): cytomegalovirus, herpetic infections; influenza, ARVI; acute and chronic viral hepatitis (recombinant drugs alpha and beta), severe bacterial (γ-interferons) ♦ Prophylaxis of opportunistic infections with AIDS, chronic granulomatosis, congenital T-cell immunodeficiency (γ-interferons) ♦ Oncologic diseases: sensitive tumors to interferon therapy (renal adenocarcinoma, sarcoma of the lung, melanoma, neuroblastomas, tumors of lymphoid endocrine and reproductive organs), virus-induced tumors (papillomae of the larynx, the urinary bladder, basal-cell carcinoma of the skin, etc.) ♦ Autoimmune (rheumatoid arthritis, systemic lupus erythemotosus, allergic diseases (γ-interferons)

INTERFERONS

Adverse effects ♦ Dose-dependent fever with the symptoms of influenza ♦ Asthenovegetative syndrome ♦ Gastrointestinal disorders (anorexia, diarrhea) ♦ Dermatological ♦ In case of long-time usage of high doses — reversible depression of all elements of bone marrow (thrombocytopenia, leukopenia, etc.)

190 Раrt IХ PHARMACOTHERAPY OF OTHER SYSTEMS PATHOLOGY

Topic 28 DRUGS AFFECTING FUNCTIONS OF DIGESTIVE, RESPIRATORY ORGANS, MYOMETRIUM

DRUGS AFFECTING FUNCTIONS OF DIGESTIVE ORGANS

♦ On appetite and digestive function: • stimulating • lowering appetite (anorexia-genic) ♦ On the function of salivary glands ♦ At secretory dysfunction of the stomach: • stimulating • suppressive • gastroprotectors • improving regeneration of gastric and duodenal mucosa ♦ Emetics, anti-emetics ♦ On gastrointestinal motility: • the drugs stimulating motility and purgatives, antiflatulent drugs • diminishing motility and antidiarrheal ♦ Hepatotropic ♦ Regulating the pancreas function

191 AFFECTING APPETITE AND DIGESTIVE FUNCTION

♦ Stimulating appetite: • reflex action — bitters: extracts and tinctures of bitter herbs (common centaury, wormwood, dandelion); taste and extractive substances (cinnamon, pepper, garlic, clear soups, vegetable decoctions)

• central action: H1-histamino- and serotoninoblocker — peritol (ciproheptadine) ♦ Lowering appetite (anorexia-genic)*: central action (main serotoninomimetic effect!) — derivatives of phenylalkyl- amine (the amphetamine series) — fepranon, dezopimon; serotoninomimetics — fenfluramine (izolipan), sibutramine, masendol; dopaminomimetics — bromcriptin * For treatment of obesity they use also drugs which inhibit absorption of fats: orlistate (xenical); antidiabetic drugs (biguanides), etc. ↓ appetite as well All anorexia-genic drugs are administered only by strict indications!

AFFECTING FUNCTIONS OF DIGESTIVE ORGANS

Pharmacological regulation of salivary glands secretion ♦ Stimulators — M-cholinomimetics, anticholinesterase drugs ♦ Inhibitors — M-cholinoblockers At secretory dysfunction of the stomach and intestine ♦ Stimulating: • for diagnostics — pentagastrin, gastrin, histamine • for replacement therapy — natural gastric juice, acidine-pepsin, pepsidil, abomin, panzynorm forte; carbonic mineral waters ♦ Inhibiting: still to come

192 DEPRESSING SECRETORY FUNCTION OF THE STOMACH

Indications ♦ Different acid-dependent diseases: peptic ulcer (PU) of the stomach and duodenum, functional and other types of dyspepsia, gastroesophageal reflux disease, Zollinger — Ellison syndrome (displays of gastrin-secreting neuroendocrine tumor — gastrinomes), NSAIDs-gastropathies, etc. Factors stimulating ulcer formation ♦ Male gender ♦Blood group 0 (I) ♦ High acid forming function of the stomach ♦ Smoking, alcohol abuse ♦ Stress

ETHIOPATHOGENESIS OF PEPTIC ULCER

Balance disorder ♦ Rise of aggressive factors: • Endogenic:  hypersecretion of hydrochloric acid because of ↑ mass of parietal cells, gastrin hyperfunction, nervous and humoral deregulation  ↑ pepsinogen and pepsin secretion  motive dysfunction of the stomach and duodenum (delay or acceleration of evacuation from the stomach) • Exogenous: Helicobacter pilori, alcohol, NSAIDs ♦ Weakening of protective factors: • ↓ secretion and/or disturbance of composition of gastric mucus (at alcoholism) • ↓ secretion of bicarbonates (at chronic pancreatitis) • ↓ regenerator activity of epithelial cells • ↓ blood supply of mucous membrane of the stomach • ↓ contents of prostaglandins in the wall of the stomach (NSAIDs intake)

193 TREATMENT OF PEPTIC ULCER

♦ Basis therapy (for treating exacerbations of diseases and maintaining therapy): depressing a secretory function of the stomach — antisecretory (Inhibitors of proton pump, H2-histaminoblockers, M-cholinoblockers); neutralizing secretion (antacids; refer to Topic 4) ♦ Auxiliary (by special indications): • antichelicobacter drugs: antibiotics (semi-synthetic penicillins, macrolides, tetracycline), synthetic antimicrobial drugs (metronidazole, drugs of bismuth) • gastroprotectors and improving regeneration of mucous membrane (see below), more frequent appointed for the treatment and prophylaxis of gastropathies caused by introduction of ulcerogenic drugs • normalizing motility function of the stomach and duodenum (spasmolytics, prokinetics) • for the psychoemotional correction of patient (psychosedatives, tranquilizers, etc.)

DEPRESSING SECRETORY FUNCTION OF THE STOMACH

♦ Inhibitors of H+, K+-ATP-ase (proton pump): • I generation — omeprazole • II generation — pantoprazole, rabeprazole, etc. ♦ H2-histamine blockers: • I generation — cimetidine • II generation — ranitidine • III generation — famotidine, nizatidine, roxatidine, etc. ♦ M1-cholinoblocker — gastrozepine ♦ Substances regulating intensity of CNS excitation and vegetative centers — psychosedatives, tranquilizers, antidepressants ♦ Lowering irritation of the afferent endings of the vagus nerve — antacids, enveloping drugs, astringent, adsorbents, local anesthetics

194 DEPRESSING SECRETORY FUNCTION OF THE STOMACH

Gastrin Histamine Acetylcholine123 Prosta- 123

123 glandins 123 12345678 Somatostatin 12345678М-blockers Н2-blockers 12345678 Сa2+ + 12345678 Сa2+ – 12345678– – 12345678

12345678 G- Н2- – PG- М- Adenylate cyclase Сa2+ Сa2+ cAMP Parietal cell

К+ – Inhibitors of ATP-ase proton Сl- pump Antacids – Н+

PROTON PUMP INHIBITORS

Derivatives of benzimidazole ♦ I generation — omeprazole ♦ II generation — pantoprazole, rabeprazole (pariet), esomeprazole, lansoprazole Pharmacodynamics ♦ Being weak bases, after absorption and distribution in an organism they accumulate at sites where pH are the lowest: in the acidic medium of secretory tubules of a parietal cell, where their transformation into tetracyclic sulfenamide takes place, the latter covalently by the help of disulfide bonds binds to cysteine groups of the proton pump, which results in its irreversible (!) inhibition and prolong depression of acid secretion (renewal of 1/2 molecules H+,K+-ATP-ase in 30–48 hrs); the action depends on pH: rabeprazole > omeprazole (ezomeprazole) = lansoprazole > pantoprazole ♦ They have an independent antihelicobacter effect

195 PROTON PUMP INHIBITORS

Pharmacokinetics ♦ Absorption: are quickly absorbed in the alkaline medium of the small intestine (are protected by acid-stable capsules) ♦ Bioavailability: 35–90% (omeprazole — after the repeated intake ↑ availability up to 60%); peak of concentration in the blood in 3–4 hrs ♦ Binding with proteins: about 90% ♦ Distribution is even, accumulation in tissues with low pH (parietal cells of the stomach) ♦ Biotransformation in the liver with participation of CYP 2C19 and CYP 3A4, isoenzymes of cytochrome R-450, excluding rabeprozole; omeprazole — inhibitor ⇒ ↑ toxicity of drugs metabolizing by the cytochrome R-450 system (diazepam, warfarin, phenytoin, ethanol, caffeine, anaprilin, etc.) ♦ Excretion by urine as nonactive metabolites (different T1/2)

PROTON PUMP INHIBITORS

Adverse effects ♦ Short courses up to 3 months: headache (23%), fatigue (2%), dizziness (1%), diarrhea (2%) or constipation (1%); rarely — allergic reactions (skin rash, bronchospasm); with i.v. introduction of omeprazole visual and hearing disorders are possible ♦ Prolong, continuous (a few years), especially large doses (no less than 40 mg of omeprazole, 80 mg of pantoprazole, 60 mg of lansoprazole): can result in hyperplasia of enterochromaffin cells of gastric mucosa, atrophic gastritis; to decline of vitamin B12 absorption ♦ Carcinogenic action of omeprazole was marked in the experiment in rats; it has not proved in humans yet

196 Н2-HISTAMINE BLOCKERS

♦ I generation — cimetidine (is not used today) ♦ II generation — ranitidine ♦ III generation — famotidine, nizatidine, roxatidine, etc. Pharmacodynamic ♦ Concurrent and irreversibly block H2-histamine receptors of parietal cells of the gastric mucosa ⇒ ♦ ↓ night and general daily secretion of hydrochloric acid caused by histamine as well as gastrin, cholinomimetics, ↑ vagus ♦ ↓ volume of the gastric content, basal and stimulated concentration of pepsin ♦ ↑ secretion of gastric mucus and bicarbonates (insignificantly) ♦ ↑ synthesis of prostaglandins in the stomach wall ↑ microcirculation in mucosa, ↑ reparative processes in the gastric mucosa

Н2-HISTAMINE BLOCKERS

Pharmacokinetic ♦ Absorption: in the proximal parts of the small intestine ♦ Bioavailability: 50–100%; peak of concentration in blood in 30–60 min ♦ Binding with proteins: about 90% ♦ Distribution is even; some of them (ranitidine) are lipophilic, penetrate through the placental barrier; less through the BBB ♦ Biotransformation in the liver; some (cimetidine, ranitidine) — inhibitors of microsomal oxidization of liver ⇒ ↑ toxicity of drugs metabolized by the cytochroma R-450 system (diazepam, warfarin, phenytoin, ethanol, caffeine, anaprilin, etc.) ♦ Excretion by kidneys and intestine; unchanged up to 50–90%; T1/2 — 2 hrs (cimetidine), 8 hrs (famotidine); ↑ at severe renal failure

197 Н2-HISTAMINE BLOCKERS

Adverse effects ♦ Cimetidine, rarely ranitidine, famotidine • Antiandrogenic action (binding with androgenic receptors): ↑ level of prolactin in the blood, galactorrhea and amenorrhea, ↓ spermatozoons, gynecomastia and impotence • Hepatotoxicity: ↓ hepatic blood flow, ↑ transaminase level in blood, cholestasis, rarely — acute hepatitis • Neurotoxicity (especially in elderly people): headaches, anxiety, fatigue, fever, depression, hallucinations, mental confusion, sometimes coma • Hematoxicity: neutro-, thrombocytopenia • Cardiotoxicity: arrhythmias • Nephrotoxicity: ↑ level of creatinine in the blood serum

Н2-HISTAMINE BLOCKERS

Adverse effects ♦ All the drugs in 1–2% patients — dyspeptic disorders (constipations, diarrhea, flatulence) and allergic reactions (mainly as urticaria) ♦ At sharp withdrawal (especially cimetidine) — “rebound” syndrome — the secondary hypersecretory reactions ♦ At prolong application (more than 8 weeks), especially in the high doses — a possibility of hypergastrinemia development with hyperplasia of enterochromaffin cells in the gastric mucosa; and also tolerance to the antisecretory effect with re-intakes ♦ Some patients with the gastroduodenal ulcers are resistant to these drugs ♦ Carefully during pregnancy; all H2-histamine blockers penetrate the breast milk

198 IMPROVING RESISTANCE OF GASTRIC AND INTESTINAL MUCOSA

♦ Gastroprotectors: • rendering mechanical defence of mucosa — sucralfate, drugs of colloid bismuth: colloid subcitrate of bismuth (de-nol, tribimol) • promoting resistance of mucosa to the damaging factors — dalargin, analogs of prostaglandin — misoprostol ♦ Improving regeneration of the mucosa: steroid anabolic (nerobol, retabolil), nonsteroidal anabolic (methyl uracyl, riboxin, potassium orotate), vitamin U (methylmethionine), deoxycorticosterone acetate, gastropharm, sodium oxyferriscarbon, dalargin

MODERN APPROACHES TO THE TREATMENT OF PEPTIC ULCER DISEASE

♦ Removal of disease exacerbation symptoms (optimum during 3–4 days) ♦ Achievement of ulcerous defect rapid healing (better during 14–28 days) ♦ Prevention of disease relapses (by the antihelicobacter therapy ↓ relapses rate during a year 10–15 times as much) ♦ Proton pump inhibitors (PPI) — an obligatory component of eradication antihelicobacter therapy: during 7 days • 1st line therapy (triple):  PPI (as a standard dose 2 times per a day) + claritromycin 0.5 g × 2 times per a day + amoxicillin 1 g × 2 times per a day or metronidazole 0.5 g × 2 times per a day  ranitidine + bismuth citrate (piloride) 400 mg × 2 times per a day + claritromycin 0.5 g × 2 times per a day + amoxicillin 1 g × 2 times per a day or metronidazole 0.5 g × 2 times per a day • 2nd line therapy (quadric therapy): PPI as a standard dose 2 times per a day + bismuth subsalicylate/subcitrate 0.120 g × 4 times per a day + metronidazole 0.5 g × 3 times per a day + tetracycline 0.5 g × 4 times per a day

199 AFFECTING FUNCTIONS OF DIGESTIVE ORGANS

Emetics and antiemetics ♦ Emetics (refer to Topic 4) and antiemetics ♦ Antiemetics: • central action — neuroleptics (aminazine, etaperazine), antiserotoninergic (granisetron, ondasetron, tropisetron); dopamine blockers (domperidon (motilium), metoclopramide (cerucal)), M-cholinergic blockers (atropine, scopolamine, aeron), antihistaminic (diprasin, dimedrol). • peripheral action — weakening excitability of afferent terminals of vagus (anesthezine, mint extract, menthol, enveloping, astringent) • antiregurgitants (against the reverse direction — eructation, regurgitation) — serotonin blocker and cholinomimetic cizapride

AFFECTING MOTOR FUNCTION

Stimulating ♦ Stimulating efferent innervation: M-cholinomimetics, anticholinesterase drugs, serotonin and dopamine blockers (metoclopramide, domperidone, cizapride); sodium chloride, etc. ♦ Purgatives: refer to Topic 4 ♦ Antiflatulents: synthetic — superficially active substance — simeticon (espumisan); vegetable — extracts of fennel, dill, ceraway, peppermint, chamomile, etc.

200 AFFECTING MOTOR FUNCTION

Inhibitors ♦ Inhibiting efferent innervation: M-cholinoblockers, myotropic spasmolytics ♦ Antidiarrheals: • symptomatic drugs: coating, astringent, adsorbent (lignosorb, attapulgit, smecta), spasmolytics, M-cholinoblockers, agonists of opiate receptors of the intestine — loperamide (imodium), etc. • at diarrhea caused by the infectious process: antimicrobial (phthalazole; tetracyclines, levomicetine; intetrix, entero-sediv, etc.), drugs regulating intestinal biocenosis (probiotics — biphidumbacterin, bactisubtile, linex, chilac, etc.)

HEPATOTROPIC

Basic principles of treatment ♦ Ethiotropic therapy (viral hepatitis) — antiviral and antimicrobial drugs ♦ Pathogenetic (universalism of basic links of pathogenesis of many diseases of the liver!): • hepatoprotectors • affecting processes of tissue metabolism (antioxidants, vitamins, amino acids and protein hydrolysates, peptides, steroid and nonsteroid anabolics, adaptogens) • ↑ desintoxication function of the liver and other organs (adsorbents, antidotes) • inhibitors and inductors of the microsomal systems carrying out metabolism of xenobiotics • immunomodulators • anti-inflammatory (steroid and nonsteroid) • bile-expelling • cholelitolytic: chenofalc, ursofalc 201 HEPATOPROTECTORS

“Ideal hepatoprotector” ♦ Enough complete absorption ♦ Presence of “first pass elimination” through the liver ♦ Pronounced ability to bind or prevent formation of high-active damaging compounds ♦ A possibility ↓ extremely pronounced inflammation ♦ Depression of fibrogenesis ♦ ↑ regeneration of the liver ♦ Natural metabolism at liver pathology ♦ Extensive enterohepatic circulation ♦ Absence of toxicity

HEPATOPROTECTORS

Classification ♦ Containing natural or half-synthetic flavonoids of milk thirstle (Silibium marianum — thistle, Maria flower): hepabene, legalon, carsil, hepatofalc-planta, silibor ♦ Containing natural or half-synthetic flavonoids of other plants: hofitol, catergen (cianidanol), LIV-52 (hepaliv) ♦ Organ drugs of animal origin: sirepar, hepatosan ♦ Containing essential phospholipids: essentiale, phosphogliv, essliver, eplir ♦ Drugs of different groups: bemitil, ademethionine (heptral), lipoic acid (thioctacid, berlition), hepa-merc (ornitin), etc.

202 AFFECTING FUNCTIONS OF PANCREAS

♦ Stimulators: bitters, acids ♦ Inhibitors: inhibitors of proteolysis (contrykal, gordox), phytodrugs ♦ Replacement therapy: polyenzymatic drugs of animal and vegetable origin — pancreatin, mesym-forte, festal, pansitrate, pansynorm, betain NB! Drawbacks (especially animal origin): • syndrome of “lasy pancreas” ⇒ ↑ dose 5 and more times • at insufficient bioclearance of remnants of organ tissues (additional allergens) or dangerous microorganisms (virus of spongy encephalitis, etc.) • ↓ stability and ↑ enzyme destruction rate (lipase loses 20% of its activity in 8 months after production) • inactivation in acidic gastric medium (destruction at pH < 5); it is actual in patients with ↑ acidity and ↓ evacuation rate from the stomach ♦ Normalization of function: antihomotoxic drugs — momordica compositum, hepar compositum, etc., antioxidants, etc.

AFFECTING FUNCTIONS OF RESPIRATORY ORGANS

♦ Stimulators of breathing: analeptics (refer to Topic 10) ♦ Expectorants: (refer to Topic 4) ♦ Antitusive drugs • Non-narcotic:  inhibiting mainly central link of tussive reflex — glaucin, tusuprex  inhibiting mainly peripheral link of tussive reflex — libexin, falimint • Narcotic: codeine phosphate, ethylmorphine hydrochloride, estocin ♦ Used at pulmonary edema: (refer to Topic 29)

203 AFFECTING FUNCTIONS OF RESPIRATORY ORGANS

♦ Used at bronchial asthma and bronchospastic states: • Bronchodilating (broncholytics):  adrenomimetics — salbutamol, fenoterol, isadrine, ephedrine, etc.  M-cholinoblockers — ipratropium  Myotropic spasmolytics — theophylline, aminophylline, no-spa  combined — ditec, berodual, broncholytin, solutan • Antiallergic and desensitizing:  glucocorticosteroids — prednisolone, beclomethasone, budesonide, etc.  stabilizators of mast cells — cromolyn-sodium (intal), ketotifen  H1-histamine blockers — dimedrol, suprastine, tavegil, histadin, etc.  antagonists of leukotriene receptors — zafirlucast, montelucast

AFFECTING MYOMETRIUM

♦ ↑ uterine muscles (uterotonics): • Stimulating labour activity (cause tonic contractions of a pregnant uterus)  biogenic — oxytocin (2–5 U), pituitrin, estron, serotinin, dinoprost, dinoproston, prostenone, vitamins B1, C  vegetable — pachicarpin, quinine, castor oil  synthetic — isoverin, anaprilin, proserin, salts of calcium • For stoppage of the uterine bleeding (cause the tetanic contractions):  biogenic — oxytocin (10 U);  vegetable — ergot alkaloids (ergometrin, ergotamine, ergotal), as well as sferofizine, barberry piperidge, shepherd’s purse, water pepper, etc.  synthetic — cotarnine chloride

204 AFFECTING MYOMETRIUM

♦ ↓ uterine muscles (utero-, tocolytics): • Beta-adrenomimetics — salbupart, partusisten, ritodrin • Cholinergic blockers — atropine sulfate • Hormonal drugs — gestagens (progesterone, norcolut) • Drugs for anesthesia — nitrogen protoxide • Tranquilizers — sibazon • Vitaminic drugs — tocopherol acetate • Different — magnesium sulfate

205 Раrt Х PHARMACOLOGY OF EMERGENCY

Topic 29 PHARMACOTHERAPY OF ACUTE POISONINGS AND STATES OF EMERGENCY

ACUTE POISONINGS

A human uses regularly more than 60,000 xenobiotics; ≈ 500 new chemical substances get to the market annually Factors determining toxicity ♦ Physical-chemical properties of toxin ♦ Dose (concentration), way and rate of toxin penetrating an organism ♦ Biological species (a man, animals), age, sex, weight, individual features (genetic predisposition, diet, concomitant diseases, etc.) ♦ Other factors: geographical, temperature, chronological, ecological, industrial, etc.

206 PHYSICAL AND CHEMICAL PROPERTIES OF TOXIN

(state of aggregation, degree of dispersiveness, crystalline polymorphism, volatility, solubility in different liquids, degree of ionization)

♦ Toxicity of potential gases ↑ than liquid and solid substances ♦ The higher dispersion of solid toxins, the higher degree of their toxicity ♦ The amorphous substances develop ↑ toxic effect ♦ The ↑ volatility, the ↑ risk of poisoning (↑ adsorption) ♦ The most ↑ molecules are adsorbed with an average coefficient of distribution (liquid/water) ♦ The ↑ lipid solubility, the ↑ penetration into an organism (↑ damage of the skin and membranes of the cells)

PHYSICAL AND CHEMICAL PROPERTIES OF TOXIN

♦ Toxicity of water-soluble toxins is directly proportional to the degree of their solubility in water (insoluble barium sulfate is nontoxic, and its other water-soluble salts are toxic) ♦ ↑ toxicity reactive chemical groups of toxin, stereochemical structure and its electronic activation ♦ Affinity of a toxin to a receptor, stability and dynamic quality of this bond are determined by its optical and geometrical structure, distribution and electronic conformation of a molecule ♦ Toxin ionization degree is directly proportional to its toxicity; for example, toxicity of heavy metals compounds determines their ability to release ions of metals (a metallic mercury even with i.v. introduction is nontoxic, and the small doses of chloride and mercury oxide result in lethality)

207 DOSE OF TOXIN

The most important factor determining substance toxicity! Depending on the lethal dose (LD)* the substances are divided into 6 categories (by Hodge and Gleason):

1. Supertoxic — LD100 = 3 mg/kg and less 2. Extremely toxic — LD100 = 5–50 mg/kg 3. Great toxicity — LD100 = 50–500 mg/kg 4. Moderate toxicity — LD100 = 0.5–5 g/kg 5. Small toxicity — LD100 = 5–15 g/kg 6. Practically nontoxic — LD100 > 15 g/kg

* LD10; LD50; LD100 — the dose causing death in 10, 50 and 100% cases accordingly; ED50 (effective, or average therapeutic) — the dose causing a necessary effect in 50% patients

CONCENTRATION, WAY AND RATE OF TOXIN PENETRATION INTO AN ORGANISM

Concentration — a dose of liquid and gaseous substances is expressed by concentration: 5 ml of concentrated sulfuric acid cause mortal damages; 0.2–0.3% solutions are harmless ♦ Maximum possible concentrations (MPC), mg/m3: tetraethylene lead — 0.005 (in the USA — 0.1); vapours of mercury — 0.05; compounds of lead — 0.2; nicotine — 0.5; carbon oxide — 9.0; acetone — 9.4 (in the USA 10 times greater); sulfur dioxide — 13.0; aniline — 19.0 (in the USA 10 times greater), phenols — 19.0; tetrachlorethan — 65.0; methanol — 260.0 Way of introduction: ♦ by toxicity: inhalation > i.v. > enteral > through mucous > transcutaneous ♦ by frequency: 85.6% — through the GIT; 11.6% — respiratory tracts; 2.7% — through the skin; 0.1% — other (placenta); Rate of introduction: depends on physical-chemical properties of toxin (lipophility) and site of penetration (vascularization, etc.)

208 BIOLOGICAL SPECIES

♦ Foxglove and Belladonna (Digitalis et Belladonna) are extremely toxic for a man and safe for herbivorous ♦ Datura stramonium (datura), containing atropine and scopolamine, is toxic for man and nontoxic for animals ♦ Toxicity of atropine ↑ in rabbits, and foxgloves ↓ in rats ♦ Poison of may-bugs (cantarida) is mortal for human and safe for birds ♦ Phenylthiourea (rat poison) causes a pulmonary edema in rats; for monkeys is nontoxic (LD50 for rats — 5 mg/kg, rabbits — 40 mg/kg, hens — 100 mg/kg, guinea-pigs — 250 mg/kg) ♦ Herbicide of “paraquate” is toxic for rats and nontoxic for human

FEATURES OF AN INDIVIDUAL

♦ Age: children (underdevelopment of the systems and organs participating in adsorption, biotransformation and excretion of toxins), persons of elderly and senile age are the most susceptible (disease of liver, kidneys, etc.) ♦ Gender: women are more sensitive (especially during pregnancy, lactations, mensis): • LD50 for rat-male — 4.01 mg/kg, for female — 1.81 mg/kg ♦ Weight: predetermines a dose of toxin ♦ Feeding: • protein feeding ↓ toxicity • hypolipidemia ↑ toxicity of heptachloride • honey ↓ toxicity of alcohol ↓ • Vitamins B6, B12 toxicity of lead, isoniazide ♦ Genetic features (for example, change of the enzymatic systems: “rapid” and “slow” acetylators, oxidants, etc.) and concomitant pathology (foremost of the liver, kidneys): change kinetics of a substance, converting it into poison or ↑ its toxicity

209 TYPES OF POISONINGS

♦ Clinical-evolution (acute, subacute, chronic) ♦ Social-legal: • intentional (suicides, murders, toxicomania and drug addictions) • Unintentional or accidental ♦ Ethiologically determined (poisonings by mushrooms, carbon monoxide, hydrocanic acid, methyl alcohol and other technical alcohols) Statistics of the World Health Organization ♦ Poisonings take place as a rule under the age of 16 ♦ Intentional — 80% (in women — 67%, men — 33%); accidental — 20% (in women — 40%, men — 60%) ♦ Acute poisoning are 2–3 times more frequent in women (26% — 17–20; 53% — before 30; 6% — 60 years old and older)

COMBINATIONS OF POISONINGS

♦ Synergism: • summation (addition): addition of toxins actions through the identical mechanisms — 1+1 = 2 (tetrachlormethane and dichlorethane; adrenaline and noradrenaline; etc.) • potentiation: ↑ toxicity due to other toxin — 1+1 > 2 (alcohol and calcium cyanamide; toluene and buthylacetate; buthyl alcohol and tetrachlormethane; peroxide of hydrogen and sulfur dioxide (CO2); etc.) ♦ Antagonism: 2 and more toxins ↓, accumulate or reverse effects of each other — 1+1 < 2 or = 0 (sodium and calcium citrate; heavy metals and SH-groups; etc.) ♦ Synergism-antagonism

210 CLASSIFICATION OF TOXINS

♦ Supertoxic — military poisoning substances (MPS), arsenous anhydride, strychnine, a row of already forbidden insecticides (thiophos, mercaptophos), etc. ♦ Highly toxic — industrial poisons and chlorinated insecticides (tetrachlormethane (CCl4), dichlorethane, isocyanates, etc.), agents polluting the air (ozone, carbon tetrachloride, nitrogen, sulfur dioxide, etc.) ♦ Moderate toxic — agents polluting the air (carbon oxide, benzol, phenol, toluene, etc.), POC (phosphoorganic compounds), chlorphenoxyl herbicides, etc.

12345678 ♦ Low-toxic — hydrocarbons of the methane row, 12345678POISON! bipyridine herbicides (paraquate)

EXAMPLES OF TOXINS TROPISM

♦ Neurotropism — some MPS row, POC, opioids, barbiturates, tranquilizers, analeptics, etc.

♦ Hepatotropism — industrial poisons and chlorinated insecticides: tetrachlormethane (CCl4), dichlorethane; phosphorus, etc.

♦ Nephrotropism — mercury, acetic acid, etc.

♦Hematosis — agents polluting the air: carbon oxide, benzol, phenol, toluene; nitrates (methemoglobinemia), arsenic (hemolysis), etc.

211 ACUTE POISONING RATE

♦ Drugs — 55.4%: • polymedicamentous — 25% • benzodiazepins — 17% • opioides — 15% • phenothiazines — 12% • barbiturates — 8% • antidepressants — 7% • different groups — 13% • unknown — 3% ♦ Insecticides* — 11.4% (from them POC — 41.4%) ♦ Ethyl alcohol — 8.6% ♦ Fungicides*/raticides* — 5.0% ♦ Toxic gases — 3.3%: • carbon-monoxide fumes (carbon oxide) — 80.7% • domestic (utilitarian) — 11.4% • bog (methane) — 5.3% • welding — 1.6% • sewage — 0.8% * refer to “Pesticides”

ACUTE POISONING RATE

♦ Mushrooms — 2.6% ♦ Industrial toxic liquids (antifreezes, etc.) — 2.1% (trichlorethylene — 28%; formaline — 23%; ethylenglycol — 18%; chlormethyl — 13%; anyline — 8%) ♦ Organic solvents — 2.4% (turpentine — 58%; acetone — 21%; CCl4 — 4%; toluene — 4%) ♦ Methyl alcohol — 1.2% ♦ Detergents — 1.9% ♦ Oil-products — 1.7% (petrol — 69%; kerosene — 16%; solar oil — 9%) ♦ Caustic substances (from Gr. kaustikos — burning) — 1.7%: caustic soda (concentrated alkaline solution, with the help of which the metal is processed for neutralization of acid or deleting organic materials like lubricating oils or paints) — 40%; calcinated — 18%; sulfuric acid — 9%; nitrous — 7%; nitric — 5%, hydrogen peroxide — 5% ♦ Unknown poisons — 5.1%

212 PESTICIDES

(from Lat. pestis — contagion, caedo — kill) — chemical drugs for the fight with wreckers and diseases of plants, weeds, ectoparasites of domestic animals, carriers of dangerous diseases of man and animals, as well as substances, facilitating harvesting (defoliants and desiccants), regulators of plant growth (auxines, gibberellins, retardants), etc. There are distinguished the substances for the fight: ♦ Insecticides — with the harmful insects; ♦ Accarisides — with ticks ♦ Herbicides — with the undesirable vegetation ♦ Zoocides — with harmful vertebral (rodenticides — with rodents, raticides — only with rats) ♦ Fungicides, bactericides, virusocides, nematocides — with fungal, bacterial, viral, nematode diseases of plants ♦ Molluscocides — with harmful shellfishes ♦ Repellents — frightening off harmful insects, ticks from mammals and birds, and antifidings — frightening off insects from plants ♦ Attractants — for attracting arthropoda with the purpose of their destraction ♦ Chemosterilizators — causing infertility in insects, rodents, ticks

PHASES OF TOXIN ACTION

I phase — II phase — III phase — pharma- pharmaco- pharmaco- ceutical kinetic dynamic

Adsorp- interaction Dose toxin tion Adsorption Action Effect desintegra- with Pharma- distribution tion biological receptor, ceutical metabo- “readi- lism tissue, dissolution of “readi- ness” a target ness” active sub- Excrection organ stance

Exposition Toxicokinetic Toxicodynamic

213 AID AT ACUTE POISONINGS

1. Prevention of further poison income to an organism 2. Acceleration of poison excretion from an organism POISON! 3. Usage of antidotes: ♦ before absorption (inhibiting its further income to an organism) ♦ after absorption 4. Normalization of major physiological functions of an organism

PREVENTION OF POISON INCOME AT POISONING

♦ Through the lungs: to take a patient to the fresh air, protection of respiratory organs, inhalation of oxygen ♦ Through the skin, mucosa: washing off the running cool water; if necessary — by weak alkalines (sodium hydrocarbonate) or acid solutions (lemon and other organic acids) ♦ per os: а) to cause vomiting (by the mechanical way or hypertonic salt solution — 1 table spoon of sodium chloride on a glass of water); it is forbidden in unconscious persons and at poisoning by cauterizing poisons b) gastric lavage several times (in 3–4 hrs) up to complete clearing by the warm water and/or with the use of drugs of binding and inactivation of poison (see below), at coma — through the probe

214 REMOVAL OF POISON FROM ORGANISM (1)

♦ Unabsorbed: usage of salt (!) laxatives (25.0 magnesium or sodium sulfate), cleansing enemas, stimulation of intestinal peristalsis ♦ Absorbed: • forced diuresis — for removal of hypovolemia and disturbances of electrolyte balance at first i.v. 400–800 ml polyglukin, 1.5–2 l of physiological solution or 5% solution of glucose or salt solutions, and then drastic diuretics: manitol (15–20% solution at a rate 1– 1.5 g/kg of the weight) or furosemide (60–90 mg); if necessary polarizing mixture • change of acid-base balance of urine for ↓ poison reabsorption in renal tubules and ↑ their excretion (control of ABE):  with poisoning by weak acids (barbiturates, salicylates, sulfonamides, herbicides, etc.) — urine alkalinization: 1,000 ml of 4% solution of sodium hydrocarbonate  with poisoning by weak bases (alkaloids) — acidifying urine: ascorbic acid at a rate 2 g on every 400 ml of isotonic solution of sodium chloride

REMOVAL OF POISON FROM ORGANISM (2)

• Hemosorption — removal of toxins from the blood and regulation of hemostasis by the way of blood contact with a sorbent outside of organism (poisoning by chloramphenicol, depressants of CNS, cardiac glycosidess, etc.) • Hemodialysis — is based on the phenomenon of selective diffusion through the half-permiable membrane, which from one side is washed by blood, and from the other one — dialysating solution — an “artificial kidney” (poisoning by bromides, chloralhydrate, ethanol, ethylenglycol, isopropyl alcohol, methanol, lithium, heavy metals, salicylates) • Gastrointestinal dialysis — removal of poisons from GIT after their excretion through the gastric mucosa by irrigation of stomach and intestine by the isotonic solution of sodium chloride • Peritoneal dialysis — introduction of dialyzing solution to the peritoneum, exchange between it and blood and toxins excretion with solution • Method of physiochemotherapy (UVI) — is based on the ultraviolet irradiation of blood • Method of plasmapheresis — replacement of a part or all plasma in patient • Blood transfusion, etc.

215 ANTIDOTES

Drugs for treating poisonings with the purpose of detoxication and removal of the toxic effect caused by poison; the action is based on the phenomenon of antagonism By the mechanism of action ♦ Physical-chemical: use of physical-chemical reactions (adsorption) ♦ Chemical: use of chemical reactions (oxidizations, binding, sedimentation, neutralization) for detoxication ♦ Physiological (functional): functional antagonists for biological substrate of an organism (receptor, enzyme, etc.) ♦ Immunological: antitoxic serums By selectivity of action ♦ Unspecific ♦ Specific By the term of action: ♦ Before absorption of poison — physical-chemical and a number of chemical (as a rule, unspecific) ♦ After absorption — chemical, physiological (as a rule, specific)

REACTIONS OF INACTIVATION OF NONABSORBED POISON IN THE GASTROINTESTINAL TRACT (1)

♦ Adsorption — adsorbents (absorbed carbon 30–50 g on 100 ml of water 10 min before gastric lavage) and enterosorbents (poisoning by alkaloids, glycosides, NSAIDs, salts of heavy metals, etc.) ♦ Oxidization — gastric lavage by 0.1–0.25% solutions of potassium permanganate (universal oxidant with poisoning by alkaloids) ♦ Neutralization — gastric lavage with application of: • weak acids (1% acetic, lemon) — poisoning by alkalines • weak alkalines (5% solution of sodium hydrocarbonate) — poisoning by acids • thiosulfate sodium (30% solution) — poisoning by iodide, salts of metals (formation of nontoxic sulfites) • soapy solution — poisoning by detergents

216 REACTIONS OF DETOXICATION OF NONABSORBED POISON IN THE GASTROINTESTINAL TRACT (2)

♦ Binding: • tanin precipitates alkaloids, glycosides, heavy metals • iodide extract (15 drops on 100 ml of water) — Pb, Ag, Hg, quinine, strichnine • starch — iodide ♦ Sedimentation (formation of insoluble products): • copper sulfate — poisoning by phosphorus (insoluble phosphorous copper) • magnesium sulfate — poisoning by salts of barium (insoluble barium sulfate) • sodium chloride — poisoning by nitrate of silver, bromides, lithium • calcium gluconate — poisoning by oxalic, hydrofluoric acids ♦ An egg-white (no less than 10 items), milk (are contraindicated with poisoning by liposoluble poisons), enveloping (mucuses, jelly, kissel) — poisoning by irritating and cauterizing poisons (acids, alkalines, salts of heavy metals) bind and sediment too

АNTIDOTES AFTER ABSORPTION OF POISON

Antidotes Toxin Mechanism of action Chemical Complexones: Cyanides, cardiac Complexoforming with formation ethylendiaminotetraacetate glycosides, heavy of the chelate compounds (EDTA), penicillamine metals Deferoxamine Iron The same (100 mg bind 8.5 mg of iron) SH-groups donators: Metals, cardiac Complex compounds with unithiol, acetyl cysteine glycosides, metals, toxic metabolite (para- paracetamol, cetamol), concurrence dichlorethane forbinding with SH-groups of proteins (↑ affinity) Protamine sulfate Heparin Forms a stable complex (by 100 IU heparin — 1 mg of protamine) Physiological Atropine Muscarin, POC M-cholinoblockator Physostigmine Atropin-like Inhibitor of acetylcholinesterase Proserin Nondepolarizing The same ⇒ weakening of myorelaxants neuromuscular block 217 ANTIDOTES AFTER ABSORPTION OF POISON

Antidotes Toxin Mechanism of action Physiological Dipyroxime, POC, Reactivators of cholinesterase alloxime anticholinesterase Flumazenil Benzodiazepines Antagonist of benzodiazepine receptors Naloxone Opioids Antagonist of opiate receptors Sodium nitrite Cyanides Methemoglobin-forming, concurrent with cyanide after cytochromoxidase (formation of cyanhemoglobin) Sodium Cyanides, heavy Converts cyanhemoglobin into thiocy- thiosulfate metals anate; with metals forms insoluble sulfides Methylene dark Cyanides; In the high doses converts blue methemoglobin- oxyhemoglobin in methemoglobin forming (aniline, (with poisoning by cyanides); in the nitrates, small doses restores methemoglobin chlorates, etc.) in hemoglobin

АNTIDOTES AFTER ABSORPTION OF POISON

Antidotes Toxin Mechanism of action Physiological Ascorbic acid Cyanides see Methylene dark blue Cyanocobalamin Cyanides Functional antagonist Vicasol Indirect Antagonist on the mechanism of anticoagulants action Pyridoxine Isoniazid Removal of hypovitaminosis Calcium chloride Magnesium Antagonists, ↓ activity of sulfate dependent enzymes Sodium chloride Lithium, bromides The same; ↑ bromide excretion Ethyl alcohol Methyl alcohol, Concurrent for the enzyme of ethylenglycol alcoholdehydrogenase ⇒ ↓ formation of toxic metabolites Bemegride Barbiturates, Physiological antagonists general anesthetics

218 ANTIDOTES IN CASE OF POISONING

♦ By salts of heavy metals: • SH-groups donators — unithiol (poisoning by Hg, As, Sb, Co, Zn, Cr, Ni), i.m. 7–10 ml 5% solution each 6 hrs • complexones — EDTA (poisoning by Pb, Cd, Ni, Cr, Cu, Mn, Co) i.v. droply 20 ml 5% solution in 200 ml physiological or 5% solution of glucose; penitcillamine (the Cu, Hg, Pb poisoning) — 0.2% solution by 1 ml i.v. on physiological saline or s.c.; sodium thiosulfate (poisoning by Hg, As, Pb), i.v. 50 ml 30% solution ♦ By cyanides: EDTA, i.v. droply 20 ml 5% solution in 200 ml physiological saline or 5% solution of glucose; nitrite of sodium, i.v. droply 10–15 ml 3% solution; sodium thiosulfate, i.v. 50 ml 30% solution; methylene dark blue, i.v. 50–100 ml 1% solution in 25% solution of glucose (“chromosmon”); and also ascorbic acid, i.v. 1 g slowly; cyanocobalamin, i.m. 100–1000 mg ♦ By methanol, ethylenglycol: ethyl alcohol, 30% solution 50–100 ml orally, each 2 hrs by 50 ml and i.v. droply 100–400 ml 5% solution about 1 ml/(kg·day) ♦ By paracetamol, dichlorethane: acetylcysteine, i.v. 10 ml 5% solution

ANTIDOTES IN CASE OF POISONING

♦ By cardiac glycosides: • SH-groups donators — unithiol, i.m. 7–10 ml 5% solution each 6 hrs • complexons — EDTA, i.v. droply 20 ml 5% solution in 200 ml physiological saline or 5% solution of glucose • potassium salts (panangin), i.v. 10–20 ml in 100 ml of physiological saline • monovalent antidigoxin serum ♦ Iron preparations: deferoxamine, i.m. 1–2 g repeatedly in 12 hrs; i.v. 15 mg/kg every 1 hr (DD about 80 mg/kg) ♦ Benzodiazepines: flumazenil, i.v. 0.2 mg during 30 sec to the general dose of 3–5 mg, 0.2% solution on 1 ml i.v. on physiological saline or s.c.; euphyllin, i.v. 1 mg/kg ♦ Opioids: naloxon, i.v. 0.4–1.2 mg up to 2 mg ♦ Barbiturates: bemegride, i.v. 10 ml 0.5% solution, 3–4 injections untill reflexes restore ♦ Magnesium sulfate, oxalic acid, salts of fluorine acid: calcium chloride, i.v. 5 ml of 10% solution i.v. stream infusion during 3–5 min

219 ANTIDOTES IN CASE OF POISONING

♦ Bromides: sodium chloride, 0.9% solution of i.v. droply ♦ Muscarine: atropine sulfate, i.v., i.m., s.c. 0.6–1.2 mg in 15 min until complete atropinization ♦ POC: cholinesterase reactivators — aloxime, dipyroxime — 1 ml 15% solution i.m. or i.v., in each 3–4 hrs, or droply i.v. 250–400 mg/hr; atropine sulfate, i.v. 0.6–2 mg in 15 min until complete atropinization ♦ Atropin-like: physostigmine, i.v., i.m., s.c. 1–2 mg every 1–2 hrs ♦ Undepolarizing myorelaxants: proserin, i.v. 3 ml 0.05% solution in 10 ml physiological saline or 10–12 ml 0.05% solution s.c. during 20–30 min ♦ Direct coagulants (heparin): protamine sulfate, i.v. stream infusion 1 ml 1% solution (1 mg — 100 IU of heparin) ♦ Indirect coagulants (neodicumarin): vicasol, i.m. 1 ml of 1% solution ♦ Carbon monoxide: inhalation by 100% oxygen

SYMPTOMATIC THERAPY

♦ At respiratory disturbances of different ethiology (respiratory obstraction, bronchospasm, larynx and lungs edema, respiratory center depression, paralysis of respiratory muscules): • providing patency of airways • endotracheal probing and ALV (at the pre-hospital period — respiratory analeptics) • if necessary — oxygen, broncholytics ♦ At vascular tonus dysfunction: • ↓ ABP (poisoning by hypnotics, ganglioblockers, sympatho- and adrenolytics, drugs of myotropic action): at SBP below 80–90 mm Hg — to raise the feet on 20 cm; hemodynamic plasmosubstitutors; at hypervolemia — dobutamine i.v. 2.5–10 mcg/kg per 1 min; for ↑ renal blood flow — small doses of dopamine (5 mcg/kg per 1 min); at neces sity alfa-adrenomimetics, glucocorticoids; ↑ SBP up to 100 mm Hg • ↑ ABP (poisoning by the vasoconstrictive drugs, analeptic, fenamine): hypotensive drugs of emergency aid (i.m., i.v. — myotropic, ganglioblockers, saluretics, alfa-adrenoblockers; sublingually — beta-adrenoblockers, vasotropic calcium channels blockers, etc.)

220 SYMPTOMATIC THERAPY

♦ At disturbance of cardiac activity (myocardial defeat, tachy- and bradyarrhythmias, heart arrest): see Antiarrhythmic drugs; at heart arrest — defibrillation ♦ At convulsive syndrome (poisoning analeptics, anticholinesterase, H-cholinomimetics, phenothiasine derivatives, insulin, strichnin and other convulsive poisons): tranquilizers (diazepam, i.v. 2–4 ml 0.5% solution on 20–40 ml 40% glucoses); barbiturates (hexenal, thiopental, i.v. 10 ml 1% solution), magnesium sulfate i.v., i.m. 25% 10 ml ♦ At renal dysfunction: catheterization, BV renewal, at the low blood pressure — dobutamine ♦ At disturbance of the body temperature: • hyperthermia (poisoning by tranquilizers, barbiturates, antihistamines): ventilation, ice-pack, cold rub-down with acetic acid, lytic mixtures • hypothermia (poisoning by neuroleptics, opioids, alcohols): warm, rub-down with ethyl alcohol (30–40%)

SYMPTOMATIC THERAPY

♦ At metabolic disturbances: • acid-base balance: acidosis — 4% solution of sodium hydro- carbonate; alkalosis — 1% solutions of lemon, ascorbic acids • electrolyte balance: drugs of potassium (panangin, asparcam), calcium (calcium gluconate), sodium (sodium chloride) ♦ During dehydratation (pronounced vomiting, diarrhea): hemodynamic plasmosubstitutes ♦ At the acute pain syndrome: narcotic analgesics (for preventing shock development) ♦ At psychomotor excitation: neuroleptics (aminazine, haloperidol, droperidol) ♦ At hypoxia of different ethiology (disturbance of breathing and circulation, hemolysis, blockade of respiratory enzymes, change of haemoglobin): measures directed at removal of indicated defeats; antihypoxants

221 EXTREME STATES

Acute heart failure (AHF) ♦ Clinical syndrome characterized by the rapid appearance of symptoms of ↓ cardiac output, insufficient tissue perfusion, ↑ pressure in the lung capillaries and tissue congestion as a result of disturbance of contractile ability of the myocardium, ↓ systolic and minute heart volume (myocardial infarction, myocarditis, arrhythmias, heart diseases, a sudden myocardial overload (in the aorta — hypertensive crisis; in the pulmonary artery — thromboembolia of the pulmonary artery, etc.), decompensation of chronic heart failure, etc.) • With the congestive type of hemodynamics:  right-ventricle AHF — venous congestion in the systemic circulation  left-ventricle AHF — cardiac asthma, lung edema • With hypokinetic type of hemodynamics: cardiogenic shock — arrhythmical, reflex or original

EXTREME STATES

General measures of acute heart failure treatment

Removal of hypoxemia Respiratory support Removal of lung fluid

Hemodynamic unloading of the heart, Vasodilators reduction of pressure in the lung (nitrates), opioids capillaries (morphine)

Removal of fluid overload Diuretics (furosemide)

Keeping sufficient cardiac output, Cardiotonics increase of myocardial contractility (glycoside and nonglycoside)

222 EXTREME STATES

Treatment of acute heart failure at the pre-hospital stage ♦ Right ventricle: liquidation of the main cause (thromboembolia of branches of pulmonary artery, asthmatic status etc.), ↓ hypoxia, influence on blood flow in the pulmonary artery ♦ Left-ventricle (lung edema): • removal of “respiratory panic” — narcotic analgesics (morphine) • ↓ pre-loading and ↓ pressure in the system of pulmonary artery — diuretics (furosemide), nitrates, morphine • ↓ post-loading — nitrates, other vasodilatators • inotropic stimulation of heart — cardiotonics: cardiac glycosides (digoxin), non-glycoside (dobutamine, dopamine*) • foam-suppression – vapors of ethyl alcohol, synthetic foam-suppresers • oxygen therapy, AVL * Dopamine in doses: < 2.5 mcg/(kg·min) — renal effect (stimulation of renal arteries’ dopamine receptors ⇒ ↑ renal blood flow and diuresis); 2.5–15 mcg/(kg.min) — vasodilating; > 5 mcg/(kg·min) — “+” ino- and chronotropic effects (↑ β -adrenoreceptors); > 15 mcg/(kg·min) — 1 α vasopressive effect (stimulating of 1-adrenoreceptors)

EXTREME STATES

Pulmonary edema (algorithm of treatment on the pre-hospital stage) Morphine i.v. fractionally by 4–10 ml every 10–15 min 1% solution on 20 ml physiological saline SBP < 90 mm Hg SBP ≥ 90 mm Hg

Dobutamine or dopamine i.v. (at Nitroglycerine or isosorbide dinitrate SBP < 60 — noradrenaline) per os or i.v.

Furosemide 20–80 mg i.v.

Growth of edema Growth of edema

Foam-suppression Stabilization Foam-suppression

Growth of edema Growth of edema

AVL Hospitalization AVL

223 EXTREME STATES

Treatment of left ventricle acute heart failure ♦ Any case of AHF needs immediate correction of the condition which caused it • At rhythm disturbances: antiarrhythmics • AHF with hypertensive crisis: + usage of hypotensive drugs (sodium nitroprusside) • With low cardiac output (cardiogenic shock):  fight with hypovolemia (i.v. 200 ml physiological saline) and stabilization of hemodynamics  fight with arrhythmia (at bradycardia — 0.3–1 ml 0.1% solution of atropine)  anesthesia (morphine)  increase of cardiac output and oxygenation of tissues — nonglycoside cardiotonics (dobutamine, dopamine), vasodilators

EXTREME STATES

♦ Myocardial infarction: (refer to Topic 13) ♦ Acute vascular failure — hypertensive drugs (refer to Topic 15) ♦ Spasms of smooth muscles of abdominal organs (renal, hepatic, intestinal colics) — cholinolytics, myotropic spasmolytics, non-narcotic and narcotic analgesics ♦ Hypertensive crisis: (refer to Topic 15) ♦ Anaphylactic shock: (refer to Topic 23) ♦ Hyperglycemic (diabetic) and hypoglycemic comae (refer to Topic 18)

224 Раrt ХI PHARMACOTOXICODYNAMICS

Тopic 30 PROBLEM OF PHARMACOTHERAPY SAFETY: CAUSES AND WAYS OF ITS SOLUTION

RULES OF DRUG SAFETY

We cannot do without drugs as well as without fire or cars, that is why for the comfort life we should keep not only traffic regulations or rules of fire safety, but also the rules of drug safety! To the doctors: • Never prescribe drugs when there is a minimal possibility • Prescribing drugs ask yourself: “What is the cause of patient’s complaints” or “How can I help him?”, instead of “Which preparation should I prescribe?”

225 RULES OF DRUG SAFETY

To the patients: ♦ You should consult your doctor before making any changes in the scheme of treatment ♦ Try give no credence to advertisement. As a rule, negative properties of a drug are not highlighted at all or insufficiently expounded in the advertisement and drug’s efficiency is set too high ♦ If you have got instructions or advices at a pharmacist, before following them, necessarily discuss this problem at your doctor. A pharmacist can not fully estimate your state: he has neither analyses, nor possibility of examination, nor sufficient qualification — he is not tought to cure people

PHARMACOLOGICAL SUPERVISION

is the state system of gethering, scientific estimation of information about adverse effects of drugs at their medical usage with the purpose of adoption of proper regulations (Article 29A, part 5a of Statute of Pharmaceutical Charter of EC Legislation)

226 REASONS FOR PHARMACOLOGICAL SUPERVISION CREATION

♦ Bitter experience of drugs usage history ♦ Search and creation of drugs with the high biological activity ♦ Imperfection of system of pre-clinical and clinical research of drugs ♦ Sharp increase of available drugs in a doctor’s store ♦ Difficulties in detection of adverse effects of drugs and definition of their frequency and severity, medical errors ♦ Increase of poor quality and falsified pharmaceutical production

DEMANDS TO A MODERN DRUG

♦ Efficacy and safety (proved at pharmacoepidemiologic researches)

♦ Presence of a drug in the standards of treatment (application corresponds to modern scientific knowledge about disease management)

♦ Appropriateness for a patient

♦ Availability for a patient (being at the market and low costs)

227 PHASES OF CLINICAL RESEARCHES OF DRUGS

PHASE I Ranging, Healthy (or ill), study of 20–50 clinical-phar- pharmacokinetics, persons macological pharmacodynamics PHASE II Clinical Patients (necessarily control 60–300 research group of patients), study of pharmacokinetics, pharmaco- dynamics, determination of effective doses PHASE III Official clinical Study of efficiency, safety in 250–1,000 tests the range of offered doses in and more comparison with other drugs PHASE IV Postregistration Supervision after safety and (after being on efficiency, continuation of 2,000– sale in the official researches 10,000 pharmacy) and more

DEGREE OF PROVED RELATIONSHIP OF AE/AR WITH INFLUENCE OF DRUGS

AE development coincides with development of DEFINITE drug action, the reaction corresponds to the picture of AR, at withdrawal is removed, with re-intake appears again AR development coincides with development of PROBABLE drug action, the reaction corresponds to the picture of AR, at withdrawal is removed, the effect cannot be explained by the current pathological process AE development after the drug administration, the reaction corresponds to the picture of AR, it can be POSSIBLE explained by both a pathological process manifestation and drug action AE development after the drug introduction, the reaction does not correspond to the pictures of drug CONDITIONAL action onset, effect cannot be explained by the cur- rent disease The case does not correspond to the above-men- DOUBTFUL tioned criteria

228 CLASSIFICATION OF ADVERSE REACTIONS TO DRUGS

1. DOSE-DEPENDENT (type A) — organotoxic ♦ Associated with pharmacological activity ♦ At drug overdose ♦ In case of drug interaction

2. DOSE-INDEPENDENT (type B) — unpredictable ♦ Immunological reactions (allergy, disturbances of immunobiologic properties) ♦ Pseudoallergic reactions ♦ Pharmacogenetic variability (idiosyncrasy)

CLASSIFICATION OF ADVERSE REACTIONS TO DRUGS

3. AT PROLONG APPLICATION ♦ Adaptive changes ♦ At drug withdrawal (“rebound”, “withdrawal”, abstinence syndrome) ♦ Organotoxic action 4. DELAYED ACTION ♦ Blastomogenic (carcinogenic) ♦ Associated with reproductive function and fetus (decreased fertility, mutagenicity, teratogenicity, embryo- and fetotoxicity) ♦ Drugs in the breast milk

229 FACTORS PROMOTING ADVERSE REACTIONS

Unconnected with drug action ♦ Peculiarities of a patient’s organism (age, gender, genetic, susceptibility to allergy, specificity of the disease course, harmful habits, etc.) ♦ External factors in relation to a patient (pharmacotherapy conducted by a doctor, ecological, working conditions, etc.) Connected with drug action ♦ Peculiarities of the clinical-pharmacological characteristics of the drug ♦ Adequacy of its choice ♦ Method of drug application ♦ Interaction of drugs at polypragmasy Connected with drug quality ♦ Substandard drugs ♦ Falsified drugs

CIRCUMSTANCES AFFECTING SAFETY OF DRUG USAGE IN UKRAINE

♦ Putting drugs without prescription ♦ Uncontrolled advertising of drugs ♦ Illegal sale of drugs and narcotics over the Internet ♦ Increase of self-treatment practice and treatment in a drug-store ♦ Increase of production and sale of falsified and substandard drugs ♦ Increase of folk medicine drugs application outside the countries having cultural traditions of their use ♦ Increase of application of homoeopathic and phytopreparations, BAS in complex with other drugs

230 DEVELOPMENT OF ADVERSE EFFECTS OF DRUGS — FUNDAMENTALS (I. M. Mikhailov, 2002)

♦ Any drug may cause adverse reaction ♦ Adverse effects of drugs are diverse, may be specific and simulate clinical manifestations of the disease ♦ The patients (in pediatrics — parents, tutors, in psychiatry — tutors) must be fully informed about adverse effects of the drugs, especially during a long therapy course ♦ A doctor should register (!) every case of adverse effects and in time inform (!) the state regulation system organs about it

BASIC WAYS OF DRUG USAGE SAFETY PROBLEM SOLUTION

♦ Development of optimal system of control after drug usage safety — pharmacological supervision

♦ Introduction and development of record card system

231 APPROACHES TO OBJECTIVE DETECTION OF ADVERSE EFFECTS

VOLUNTARILY EPISODIC ORGANIZED ACCIDENTAL REPORTS REPORTS (Cards of spontaneous reports) METHODS

OTHER SYSTEMS OF SUPERVISION ORGANIZATION (prospective, retrospective, population statistics, etc.)

METHODS OF OBTAINING REPORTS ABOUT DRUG ADVERSE EFFECTS

Spontaneous reports

Prescription Active monitoring monitoring of hospitals METHODS

Study in the groups Reports of drug of patients producers

232 THE FACTS SHOULD BE INFORMED ABOUT

About all adverse effects/actions of drugs registered in Ukraine 1. Unknown and unpredictable (which were not mentioned in a loose-leaf and instruction for the medical application) 2. Serious (any leading to death, hospitalization, disability) 3. Predictable probable (proved) 4. Possible (symptoms, disease, coinciding by term with drug action onset) 5. At drug interaction 6. At pregnant women, during lactation, on fetus and newborn 7. At abuse and development of dependence

PROBLEMS ARISING IN CASE OF REVEALING DRUG ADVERSE REACTIONS

♦ Determination of the causal relationship of drugs ♦ Severity of the disease course can mask the manifestations of the negative properties of drugs ♦ Complication of quantitative estimation of real contribution of a few simultaneously administered drugs to development of adverse effects ♦ Unknown real frequency of adverse effects ♦ Revealing of postponed manifestations of adverse effects ♦ Personal attachments and persuasions of specialist in relation to efficiency and safety of a definite drug

233 PURPOSE OF DRUG ADVERSE EFFECTS MONITORING

♦ Early detection of new adverse effects ♦ Estimation of drug advantage over an existing one ♦ Analysis of impartially obtained information ♦ Bringing changes in instructions, card records and protocols of treatment ♦ Improvement of treatment quality

RECORD CARD SYSTEM

it is an informational-methodological strategy of organization of health care under conditions of market economics, which is capable to provide the modern qualitative medical health The aim Improvement of pharmacological treatment and optimization of expenditures for rendering medical care The main principle Application of economically expedient and available drugs with proved efficacy under direct indications

234 RECORD CARD SYSTEM

The main elements ♦ Treatment standards ♦ Record card reference books — a list of drugs containing objective and clinically important information about carefully selected (vital) drugs in the items of definite nosologies

Types of record cards ♦ For different levels of rendering medical care (primary, specialized, highly specialized) ♦ For different territorial levels: • State (The state record card of drugs: 2 ed. — Kyiv, 2010) • Regional • Local (treatment and prophylactic institutions) and personal

RECORD CARDS OF DRUGS

important instruments for resolving the problems of medication because they

♦ Give precise, modern and independent information about drugs, which allows neutrolize aggressive commercial advancement and advertisement of drugs ♦ Favour a proper usage of the most safe, effective and high quality drugs ♦ Favour rejection from more toxic, ineffective and low-quality drugs ♦ Favour effective expenditure of means for drugs and increase availability of vital drugs

235 RECORD CARD PROCESS

♦ Estimation of efficacy, safety, economic efficiency, cost, comfort in drug usage ♦ Organization of the work of record card committees in regions and phamacotherapeutical commissions in treatment and prophylactic institutions ♦ Selection and formation of drug lists on the basis of this estimation ♦ Preparation of record card guidences ♦ Training of doctors (and other medical workers) in rational administration of drugs ♦ Creation by a doctor of a personal doctor record card ♦ Training of patients in correct application of drugs

MODERN APPROACHES OF THE DOCTOR FOR DECREASING THE RISK OF ADVERSE EFFECTS

♦ To compare the risk and possible role of pharmacotherapy ♦ To know clinical and pharmacological characteristics of an administered drug and other drugs which are possible to be administered in case of joining the other disease or in case of emergency ♦ To be convinced that the patient realizes which drug he is administered and won’t increase a possible risk connected with the drug usage because of the lack of information, light-headedness and inefficiency of the prescribed drug

236 REFERENCES

1. Белоусов Ю. Б. Клиническая фармакология и фармакотерапия / Ю. Б. Белоусов, В. С. Моисеев, В. К. Лепахин. – 2-е изд., испр. и доп. – М. : Универсум Паблишинг, 1997. – 530 с. 2. Венгеровский А. И. Лекции по фармакологии / А. И. Венгеровский. – М. : ГЭОТАР-Медицина, 2006. – 704 с. 3. Дроговоз С. М. Фармакологія на допомогу лікарю, провізору та студенту : підручник-довідник / С. М. Дроговоз, В. В. Страшний. – К., 2002. – 480 с. 4. Катцунг Б. Базисная и клиническая фармакология. В 2-х т. / Б. Катцунг. – 2-е изд., доп. и перераб. – СПб. : Бином Диалект, 2007. 5. Кресюн В. И. Врачебная рецептура с общей фармакологией : рук. для студентов-медиков и врачей / В. И. Кресюн, В. В. Годован. – 2-е изд., доп. и перераб. – Одесса : Одес. гос. мед. ун-т, 2005. – С. 118–209. 6. Машковский М. Д. Лекарственные средства / М. Д. Машковский. – 15-е изд., перераб., испр. и доп. – М. : Новая Волна, 2007. – 1206 с. 7. Фармакологія / В. М. Бобирів, Ю. Ф. Крилов, І. С. Чекман [та ін.]. – К. : Здоров’я, 1996. – 416 с. 8. Фармакологія / за ред. акад. І. С. Чекмана. – К. : Вища школа, 2001. – 490 с. 9. Фармакология: общая, частная и основы клинической : учебник / под ред. В. М. Виноградова. – 2-е изд., доп. и перераб. – Л. : ВМА, 1985. – 515 с. 10. Харкевич Д. А. Фармакология / Д. А. Харкевич. – Изд. 9-е, перераб. и доп. – М. : ГЭОТАР-Медицина, 2006. – 736 с.

237 LIST OF ABBREVIATIONS

AB — antibody ABE — acid base equilibrium ABP — arterial blood pressure ACC — acetylcysteine AcCoA — acetylcoenzyme A ACE — angiotensin-coverting enzyme ACH — acetylcholinesterase ACTH — adrenocorticotropic hormone ADH — antidiuretic hormone (vasopressin) AE — adverse effect (of drugs) AH — acetylcholine AHF — acute heart failure AIDS — acquired immunodeficiency syndrome ALG — antilymphocytic globulin AMI — acute myocardial infarction AP — action potential APTT — active partial thromboplastine time AR — adverse reaction ARP — absolute refractory period ARVI — acute respiratory viral infection ASA — acetylsalicylic acid ATG — antithymocytic globulin ATP — adenosine triphosphate AT-receptors — angiotensin receptors AVL — artificial ventilation of lungs BAS — biologically active substances BBB — blood brain barrier BV — blood volume CA — catecholamine cAMP — cyclic adenosine monophosphate CG — cardiac glycosides cGMP — cyclic guanosine monophosphate CHF — chronic heart failure

238 CM — chilomicrones CNS — central nervous system COG — cyclooxygenase COGI — cyclooxygenase inhibitors COMT — catecholorthomethyltransferase CRF — chronic renal failure CRH — corticotropin-releasing-hormone CS — cholesterol CVS — cardiovascular system D — dopamine receptors DA — dopamine DBP — diastolic blood pressure DD — daily dose DDs — drug disease DF — drug form DH — delayed hypersensitivity DIT — diiodothyronine DN — daily need DNA — deoxyribonucleinic acid DOCA — deoxycorticosterone acetate DR — drug resistance ECG — electrocardiogram ED — effective dose EDTA — ethylene diamine tetraacetate EEG — electroencephalogram ERP — effective refractory period ESR — erythrocyte sedimentation rate FAD — flavin adenine dinucleotide FFA — free fatty acids FMN — flavinmononucleotide FSH — follicle-stimulating hormone GABA — gamma-aminobutyric acid GCP — good clinical practice GIT — gastrointestinal tract GLP — good laboratory practice GMP — good manufacture practice GnRH — gonadotropin-releasing hormone Gr+, Gr- — gram-positive and gram-negative microflora GRT — good retail trade GTP — guanosintriphosphate GWT — good whole-sale trade H1,2 — histamine receptors hCG — human chorionic gonadotropin HDLP — high density lipoproteins HF — heart failure

239 HR — heart rate ICD — international classification of diseases ICP — intractranial pressure IDLP — intermediate density lipoproteins IH — immediate hypersensitivity IHD — ischemic heart disease IIDM — insulin-independent diabetes mellitus i.m. — intramuscular introduction i.v. — intravenous introduction LA — local anesthetic LD — lethal dose LDLP — high density lipoproteins LH — luteinizing hormone LMWH — low-molecular weight heparin LP — lipoproteins LPO — lipid peroxidation LSD — d-lisergic acid diethylamide MAC — minimum alveolar concentration MAO — monoamoni oxidase MBC — minimum bactericidal concentration MBV — minute blood volume MIT — monoiodothyronine MPC — maximum possible concentrations M-receptors — muscarinic receptors MPS — military poisonous substances N- — nicotine receptors NA — noradrenaline NAD — nicotinamide dinucleotide NADP — nicotinamide dinucleotide phosphate NH — nonfractional heparin NS — nervous system NSAIDs — nonsteroidal anti-inflammatory drugs PABA — P-aminobenzoic acid PAE — postantibiotic effect PASA — paraaminosalicylic acid PC — prostacycline PDE — phosphodiesterase PG — prostaglandins PGE2 — prostaglandin E2 PGI2 — prostaglandin I2 POC — phosphoorganic compounds PPI — proton pump inhibitors PTH — parathormone PU — peptic ulcer

240 PUFA — polyunsaturated fatty acids RAS — reninangiotensin system RF — reticular formation RNA — ribonucleinic acid RP — rest potential RRP — relative refractory period RS — reticular structure S — serotonin SA — sulfonamides Sa-node — sinoatrial node SBP — systolic bloody pressure s.c. — subcutaneous introduction SG — sulfhydryl groups SSRI — selective serotonin re-uptake inhibitors SLE — systemic lupus erythematosus SRS-A — slowly reactive substance STH — somatotropic hormone SV — stroke volume of blood T — temperature of the body T1/2 — half-life of the drug T3,T4 — tri-, tetraiodothyronine TAD — tricyclic antidepressants TG — triglycerides Th — thyroid THP — tetrahydropholate TTH — thyreotropic hormone TxA2 — thromboxane A2 VLDLP — very low density lipoproteins WHO — World Health Organization

241 CONTENTS

Part V. Drugs affecting metabolism ...... 3 Topic 18. Hormonal drugs of polypeptide and aminoacid structure. Antihormonal drugs ...... 3 Topic 19. Hormonal drugs of steroid structure, their analogs and antagonists...... 29 Topic 20. Vitamin drugs. Enzymatic drugs and inhibitors of enzymes. Different drugs affecting metabolism ...... 44 Part VI. Drugs affecting blood system ...... 57 Topic 21. Drugs affecting erythropoiesis. Blood substitutes ...... 57 Topic 22. Drugs affecting leukopoiesis and blood coagulation ...... 70 Part VII. Drugs affecting immunity ...... 100 Topic 23. Immunotropic and antiallergic drugs ...... 100 Part VIII. Antimicrobial and antiparasitogenic drugs ...... 131 Topic 24. Disinfectants and antiseptics ...... 131 Chemotherapeutic drugs ...... 140 Topic 25. Antibiotics ...... 140 Topic 26. Sulfonamides. Antimicrobial drugs of different chemical structure ...... 161 Topic 27. Antituberculosis, antisyphilitic, antiprotozoal, antihelminthic, antimycotic antiviral drugs ...... 174 Part IX. Pharmacotherapy of other systems pathology ...... 191 Topic 28. Drugs affecting functions of digestive, respiratory organs, myometrium ...... 191 Part X. Pharmacology of emergency ...... 206 Topic 29. Pharmacotherapy of acute poisoning and states of emergency ...... 206 Part XI. Pharmacotoxicodynamics ...... 225 Topic 30. Problem of pharmacotherapy safety: causes and ways of its solution ...... 225 References ...... 237 List of Abbreviations ...... 238 Godovan V. V. Pharmacology in pictures and schemes : a handbook : in 2 volumes / V. V. Godovan ; ed. by V. I. Kresyun. — Odessa : The Odessa National Medical University, 2011. — Vol. 2. — 244 p. — English. ISBN 978-966-443-045-3 This handbook consists of two volumes and contains the questions of general and special pharmacology, history of drugs creation, mod- ern classifications of pharmacological groups, generalized data of phar- macokinetics, pharmacodynamics and pharmacotoxicodynamics of drugs applied in the modern medical practice. The material is highlight- ed in integration with other medicobiological and clinical disciplines. A schematic representation of drug action mechanisms and the effects occurring as a result of it occupies a special, unique place in the book. For the doctors, scientists, lecturers, students. UDC 615.015(075.8) BBC 52.81я73

Наукове видання

ГОДОВАН Владлена Володимирівна ФАРМАКОЛОГІЯ У РИСУНКАХ І СХЕМАХ У 2-х томах Том 2 Англійською мовою

Провідний редактор В. М. Попов Редактор Р. В. Мерешко Художній редактор О. А. Шамшуріна Технічний редактор А. В. Попов Коректор О. В. Титова Поліграфічні роботи І. К. Каневський

Формат 60х84/16. Ум. друк. арк. 15,51. Тираж 5. Зам. 1511.

Видавець і виготовлювач Одеський національний медичний університет. 65082, Одеса, Валіховський пров., 2. Свідоцтво суб’єкта видавничої справи ДК № 668 від 13.11.2001.

V. V. GODOVAN HRAOOYI ITRSADSCHEMES AND PICTURES IN PHARMACOLOGY

Vladlena Vladimirovna Godovan belongs to a new generation of the Odessa school of pharmacologists and clinical pharmacolo gists headed by a Corresponding Member of the National Academy of Medical Sciences of PHARMACOLOGY Ukraine, Honoured Worker of Science and Technology of Ukraine, professor V. I. Kre syun. Vladlena Vladimirovna occupies a pro minent place in it. Doctor of medical sci IN PICTURES AND SCHEMES ences, professor of the General and Clinical Pharmacology Department, dean of the Medical faculty of the Odessa National Medical University, scientific secretary of the In 2 volumes Odessa department of the Ukrainian Pharma cologists Association, a leading research worker of the State Expert Center of the Ministry of Health of Ukraine, scientific sec retary of a specialized council. Basic direc Volume 2 tions of her scientific activity are search and creation of drugs on the basis of natural metabolites of a human organism, including coordinating compounds of germanium with bioligands; elaborations in the field of clinical pharmacology of hepatoprotectors and drug usage safety. She is an author of more than 300 scientif ic works, including 2 monographs, 35 training handbooks, manuals, dictionaries in Uk rainian, Russian and English, 18 patents of Ukraine and certificates of authorship.

The ODESSA NATIONAL 2 MEDICAL UNIVERSITY