(An-Non, Aesthesis-Sensitivity, Pain) at the Site of Inject

PHARMACOLOGICAL DESCRIPTION OF LOCAL ANAESTHETICS Local anaesthetics (an-non, aesthesis-sensitivity, pain) at the site of injection decrease reversibly the sensitivity of nerve endings and/or block nerve impulse formation and conduction through the nerve fibers. First of all LAs decrease pain sensation, then other types of sensation. As LAs mainly inhibit pain receptors and sensory nerve fibers, that`s why practically are used in the certain part of body to inhibit pain sensation. Action mechanism

LAs in the sensory nerve fibers block potential–dependent Na channels. LAs consist of 3 parts – aromatic ring, hydrophyllic group and intermediate chain, which can be either etheric or amide.

Aromatic ring determines drug lipophylicy (entrance through tissues), amine group – affinity toward receptors, intermediate etheric or amide chain - effect duration. For the optimal activity the ratio between lipophylic and hydrophyllic groups is necessary. LAs are weak basis. They are used as hydrochloride salts to increase their solubility and stability in the water. In tissues` weak basic environment (pH=7.4) they are hydrolyzed releasing free basis. The free basis are solved in lipid bilayers, have good penetration through nerve endings and nerve fibers, where are transformed into ionized-cationic form. LAs` cationic form interacts with receptors, which are located in the inner site of Na –channels and block channels. LAs block open Na channels increasing their inactivated state.

LAs don`t have action on the closed Na channels in the resting state.

Selectivity of LAs LAs in the different dosages can block nerve impulse conduction through sensory, autonomic and motor fibers. The sensitivity of nerve fibers toward LAs depends on the nerve fiber myelinization level, frequency of impulse generation, diameter. The most sensitive are nonmyelinated C fibers and myelinated thin A delta fibers, which are generating high frequency and long-lasting action potentials. As a result first of all pain impulses are blocked. In somatic afferent nerves the blockage is going by the following sequence: pain sensation >heat sensation > tactile sensation > deep pressure sensation.

In myelinated fibers LAs block impulse conduction in Ranvye nodes, by the way in 3 Ranvye nodes blockade is necessary. The thicker is nerve fiber the more is distance between Ranvye nodes. That`s why tactile, deep pressure sensitivity conducting nerve fibers and motor nerve fibers are less sensitive toward LAs. Besides, motor nerve fibers are less sensitive toward LAs, because they are generating impulses with low frequency and short duration. In the inflammation site, because of acidosis, dissociation of LAs hydrochloride salts and formation of free basis is deteriorated, resulting in the weakening of the action of LAs.

Classification of LAs by the chemical structure 1. Esthers Cocaine

3 Procaine (Novocaine) Tetracaine (Dicaine) Anaesthesine (Benzocaine) 2. Amides Lidocaine (Xilocaine) Trimecaine (Mesocaine) Bupivacaine (Marcaine) Articaine (Ultracaine)

Pharmacokinetics Estheric LAs are hydrolyzed fastly in blood by pseudocholinesterase enzyme. Their duration of action is 1.5-1 hour. Amide LAs are metabolized in liver by microsomal enzymes. Their duration of action is 2-3 hours. Bupivacaine action duration is 6 hours, leading to long-lasting anaesthetic effect.

Demands for LAs: high selectivity of the action, high efficacy for all types of local anaesthesia /universality/, additional vasoconstrictor action, short latent period of action, long duration of action, low toxicity.

Types of local anesthesia and drugs

Superficial (terminal anesthesia) Superficial anaesthesia is developed due to inhibition of sensory nerve endings (terminals).

For superficial anaesthesia are used drugs with high lipophylicy, which have good penetration through pain endings. Usage of LAs on the surface of tongue leads to loss of sensations by the following sequence bitter> sweet > sour > salt Only for the superficial anaesthesia drugs with high toxicity are used, which are not useful for other types of anaesthesia (Cocaine, Tetracaine), also drugs which have bad solubility in water (Anaesthesine). Anaesthesine as ointments and powders is used for the treatment of wounds, as tablets in a case of gastric diseases. Mepivacaine, Bupivacaine, Lidocaine, Trimecaine, Articaine are used also in superficial anaesthesia, because they have sufficient efficacy and low toxicity. By the anaesthetic activity and toxicity there is the following sequence of drugs. Tetracaine>Cocaine>Mepivacaine>Bupivacaine>Benzocaine=Lidocaine=Articaine>Trim ecaine. Superficial anaesthesia is used in opthalmology, for the treatment of burnings, in dentistry and LOR-practice.

Conductive anesthesia LAs are injected in the tissues surrounding large nerve trunks. In the trunk`s sensory nerve fibers impulse conduction is blocked, leading to sensory loss (first of all pain sensation) of that part of body which is innervated by the following trunk.

In the mixed nerves impulse is inhibited firstly in sensory nerves than in motor nerves. The less is the distance of CNS to the injected site, the more is anesthesia surface. For the conductive anesthesia Bupivacaine, Lidocaine, Articaine, Trimecaine, Procaine is used. The spinal anesthesia is the example of conductive anesthesia. Solutions in small volume are injected in subarachnoid or epidural space. Impulse conduction is inhibited in spinal cord dorsal roots leading to regional anesthesia and myorelaxation.

Infiltration anesthesia

LAs are injected in the surgical surface layer by layer leading to blockade of sensory nerve endings and sensory nerves. Procaine, Trimecaine, Bupivacaine, Lidocaine, Articaine are used for infiltration anesthesia.

Drugs` diluted (0.25 % - 0.5%) solutions with large volume (till 800ml) are used for infiltration anesthesia. The large volume of diluted solution is expanded on the surface, but its` diffusion is insignificant, meanwhile concentrated solution in small volume isn`t expanded well, but has good diffusion. Less toxic drugs are used for infiltration and conductive anesthesia, because LAs can be absorbed having systemic toxic effect. Vasoconstrictors (adrenomimetics - adrenaline, noradrenaline, mesatone, xylometazoline, naphthyzine), vasopressine are used to decrease systemic toxic effect of LAs, to increase their duration of action and to decrease the possibility of bleeding. Overdosage of adrenomimetics increases the possibility of edema development at the site of injection, decreases wound healing, increases blood pressure, leads to arrhythmias development, makes injection more painful. Lidocaine and Articaine are used for all types of anesthesia.

Interaction with other drugs Anticholinesterases increases the action of esthers. The product of hydrolysis of esthers – paraaminobenzoic acid decreases the bacteriostatic effect of sulfanylamides.

7 Side effects of LAs

1. Systemic effects All LAs from the site of injection can be absorbed leading to systemic effects.

CNS: For the first period all LAs leading to CNS stimulation followed by inhibition. It is explained by the fact that LAs are inhibiting firstly CNS inhibitory neurons. In the higher doses LAs are inhibiting all neurons.

At the middle therapeutic concentrations, all LAs have the ability to produce sleepiness, light-headedness, visual and auditory disturbances and restlessness. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and metallic taste. At higher concentrations nystagm and muscular twitching occur, followed by tonic- clonic convulsions.

Cardiovascular system The cardiovascular effects of LAs result partly from direct effects on the cardiac and smooth muscle membranes and partly from indirect effects on the autonomic nervous system. LAs also depress the strength of cardiac contraction and cause arteriolar dilation, leading to systemic hypotension. Bupivacaine in high dosages leads to cardiotoxicity and development of collapse.

Smooth muscles LAs dilate bronchi, uterus and decrease intestine peristalsis.

Allergic reactions The ester-type LAs are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions such as rashes, angioedema, dermatitis, asthma and rarely anaphylaxis. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to amide LAs are extremely rare. Cocaine Cocaine, an ester of benzoic acid and methylecgonine, obtains from the leaves of the coca shrub. Besides inhibition of transmission through nerve fibers Cocaine has vasoconstrictor effect which is determined by inhibition of NA reuptake.

8 High toxicity is defined by inhibition of NA reuptake in central and peripheral nervous system. Development of Cocaine dependence is defined by DA accumulation in CNS. Cocaine leads to vasoconstriction, hypertension and different types of arrythmias. Vasoconstriction leads to ischemia development at the site of injection, in a case of chronic usage by nasal way it leads to necrosis of nasal mucous membrane, and even to septum perforation. The high toxicity of Cocaine and its` high ability to cause dependence are limiting its` usage.

Adstringents

These drugs protect nerve endings from the different impulses and substances. Adstringents bind to tissues` proteins leading to formation of colloid substances – albuminates (albuminum - protein). Application of these drugs on tissues leads to formation of strong, nonpermeable cover, which protects nerve endings from the external factors.

9 They have anti-inflammatory action, because constrict vessels and decreases their permeability and exudation. They stop also bleeding. They sediment metallic salts and alkaloids.

Classification by origin 1. organic substances - tanin, cortex Quercus decoctum 2. nonorganic substances –Plumbi acetas, Liquor Burovi, Zinci sulfas. Argentum nitras

Organic adstringents Cortex Quercus- has tanning substances in large amount, which are maintained the adstringent effect of decoctum. Herba Hyperici—contains tanning substances, has hemostatic, antiseptic, anti- inflammatory effects. Flores Calendulae - has antiseptic, anti-iflammatory effect. Tanninum (halodubilic acid) is obtained from Gallae turcicae. Is administered in a form of solutions and ointments.

Anorganic adstringents In low concentration they have adstringent effect, in high concentration-burning effect. The metallic salts` local effect depends on the released anion (acid). To obtain adstringent effect the metalls forming solid albuminates (plumbum, aluminium) and weak acids, which are not damaging tissues, are more prominent. Liquor Burovi – has adstringent, antiseptic effect. Plumbiacetas- has adstringent Zinci sulfas – has adstringent, drying, bacteriostatic effect. Adstringents are administered in inflammation of skin and mucous membranes topically. Besides they can be administered per os (tanalbin, Bismuth preparations) during enteritis and collitis. Tanin solution is used in burnings, also during intoxication by heavy metalls and alkaloid salts when they are existing in the stomach. Tanin can form unsoluble complexes with them preventing their absorbtion. Tanin can form unstable

10 complexes with several alkaloids (morphine, atropine etc.). In this case stomach leavage is necessary.

The main list of drugs Lidocaine 1,2,4% solution for parenteral usage Articaine 4 % solution for parenteral usage Procaine 1,2, 10 % solution for parenteral usage Anaesthesine 5, 10% ointment Bupivacaine 0.25, 0.5 % solution for parenteral usage.

Tests The right description of LA`s molecule. 1. amine group- affinity for receptors 2. aromatic ring- drug lipophylicy 3. intermediate etheric chain- side effects 4. intermediate amide chain – duration of effect a) the all, b) 1.2.4 c) 2.3.4 d) 1.2.3 Local anaesthetics blocks sensation by the following order. a) pain- heat-deep pressure- tactile b) heat - pain- tactile -deep pressure c) pain- heat-tactile - deep pressure d) pain- deep pressure - heat – tactile Combination of vasoconstrictors with LAs is 1. decreasing systemic toxicity 2. prolonging LAs` action 3. strenghtening LAs` effect 4. decreasing the possibility for bleeding a) 1.2.3 b) 1.2.4 c) 2.3.4 d) the all

Solcoseryl is used for external, entheral usage and for injections. (Solcoseryl- pastae, Solcoseryl- ung, Solcoseryl –gel, Solcoseryl –tab, Solcoseryl –sol). Solcoseryl dental adhesive paste- it contains anaestheticpolidocanole, which rapidly leads to analgecis effect. Paste has also adhesive effect, leading to formation of protective layer. it`s used in inflammatory diseases of mucous

12 membranes: stomatitis, gingivitis, cheilitis, paradontitis, herpes, pericoronaritis, complications due to prosthesis. Solcoseryl dental gel- is used in all types wet ulcer processes, burnings, trophic ulcers. Solcoseryl –ung- is used in dry processes. Solcoseryl tab, Solcoseryl sol.- is biostimulator, is widely used as neuroprotector during brain stroke, vascular endartheritis, chronic venous insufficiency etc.: The main drug list OleumHippophae 100ml Ung Solcoseryl-20.0 Solcoseryl dental gel -20%-20.0 Tests 1. The action mechanisms of oral mucous membrane reparants: 1. stimulation of protein synthesis 2. inhibition of free-radical reactions 3. inhibition of lyzosomal enzymes release 4. stimulation of local Pgs` synthesis a) 1.2.4 b) 1.2 c) the all d) 1.2.3 2. Solcoseryl dental gel is used: 1. in all types of wet ulcers 2. in burnings 3. in trophic ulcers 4. i/v a) 2.3.4 b) 1.2.3 c)the all d)2.4 3.Tissue`s organ-specific stimulators by their selectivity are divided into: 1. Stimulators of blood system 2. Activators of bone tissue regeneration 3. Activators of cartilage tissue activators 4. Mucous reparants, regenerators

13 Pharmacological description of Analgesics This group includes general anesthetics, local anesthetics, analgesics. General anesthetics leads to reversible inhibition of CNS, which leads to loss of consciousness, as well as loss of conditional and non-conditional reflexes, decrease in skeletal muscle tone and maintenance of sufficient level of life important functions. Local anesthetics at the site of injection reversibly decrease sensitivity of nerve endings, or/and block impulse conduction through nerve fibers.

Analgesics (an-non “algos” means pain in Greek) are drugs, which selectively inhibit pain sensation. Pain formation as well as pain relief normally realizes by existence of nociceptive and anti-nociceptive systems. Nociceptive system (in Greek noceo - means injury) allows the conduction and transmission of pain impulses as well as respond to noxious stimuli. Generated by noxious stimuli impulses transfer at first to the spinal cord then to the brain. Special receptors called nociceptors are considered as a first step of pain appreciation. They are distinguished from other sorts of mechanical and other receptors by their higher threshold. Nociceptors are located in the skin, muscles, capsule of joints, inner organs and periosteal coverage. There are 3 types of nociceptors. 1. Monomodal nociceptors, which are activated by mechanical and thermal stimuli. Activation of these nociceptors causes a sensation of sharp, well-localized pain, which is called epicritic pain. Duration of this type of the pain equal to presence of such stimuli. Impulse transmission realizes by afferent (ascending) myelinated Aδ fibres, which conduct impulse rapidly (0.5- 30m/s). 2. Polymodal nociceptors which are activated by different types of stimuli. Impulse transmission is realized by non-myelinated C fibres with a low conduction velosity (0.5-2m/s). 3. “silent” nociceptors, which are activated during inflammation or tissue injury.

14 Independently of source and in the presence of intermediate neurons, the nociceptive stimuli through the C - and Aδ- fibres transfer to neurons localized in dorsal horn of spinal cord (neurons of lamina II – the substantia gelatinosa, SG). SG plays role of “gate control” in the process of transmission of afferent outflow. There are 3 pathways of impulse transmission through the dorsal horn: 1. To the motoneurons of anterior horn. An activation of such motoneurons provides a quick motor reflector reaction of skeletal muscles. 2. To the sympathetic neurons, localized in the lateral horn. Activation of such neurons provides reactions relevant to stimulation of adrenergic system such as tachycardia, rise in blood pressure, midriasis etc. 3. Accending afferent pathways to the different structures of the brain, such as medulla oblongata, midbrain, reticular formation, thalamus, hypothalamus, lymbic system, cortex. Mutual correlation between these structures provides with the pain appreciation and its evaluation and mediates formation of corresponding autonomic and behavioral reactions. Transmission of pain stimuli to the brain takes place via spinothalamic, spinoreticular and spinomesencephalic pathways.

Spinothalamic pathway (specific) is finished in specific ventral nuclei of thalamus. From this site pain stimuli run to the somatosensory part of the cortex of cerebral hemispheres, which evaluate localization of the pain (where is pain located?). Spinoreticular and spinomesencephalic pathways (nonspecific pathways) run through the medulla oblongata and reticular formation of midbrain, rich the nonspecific nuclei of thalamus, stimulate frontal cortex of brain and produce formation of affective (emotional) component of the pain and corresponding emotional worries (thalamocortical pathway- type of pain feeling). .

In nociceptive system transmission of impulse through the mentioned above pathways is realized by the presence of such mediators like glutamate, P substance, nitric oxide, calcitonin-gen-dependent peptide, cholecystokinine. Activity of nociceptive nerve terminals (as well as in other nerves) depends on voltage-dependent sodium channels. Expression of these channels causes sensitization toward external impulses, appearing during inflammation or hyperalgesia. Thus, nociception is a sum of several mechanisms which provide with peripheral impulse transmission to CNS. Pain is not always associated with the nociception due to subjective feeling at first.

17 Simultaneously with the nociceptive system there is an antinociceptive system in organism. Antinociceptive system interferes with the pain appreciation, pain impulse transmission and responds formation to the noxious stimuli. This system is a complex of different structures exerting descending inhibitory action on impulse transmission from primary nerve terminals to the intermediate neuron. Periaqueductal grey (PAG) is an important structure of descending inhibitory system. It receives impulses from different parts of the brain (thalamus, cortex, hypothalamus). Such impulses run through the nucleus raphe magnus (NRM) by serotoninergic and enkephalinergic neurons and rich dorsal horn of spinal cord where by direct action or via substantia gelatinosa (intermediate neuron) inhibit ascending spinothalamic pathway. Thus, transmitters of this part of antinococeptive system are 5- hydroxytryptamine and enkephaline. The similar inhibitory action is exerted by adrenergic descending fibres running from locus coeruleus (LC). Besides opioid, canabioid, glycin and GABA receptors inhibit release of pain mediators. Opioid antinociceptive system of brain includes neurons of central gray matter, running their axons to the hemispheres cortex, limbic system, corpus striatum, thalamus,

18 hypothalamus, reticular formation, medulla oblongata and spinal cord. Several endogen analgesic peptides are considered to be mediators of opioid antinociceptive system. At nowadays there are nearly 15 such peptides investigated which are divided into 4 groups. The main peptides are lej-enkephalin, met-enkephalin, dinorphin–A, dinorphin-B, β- endorphin. Besides that, endogen morphine and its derivatives were investigated in mammalian brain.

Opioid peptides interact with special opioid receptors. These receptors are located almost in all structures participating in pain impulse appreciation and transmission. In synapses transferring pain impulses these receptors are located in pre- and postsynaptic membranes. There are several types of opioid receptors with different affinity to endogen and exogenous opioids: 휇, 훿, 휅. Pain impulse transmitting synapses these receptors are located on the pre- (휇, ∆, 휅) and postsynaptic membranes (휇). The greek letter is defined by the first letter of the substance toward which receptor has affinity (morphine -휇 receptor, ketocyclazocine -휅 receptors etc.).

The all 3 receptors are Gi-protein-coupled receptors. Being coupled with G-protein, opioid receptors open potassium channels and inhibit opening of voltage-gated calcium

19 channels. Interaction of endogen opioids with their receptors leads to the following actions:

 휇 - receptors have selectivity to endorphins. Activation of such receptors causes analgesia, sedation, euphoria, physical dependence, respiratory depression, inhibition of GIT motility, bradycardia, miosis.

 ∆-receptors have selectivity to enkephalines. Activation of these receptors causes analgesia, respiratory depression, inhibition of GIT motility

 휅 − receptors have selectivity to dinorphines. Activation of such receptors causes analgesia, sedation, disphoria, myosis, slight inhibition of GIT motility, physical dependence is possible. Pain can be prevented or relieved by the 1) inhibition of ascendant nociceptive system 2) stimulation of descendant anti-nociceptive system 3) inhibition of pain perception. Analgesics according to their chemical structure, action mechanism and pharmacodynamic properties are divided into following groups. 1. Primary with the central action. A. Opioid analgesics 1. agonists 2. agonists-antagonists and partial agonists

B. Non opioid analgesics 1. nonopioid analgesics (Paracetamol, Metamisol, (Analgin), Mefenamic acid (see NSAIDs)), Ketorolak (see NSAIDs). 2. different drug groups (Clonidine, TCA) etc.) C. Drugs with mixed action (Opioid+ non - opioid) Tramadol 2. Primary with the peripheral action Non steroidal anti-inflammatory drugs (NSAIDs)

20 Primary with the central action A. Opioid, narcotic analgesics Narcotic analgesics selectively inhibit sensation and appreciation of the pain; reduce agitation, anxiety and different autonomic reactions associated with the pain. At therapeutic doses they do not lead to loss of consciousness, at high doses narcotic analgesics produce sleep. In a case of repeated administration these drugs lead to the development of physical and psychological dependence. Drug dependence is determined not only by psychological, emotional, social or surrounding factors, but also by genetic factors (50% cases). Classification of narcotic analgesics /NAs/ 1. Classification of NAs according to their sources Natural alkaloids of opium /opiates/ Morphine Codeine Semisynthetic opioids Diacetylmorphine (Heroine) Oxymorphone Hydrocodone Synthetic opioids Promedol Fentanyl Methadone Tramadol 2. Classification of NAs according to their type of action on the opioid receptors  Full agonists of opioid receptors -Morphine, Codeine, Promedole, Phentanyl, Methadone  Antagonists of opioid receptors Naloxone, Naltrexone  Opioids with the mixed action /partial agonists of opioid receptors- Buprenorphine, agonists-antagonists of opioid receptors – Butorfanol, Nalbuphin, Pentazocine.

21 Pharmacodynamics Mechanisms of analgesic action of NAs 1. Closing of voltage-gated Ca2+ channels and inhibition of transmitter release from presynaptic nerve terminals. The presynaptic action depressed transmitter release has been demonstrated for release of a large number of neurotransmitters including glutamate, the principle excitatory amino acid released from nociceptive nerve terminals, as well as acetylcholine, norepinephrine, serotonin, and substance P. 2. Stimulation of opening of K+ channels on the postsynaptic membrane leading to hyperpolarization. Postsyanptic receptors in the spinal cord directly inhibit pain impulse conduction to the interneuron.

Schematically illustrates the postsynaptic action at all three receptor types and the postsynaptic effect of μ receptors. The main targets for analgesic action of NAs 1. Inhibition of the ascending nociceptive pathway, in this case impulse transmission from the sensory nerve endings to the dorsal born neurons is impaired. 2. Activation of descending anti-nociceptive system (inhibitory action is increasing on the transmission of pain impulses from the afferent ways to the CNS). 3. Changing of emotional appreciation of the pain

22 Central /supraspinal and spinal/ and peripheral levels of analgesic action of NAs are known. Supraspinal inhibition is realized due to the activation of presynaptic opoid receptors. As a result inhibiton of GABA release from GABA-ergic interneurons is noticed (It is regulating activity of antinociceptive system). Inhibitory action of GABA is reduced, antinociceptive system is activated, leading to inhibition of pain conduction. Opioid analgesic action on the descending inhibitory pathway

Spinal inhibition is provided by the inhibition of impulse conduction from the primary sensory nerve terminal to the dorsal horn neurons. So impulse conduction intensity through the ascending afferent pathway is decreased, vegetative and motor reactions toward the pain are also reduced (substantia gelatinosa - SG). 2. Inhibition of release and receptors of substance P. 3.In a result of stimulation of presynaptic μ receptors opioid receptors inhibition of pain transmitter release from the non-myelinated C nerve fibres is developed.

Peripheral mechanisms of analgesic action of NAs are: Opioid analgesics have analgesic action also in topical application. In the nerve endings are revealed opioid receptors, which are activated by exogenous and endogenous opioids (especially in a case of nerve fiber damage).

23 Changes and alteration of pain appreciation is realized by the action of NAs on the higher structure of the brain, in a result of which summation of pain impulses in the thalamus is also impaired. In a result pain appreciation is changed and emotional feelings of the pain are changing also, because its perception is reduced. Even if the pain feeling is continuing it doesn’t bother the patient. By the type of action on the opioid receptors Full agonists of opioid receptors Morphine Source of morphine and other natural NA is opium, it is recieved from the plant Papaver somniferum. Opium contains more than twenty alkaloids. alkaloids which are derivatives of Phenantrene –Morphine (10%), Codein (0,5%), Thebain (0,2%) have analgesic and anticough action, alkaloids wich are derivatives of izochinoline such as Papaverine (1%), Noskapine /Narkotine/ (6%), they have spasmolytic activity, Morphine is phenatrene derivative and opium’s main alkaloid (10% concentration). It was named after son of God of sleep- Morphea. Morphine has the following central effects 1. Analgesia 2. Euphoria – liberation from fears and problems, non adequate feeling of freedom. There is a feeling of comfort and satisfaction. This brings to the development of drug dependence or such called morphinism. Some people can have bad feelings (disphoria). 3. Hypnotic-sedative action – condition of sleepiness (without loss of memory) which is followed by the superficial sleep with good dreams. 4. Anti cough /antitussive/ effect due to the inhibition of cough center. To this effect tolerance develops quickly. 5. Inhibition of respiratory centre is due to decreased sensitiveness of respiratory center to CO2 and it has a dose dependent character. Breathing becomes rare and deep even if morphine is taken in therapeutic doses. 6. In high doses there is an inhibition of vasomotor center and decrease of blood pressure.

24 7. Miosis – narrowing of pupils, which is typical diagnostic symptom of morphine addiction. Myosis is the result of stimulation of the center of nerve oculomotorius. 8. Bradycardia – is the result of stimulation of n. vagus center. 9. As a rule morphine inhibits vomiting center, but it can cause nausea and vomiting, which are aggravated in movements. 10. Action on the synthesis of hormones. Syntheses of prolactine, anti diuretic hormone /vasopressin/, growth hormone, are increased, which is due to stimulation of hypothalamic centers. Increased release of anti diuretic hormone brings to inhibition of diuresis. The secretion of adrenocorticotropic hormone, gonadotropic hormones (follicle stimulating, luteinizing) is inhibited. 11. Hypothermia. This effect is due to inhibition of thermoregulatory center of hypothalamus and decrease in heat production. 12. Predisposition to the convulsions, because of the inhibition of GABA-ergic neurons. 13. Increase of tonus of skeletal muscles (mainly flexor and respiratory muscles). This effect is realized in spinal level. Morphine has the following peripheral effects 1. Decrease of blood pressure which is developed due to the stimulation of histamine release. 2. Stimulation of histamine release can cause also bronchospasm especially in patients with bronchial asthma. Besides this mechanism morphine also acts on opioid receptors located in bronchial muscles 3. Inhibition of peristalsis of GIT, increase tonus of intestinal sphincters, decrease of pancreatic secretary action and bile production, constipation. Also spastic pains /colic/ are typical. 4. Morphine increases tonus of urinary tract, increased tone of urethra sphincter leads to urine retention. During repeated intake of morphine tolerance and drug dependence is developed.

25 Drug dependence (psychological and physical) is developed during drug repeated administration. During systematic usage physical dependence with abstinent syndrome is developed. Abstinent syndrome develops after sharp withdrawal of morphine. The first symptoms of withdrawal are lacrimation, perspiration, “goose-flesh” skin, then excitement, tachycardia, tremor, nausea, vomiting, diarrhea, severe abdominal pain, back pain even lethal outcome. These symptoms are disappeared after taking of morphine. In spite of the fact that tolerance is developed in a case of first dosage administration, in clinical practice it is developed only after 2-3 weeks of administration, because of frequent usage of middle therapeutic dosage. During high dosage and frequent administration tolerance is developed faster.  high degree of tolerance is developed to the such actions of morphine, which are euphoria, analgesia, hypnotic-sedative action, inhibition of respiratory and cough centers, euphoria, vomiting, reduction of diuresis.  Intermediate degree of tolerance is developed to the bradycardic action of morphine.  low degree of tolerance is typical for miosis, constipation, predisposition to the convulsions. Tolerance depends on the metabolic disturbances of opioid peptides and changes in sensitivity of receptors. Pharmacokinetics Morphine is injected parenterally (intravenous, subcutaneous). Major part of morphine turns into the polarized metabolites, which are eliminated by kidneys (85%), 9-12% are eliminated in unchanged form. Small part of morphine is eliminated by bile, goes to duodenum, from where again it is absorbed to the systemic blood circulation.

Uses 1. Morphine is used as analgesic in severe pains, which are connected with serious traumas, burns, malignant tumors, myocardial infarction.

26 2. Morphine is used in anesthesiology for premedication, as well as in postoperative pains. 3. Morphine can be used in renal, biliary colic, but as morphine increases the smooth muscle tonus, it is used with spasmolytic drugs /atropine, papaverine, no-spa/. Adverse effects Adverse effects of morphine are: 1. tolerance 2. psychic and physical dependence 3. inhibition of respiratory centre up to the respiratory arrest 4. constipation, retention of urine 5. nausea, vomiting 6. skin pruritus and hyperemia /release of histamine/ 7. pronounced bradycardia, sharp decrease of BP 8. dysphoria 9. rigidity of the trunk muscles

Contraindications Morphine is contraindicated in hypotension, chronic respirator insufficiency (emphysema, lung fibrosis, pulmonary heart), bronchial asthma, paralytic, spastic and obstructive diseases of GIT, prostate hypertrophy, pregnancy. Morphine is not recommended for delivering pains (it can inhibit respiratory center of fetus), for children till 2 years old and adults after 60 years old, to the feeding mothers.

Acute morphine intoxication Acute intoxication is accompanied by the coma, for which the following symptoms are typical- superficial breathing, bradycardia, myosis (which has a diagnostic meaning), but in terminal phase mydriasis is developed. Heavy intoxication leads to lethal outcome and irreversible inhibition of respiratory center. In order to restore the breathing antagonist of opiate receptors – Naloxone is given intravenously. Artificial ventilation of lungs also can be performed.

27 In acute intoxication morphine should be eliminated from organism as soon as possible (lavage of stomach by solution of potassium permanganate is performed, activated carbon, laxatives are given to the patient). Codein – opium alkaloid. It has all the effects of narcotic analgesics but its analgesic effects about 10 times weaker then morphine, but it inhibits cough center much stronger, so it is mainly used as antitussive drug and in a combination with NSAIDs . Trimeperidine (promedol) is a synthetic narcotic analgesic. By analgesic activity it is 2-4 times weaker then morphine, but it inhibits respiratory center very weakly, because of which it can be used during pregnancy for delivering pains, and also in children. Compared to morphine promedol has spasmolytic effect on instetine, bile dutcs, so it can be used in renal and biliary colic. Phentanyl – full agonist of opioid receptors (mainly inhibits μ-receptors). It’s about 100-400 times active than morphine, it is more effective than morphine and can be used in the case when morhine is not effective. Because of high lipophility phentanyl quickly penetrates into the brain, also it is distributed and cumulated in adipose tissue, where it’s slowly metabolized. Compared to other narcotic analgesics, phentanyl has rapid (effect develops in 1-3 minutes after i/v injection) and short action (20-30min). Phentanyl can be used separately or combined with neuroleptic drug-droperidol (combinated drug is known as Talamonal). Talamonal is used for neuroleptanalgesia. Metadone is the most known preparation as it is used for treatment in chronic morphine intoxication. It is also used as an analgesic. Metadon has 35 hour half time and so it is used in latest stage of malignant tumors to achieve long termed analgesia. Metadon is also a weak antagonist of NMDA receptors. It is used by the enteral rout of administration. Tolerance and dependence develop slower. The social risks of Metadone dependence are low. Mixed acting drugs. Partial agonists, agonists-antagonists Butorfanol and Buprenorphine can provide morphine-like analgesia, but euphoria is less prominent for these drugs. Nalbuphine provides analgesia and dysphoria. The main privilege of these drugs is a less probability for addiction development.

28 Antagonists of opioid receptors Naloxone and Naltrexone are included in this group. These drugs blocking μ,δ, κ- receptors eleminate all effects of NAs. Naloxone is used only by the parenteral rout of administration/ mainly i/v injections/ during acute intoxication with NAs. Naloxone can produce abstinent syndrome in patients with addiction. Naltrexone is only used by the enteral rout of administration. It is used during complex treatment of in alcohol abuse and drug addiction. Antidiarrheal drugs are (Immodium) Loperamide and Diphenoxylate. They have the similar structure with Phentanyl and Piritramidum, but don`t cross BBB and don`t have analgesic or central effects. They stimulate opioid receptors of GIT and have antidiarrheal effect. They can be administered without prescription.

Primary with central action non opioid analgesics

These drugs are considered to be analgesics-antipyretics. These drugs are (Metamisol) Analgin and Paracetamol. In contrast to NSAIDs having anti- inflammatory, analgesic and antipyretic effects, in Paracetamol anti-inflammatory action is almost absent, in Metamisol this effect is totally absent. The analgesic and antipyretic effects are determined due to central mechanisms- inhibition of COX-3 enzyme which is mainly existing in brain tissue, heart and is participating in Pg`s synthesis.

Central analgesic mechanisms are:

1. Decrease in formation of PGE in brain structures, participating in conduction and perception of pain. 2. Decrease in P substance release in spinal cord, which is mediated by PgE2. 3. Stimulation of release of endorphins, thus activation of antinociceptive system. There isn`t strict definition between NSAIDs and analgetic-antipyretics, but because their analgesic effect isn`t peripheral, but is central, that`s why they are investigated in the group of central acting analgesics.

29 Paracetamol. Paracetamol has negligible antiinflammatory action, because it has poor ability to inhibit СОХ in the presence of peroxides which аге generated in the site of inflammation, but are not present in brain.

Pharmacokinetics. In liver Palacetamol is metabolized by 3 main pathways:

1. conjugation with glucuronic acid (50%)

2. conjugation with sulfuric acid (50%)

3. hydroxylation by cytochrome P -450, leading to N-acetyl-p-benzoquinоnеiminе (NABQI)- active aryl metabolite formation, which can be detoxified due to conjugation with glutathione.

Side effects: It has hepatotoxic and nephrotoxic actions.

Acute paracetamol poisoning can occur in high dosages > 10g.

Mechanism оf toxicity is follow: N-acetyl-p-benzoquinоnеiminе (NABQI) is is detoxified bу conjugation with glutathione. When а very large dose оf paracetamol is taken, glucuronidation capacity is saturated, more of minor metabolite is fоrmеd - hераtiс glutathione is depleted and this metabolite binds covalently to proteins in liver cells (and renal tubules) causing necrosis.

Acute intoxication by Paracetamol is rarely in children till 12 years old, because in childhood Cytochrome P-450 system isn`t completely developed, that`s why Paracetamol is metabolized by glucuronization and sulfatation, leading to metabolites` formation, which are excreted in unchanged form.

For treatment of poisoning N-acetylcysteine should bе infused. It replenishes the glutathione stores of liver and prevents binding оf the toxic metabolite to other cellular constituents.

Uses: Paracetamol is оnе оf the most соmmonly used analgesic and antipyretic drug. It is combined with other NSAIDs, caffeine.

30 Pyrazolone derivative - Metamisol (Analgin) is primarily used as analgesic and antipyretic /central action/, but poor antiintlammatory. It is frequently combined with spasmolytics /Baralgin/. It potentiates the action of antihistamine drugs (Dimedrolum).The main side effect is agranulocytosis, that`s why their usage is limited.

Different group non-opioid analgesics

Clonidine is antihypertensive drug, central α2-mimetic. It has expressed analgesic effect on spinal and supraspinal level. It removes pain induced by hemodynamic disturbances. As a central analgesic Clonidine doesn`t lead to dependence. Although hypotensive and sedative action limits its usage.

Antidepressants- Amitriptillin, general anaesthetics-Ketamin, anticonvulsants- Carbamazepine, Natrii Valproate has also analgesic effect.

Analgesics (opioid+non opioid) with mixed action. Tramadol has opioid and nonopioid mechanism. Interacts with opioid receptors, inhibits 5-HT and CAs reuptake. Has less action on the respiratory and GIT system. The possibility of increase in dosage is less prominent, the potential of abuse is also less. Zaldiak is the combination of Tramadol+Paracetamol.

31 Main Drug list Morphini hydrochloridum solution 1ml, 1% Pentazocinum tablets 0.05 Tramadolum capsules- 0.05, solution 1ml ampules, suppositories-0.1 Loperamidum- capsules 0.002

Tests 1. The all below-mentioned signals are activating due to opioid receptor activation, except: a. inhibition of Ca transmission in presynaptic membrane b. stimulation of K transmission in postsynaptic membrane c. inhibition of adenylatecyclase activation d. inhibition of COX activation 2. Which functions are inhibited due to activation of antinociceptive system: 1. transmission of pain impulses 2. development of emotional reaction toward pain 3. pain perception 4. removal of inflammatory reaction a) the all, b) 1.3.4 c)2.3.4 d) 1.2.3 3. Why Loperamide doesn`t lead to dependence? 1. it has only peripheral action 2. doesn`t interact with central opioid receptors 3. doesn`t cross BBB 4. is antagonist of opioid receptors a) all, b 1.3.4 c)2.3.4 d)1.2.3

32 The pharmacology of general anesthetics General anesthetics (GAs) are drugs leading to reversible loss of all sensations and consciousness (general anesthesia). Classic anesthesia (greek. narkoo-sleep induction) is a reversible inhibition of CNS by the influence of drugs -is the condition of anesthesia and unconsciousness which is accompanied by the loss of conditional and non- conditional reflexes, skeletal muscle tone, but the functions of vasomotor and respiratory centers and the heart remain on the vital level. In the 40-th of XIX century the implementation of general anaesthesia into surgical practice corresponded to the idea of humanity. It was revolution in medicine which supported the development of surgery. General anesthetics are administered by inhalational and non inhalational ways (i/v, i/m, rectal).

Inhalational anesthetics Classification of general anesthetics Volatile liquids – Ether pro narcosi, Phthorothane, Enflurane, Izoflurane, Gases - N2O, Xenon The demands for inhalational anesthetics (IAs) IAs shouldn`t have bad taste or smell, local irritative action, shouldn`t lead to nausea and vomiting. Induction of general anesthesia and recovery from general anesthesia should be quick without any posteffect. The above mentioned is especially important for the patient. IAs should lead to the proper analgesia and relaxation of skeletal muscles. It shouldn`t be explosive (the possibility of safe usage of electrical knife and other equipments). It is especially important for surgeon. The usage of GAs should be easy, regulatory and universal and induction of general anesthesia should be easy and regulatory. GA should have wide interval for general anesthesia (high therapeutic index), shouldn`t lead to hypotension, shouldn`t have side effects, should have high general anesthetic ability (it should give an opportunity to use it in small dosages, which supports the proper oxygenation for body). It will be desirable to give a possibility have a quick changes in the depth of general anesthesia.

33 GA should be cheap, stable in a case of long-term storage. The above mentioned is especially important for anesthetist. In the modern anesthesiology i/v administration of ultra short drugs, narcotic analgesics and myorelaxants decreases the importance of the first 3 demands. The principal significance has only the danger of toxic influence. The activity of IAs is evaluated by minimal alveolar concentration (MAC). The dosage which contains 1 MAC prevents movements in response to surgical intervention in 50% of patients. The action mechanism of IAs (Theories of anesthesia) General anesthesia can be induced by the different chemical substances – indifferent gases (xenon), simple nonorganic (N2O) and organic (chloroform) substances, complex organic substances (haloalkanes, ethers). The first explanations of anesthesia were based on the physico-chemical properties of drugs. According to the lipid solubility theory there is a proper correlation between the anaesthetic activity and ability to solve in neural tissues. Then it was revealed that GA has more expressive action on synapses comparing to the action on axonal conductivity. I.P. Pavlov called general anesthesia the functional asynapsia. Based on the modern dates GAs change the physico-chemical properties of neuronal membranes` lipids and disturb the interactions between lipids and ionic channels. The transport of sodium ions to the neurons is decreasing, is maintained slightly hydrated potassium ions` outflow, is increasing the permeability of chlorine channels regulated by GABA-A receptors. The final result of these effects is hyperpolarization, leading to increase in inhibitory processes. GAs inhibit the entrance of calcium ions into the neurons, due to inhibition of N-cholinoreceptors, decreases the movement activity of Ca2+-ions in the membranes, thus blocking the calcium dependent release of neuromediators. The stages of general anesthesia The most sensitive parts for GAs are CNS polysynaptic systems, the cerebral cortex, thalamus, reticular formation, spinal cord. The most stable parts for general anesthetics are respiratory and vasomotor centers.

34 The different sensitivity toward GAs leads to formation of subsequent stages of general anesthesia. In 1920 Gvedel described the 4 classical stages for ether anesthesia, dividing the 3-rd stage into 4 levels (substages). In the modern medical practice the proper differentiation of general anesthesia stages isn`t noticed frequently, because of usage of fast acting GAs, premedication and the combination of many other drugs. The sequence of body responses toward different inhalational anesthetics can be slightly differ, but till nowadays the stages of classical general anesthesia has the important practical significance to identify the depth of general anesthesia. The stages of anesthesia caused by ether. 1. Analgesia (duration is 3-8 minutes). It is described by blurring of consciousness (disturbances in orientation, nonsense speech), firstly pain sensation is lost, then touch and temperature sensations). The consciousness is maintained, the patient can hear and see (dream like condition). Reflexes and respiration are on the normal level. This stage is explained by the fact that the cells of gelatine substance of dorsal horn of spinal cord (are supporting the induction of pain stimuli to thalamus) have the higher sensitivity for the inhibitory action of GAs. At the end of this stage amnesia and loss of consciousness is developed (inhibition of cerebral cortex, thalamus, and reticular formation). In this stage it is possible to make some little surgical procedures (for example drainage of pus). 2. Excitation (delirium lasts 1-3 minutes which is defined by the patient`s individual properties and by the quality of anesthetist). It is described by nonsense speech, motion restlesness (the will of patient to run from surgical table), reflexes are activating, the tone of skeletal muscles is increasing, vomiting is possible - due to the irritation of stomach mucous by the swallowed ether. The typical symptom of excitation is air hyperventillation, reflex secretion of adrenaline leading to tachycardia and hypertension (in this stage surgical procedure is forbidden). The mechanism of excitation is determined by inhibition of intracentral blockade (decrease in inhibitory action of the cortex on the cerebral cortex, also basal ganglions, cerebellum, brainstem and spinal cord). In this stage the inhibition of Golgii II type inhibitory cells occurs which are in normal conditions defining the inhibitory action from cortex to subcortical layers).

35 3. Surgical anesthesia, which is divided into 4 levels (it is developed after 10-15 minutes of ether inhalation). 3.1. The eyeballs` movement level (slight anesthesia). The circular movements of eyeballs are noticed, miosis with the maintenance of light reflex (reactivation of centers of oculomotor center in midbrain), the surface skin reflexes are decreasing, active respiration is maintained with the participation of intercostal and diaphragmal muscles. The end stage of this level is described by the stoppage of eyeballs` movement. 3.2 The level of conjunctival and throat reflexes (expressed anesthesia). The eyeballs are fixed, pupils are moderately narrowed, conjunctival, laryngeal, throat reflexes are absent, the tone of skeletal muscles is decreasing as a consequence of spreadening of inhibition on basal ganglions, brainstem and spinal cord. 3.3 The level of dilation of pupils (deep anesthesia) The pupils are dilating, with slight light reflex, reflexes are absent, the tone of skeletal muscles is decreased. 3.4 Ultradeep anaesthesia. The respiration is superficial and frequent, has diaphragmal type, the blockade of intercostal muscles is noticed. Ultra deep anaesthesia is very close to agonal stage. In the third stage with the deepening of depth of anesthesia the tone of skeletal muscles is decreasing, arterial hypotension is noticed, the frequency of heart beat is increasing, the depth of respiration and then frequency are decreasing. In this stage the expressive inhibition of reticular formation is noticed. Nowadays anesthetists are using expressive anesthesia stage for making surgical procedure, and for muscle relaxation - myorelaxants. 4. Agonal stage (inhibition of medulla oblongata). The respiration becomes superficial, intercostal and diaphragmal muscles` cooperative participation in respiratory movements is disturbed, hypoxia is increasing, blood becomes darker, pupils are maximally dilated without light reflex. Arterial pressure is expressively decreasing, venous pressure is increasing, tachycardia is developed, the heart contraction force is decreasing. If emergent interruption of anesthesia and reanimation won`t be organized, it can lead to death due to the arrest of respiratory center. There are volatile liquids and gases in the group of inhalational anesthetics.

36 The pharmacokinetics of inhalation anesthetics Volatile liquids and gases are easily diffused from the wall of alveolus and tissue barriers. The depth of anesthesia depends on the activity of drug and partial pressure in CNS, but the speed of induction of anesthesia and recovery from anesthesia is defined by the speed of changes in drug partial pressure. The transport of general anaesthetics from lungs to brain is defined by the pressure gradient alveoles blood brain. The factors which are influencing the partial pressure of inhalational anesthetics in the CNS (the factors which are determining induction of anesthesia and recovery from anesthesia). 1. The partial pressure of GAs in inhaled gas mixture. It is directly correlated to the concentration of drug in inhaled gas mixture. In a case of higher partial pressure the more concentration of general anesthetics will be transported into blood. 2. Lungs ventillation. It is determined by GAs supply to the alveoles. The hyperventillation supplies more drug during one minute, inhibition of respiration has the opposite action. 3. Alveolar exchange -Inhalational GAs are easily diffused by alveolar wall, but when alveolar ventillation and alveolar blood supply (perfusion) are in non proper level (in a case of lung emphysema and other lung diseases), the time for the GAs` alveolar and blood partial pressure balance formation can be postponed. 4. Lungs perfusion. The speed of induction of general anesthesia is oppositely correlated to the lungs blood flow. In a case of hypoperfusion the concentration of GAs is high in blood outflowing from lungs, that`s why induction is fastening. This condition can be noticed in a case of heart failure. 5. The solubility of GAs in blood. This factor is very important for speed of induction of general anaesthesia and recovery from general anaesthesia.The GAs having high solubility in blood (for example ethers) should be solving in blood for a long time (saturating blood) for having increase in partial pressure and reaching maximal significance, only after this the maximal effective transport of GAs from blood to brain can be developed. By this way can be evaluated the recovery speed, in this case the

37 transport direction can be simply changed, but the description of action can be the same. Thus induction and recovery speed is oppositely correlated to the GAs` blood solubility.

The GAs with the low solubility (for example N2O, sevoflurane, desflurane) can rapidly lead to induction. 6. The solubility of GAs in tissues. The relative solubility of GAs in blood and tissues determines the drug concentration in tissues at the time of equilibrium. The most of GAs are equally solved in soft tissues and blood, but has higher solubility in lipid tissues. More lipophyllic anaesthetics (ftorotane) can be diffused in lipid tissue for several hours and consequently can be slowly removed from there. GAs concentration in brain white matter is higher than in grey matter. 7. The role of brain blood flow. The brain is considered to be the organ with rich blood supply, that`s why GAs have rapid distribution to the CNS. This process can be activated by CO2 inhalation (it leads to expressive dilation of brain blood vessels), induction and recovery is fastened. CO2 stimulates respiration, which facilitates the transport of GAs from lungs to blood, which is again facilitates induction. The elimination of inhalational anesthetics After stoppage of inhalation of general anesthetics (partial pressures) gradient changes its direction, way of absorbtion (alveolar epithelium) takes the role of excretory way. The factors which are defined the speed of induction have also an important role in recovery process. Generally, general anesthetics can stay for a long time in lipid tissues, because of the high solubility and poor blood supply of lipid tissues. Skeletal muscles have sufficient accumulation of GAs, having the intermediate position between brain and lipid tissues. Most of GAs are excreted from body in unchanged form without elimination. Biotransformation is important for ftorotane, which is metabolized by 20% in liver. Other inhalational anesthetics are not metabolized.

Volatile liquids Modern liquid general anaesthetics (Phthorothane, Enflurane, Isoflurane, Desflurane) are considered to be halogen substituted derivatives of aliphatic substances. Halogens are increasing general anesthetic activity. The drugs are not burning, are not explosive, have high temperature of vaporization.

38 Phthorothane. Phthorothane easy vaporized liquid with sweet smell, without local iritative action. Comparing to other general anesthetics the solubility of Phthorothane in blood has intermediate position, induction is fast and pleasant. It is strong anesthetic. Vapours are obtained and measured by the special vaporizated equipment. The analgesic and myorelaxant effect is moderate, but potentiates the action of competitive myorelaxants. In a stage of surgical anasthesia it inhibits respiration due to the inhibition of respiratory center. Phthorothane decreases the sensitivity of respiratory center for CO2, H+ and hypoxic stimuli which are coming from carotid sinus (blockade of N- cholinoreceptors). In a case of phthorothane anesthesia arterial blood pCO2 is significantly increased, in the lungs gas exchange and binding of oxygen with hemoglobin is decreasing. It is possible for hypoxia development, for prevention it is necessary to increase oxygen concentration (partial pressure) in the inhaled mixture and make an artificial air ventillation. Phthorothane dilates bronchial smooth muscles, due to inhibitory action on parasympathetic ganglions` N-cholinoreceptors. Phthorothane, by decreasing the heart contraction force, decreases minute volume. Cardioprotective effect is defined by blockade of heart Ca2+-ions entrance. The stimulation of vagal center and direct inhibition of automatism of sinus node leads to expressive bradycardia (M-cholinoblockers are used to prevent it).

It sensitizes heart 1-adrenoreceptors toward catecholamines, that`s why in a case of ftorotane anaesthesia arrhythmia can be developed. Phthorothane induces expressive arterial hypotension by these mechanisms – except cardiodepressive action, inhibits vasomotor center, blocks sympathetic ganglions and adrenal medullary N-cholinoreceptors, has - adrenoblocking activity, dilates blood vessels, stimulates the synthesis of endothelial derived relaxing factor (EDRF, NO), decreases heart minute volume. Selective -adrenomimetic phenylephrine (mesatone) is injected i/v in a case of collapse. Noradrenaline and adrenaline with 1-adrenomimetic activity are not used because of high risk of arrhythmia.

39 The other effects of Phthorothane is increase in cerebral blood flow, intracranial pressure, the decrease in oxygen extraction by brain in spite of the normal level of oxygen supply and oxidative substrates. Phthorothane decreases uterus muscle tone. It has hepatotoxic action, because in liver it is metabolized with a formation of free radicals. The 80% of ftorotane is excreted by lungs, with an exhaled air during 1 day. The other part is oxydized in liver by cytochrome p450 or is excreted by kidneys in unchanged form. Recovery is soft and rapid, tremor, nausea and vomiting occurs rarely. Nowadays phthorothane is mostly used inhalational GA without local iriitative action, without explosive properties, with pleasant and rapid effect. The disadvantages (slight analgesia and myorelaxation) can be corrected with a combinative usage of N2O, opioid analgesics and myorelaxants. Other fluorinated inhalational GAs are cheaper in a comparison with phthorothane.

Gasous inhalational general anesthetics.

Nowadays in a medical practice, N2O is widely used as a gasous anaesthetic drug. From 1980 xenon has limited practical usage in some foreign countries.

N2O. It is colorless, without any taste gas, which is kept in liquid condition in metallic balloons under the 50 athmosperic pressure. It isn`t explosive, but maintains burning. Its` mixture with the volatile general anesthetics is explosive. N2O has bad solubility in blood and CNS lipids, that`s why anesthesia is developed very rapidly (fast induction). The general anesthesia by N2O is not deep. During general anesthesia the total inhibition of reflexes and myorelaxation is not induced. For the deep anesthesia development N2O is combined with inhalational and non-inhalational anesthetics and myorelaxants. N2O doesn`t inhibit respiratory and vasomotor centers. The post-effect after general anesthesia isn`t developed. N2O isn`t metabolized in body, is easily excreted by exhaled air, doesn`t damage liver, kidneys and brain, is considered to be less toxic. N2O is cheap and widely used in ambulator practice and in hospital conditions.

40 N2O is used for inducable (80% N2O and 20% O2), combined and potentiated anesthesia, for analgesia in baby delivering, myocardial infarction and acute pancreatitis (20% N2O). Non inhalational general anesthetics (NIGAs) (NIGAs) are administered i/v, i/m,intraosseous and rectal. NIGAs` classification according to their duration of action Drugs with short action (<15 minutes) Propofol, Ketamine, Propanidid. Drugs with intermediate duration (20-30 (60) minutes) Hexenal,Thiopental Drugs with long duration of action (>60 minutes) Sodium oxybutyrate (1.5-3 hours)

41 Barbiturates Hexenal (hexobarbital –natrium) and thiopental (thiopental –natrium, pentotal). Hexenal and thiopental are considered to be derivatives of barbituric acid (barbiturates). These drugs after i/v injection leads to very rapid anaesthesia, the anaesthetic effect lasts 20- 25 minutes. The ’’destiny’’ of hexenal and thiopental is different. Hexenal is rapidly oxydized in liver by cytochrome – P- 450 system, leading to formation of metabolites which are free from anaesthetic activity, thiopental is stored in fatty tissues and is oxydized in liver 15%/hour speed. The release of thiopental from fatty storages leads to postanesthetic sleepiness and depression. Barbiturates` sedative, hypnotic, anticonvulsant effect is due to midbrain`s reticular formation inhibition and decrease in its` activatory action on cerebral cortex. Barbiturates are indirect GABA-ergic synergists (see Anxiolytics, hypnotics). During general anesthesia complete inhibition of reflexes isn`t noticed, the tension of skeletal muscles are increasing due to the stimulation of N-cholinoreceptors (especially in a case of thiopental). Barbiturates inhibit respiratory center, decreasing its` sensitivity for CO2 and acidosis, but not for reflex hypoxic stimulants coming from carotid sinus. They are increasing the secretion of bronchial mucous, which is determined by stimulation of cholinoreceptors. These drugs stimulate the vagal center leading to bradycardia and bronchospasm. They are leading to hypotension because of inhibition of vasomotor center and blockade of sympathetic ganglions. Propofol (dipirivane). It is used in i/v injections as an isotonic lipid emulsion. Propofol is considered to be glutamate NMDA-receptor blocker, stimulates GABA-ergic inhibition, blocks neuronal potential–dependent calcium channels. It has neuroprotective action and fastens the recovery of brain functions after hypoxic damage. It inhibits lipid peroxydation, proliferation of T-lymphocytes, the release of cytokines from them, regulates prostaglandins` release. Extrahepatic metabolism has significant role for propofol elimination. The non active metabolites are excreted by kidneys.

Propofol has wide spread usage as an i/v general anesthetic. It leads to general anesthesia after 30 seconds of injection. It has painful injection, but rarely leads to phlebitis and thrombosis. This drug is used in a case of inducable anaesthesia, to maintain anesthesia and to maintain sedative action during diagnostic processes and intensive therapy. During anesthesia induction sometimes can be noticed nonregular contractions of skeletal muscles and seizures, the arrest of respiration is developed for 30 seconds (due to decrease in respiratory center sensitivity toward CO2 and acidosis). Propofol dilates peripheral blood vessels, in a 30 % of patients decreases arterial pressure. It leads to bradycardia, decreases brain blood flow and extraction of oxygen by brain tissue. It has more expressive negative inotropic effect comparing to ethomidate and thiopental. After propofol anesthesia wakening is fast, and patients` self-feeling is rapidly ameliorated. In spite of barbiturates` usage, nausea and vomiting are rarely noticed, because this drug has own antivomiting action. Ketamine (calipsol, ketalar, ketanest). I/v injection of ketamine leads to 10-15 minutes general anesthesia. Ketamine`s metabolite norketamine leads to analgesic effect lasting 3-4 hours after general anesthesia. Ketamine anaesthesia differs from classic anesthesia. It is called dissociative anaesthesia, leading to catatonia, amnesia and analgesia. Pain is absent in patients, is percepted very far, consciousness partially is inhibited, but reflexes are maintained, skeletal muscle tone is increased. This drug`s chemical structure is close to phencyclidine, because of its` psychotropic action it can be abused. Ketamine inhibits impulse conduction by specific and nonspecific ways to the cortical associative parts, particularly, inhibits thalamo-cortical connections. There are a lot of synaptic mechanisms of ketamine. It is considered to be the competitive antagonist of NMDA receptors of brain stimulatory neuromediators (glutamate and aspartate). These receptors activate neuronal membranes` sodium, potassium and calcium channels. In a case of their inhibition depolarization is deteriorated. Besides, ketamine stimulates enkephalins` and -endorphins` release, inhibits neuronal reuptake of noradrenaline and serotonine. The latest is expressed by tachycardia, increase in arterial pressure, brain blood circulation and

2 intracranial pressure. Ketamine is the only i/v general anaesthetic, which expressively stimulates cardio-vascular system. Ketamine dilates bronchial smooth muscles. During recovery from ketamine anesthesia it is possible to have posteffect - hallucinations, delirium, psycho-motor stimulation. Ketamine is not considered to be the general anesthetic with wide usage. The important effect of ketamine is neuroprotector action. Ketamine by blocking NMDA receptors, prevents neuronal overloading by ions during brain hypoxia and correspondingly the development of neurological deficit. The combined usage of general anaesthetics. Types of general anaesthesia Modern anesthesiology is not limited by one general anesthetic usage (monoanesthesia). More frequently is used the combination of 2-3 drugs (combined anesthesia). Inhalational anesthetics are combined with inhalational and also with non inhalational general anesthetics. The meaning of these combinations is determined by that fact, that excitatory stage is removed and rapid induction of anesthesia is reached. Anesthesia is started from i/v injection of thiopental (inducible drug), inducible anesthesia, which supports rapid development of anesthesia without excitation stage. It is especially important the combination of non- inhalational anesthetic with GA leading to expressed excitation stage (ether). The main basic anesthesia is started with the usage of non-inhalational anesthetics i/v administration. It is used during whole surgical procedure. Sometimes CNS inhibitory extra drugs are used for its` deepening, for the development of extra anesthesia. There is also superficial or Raush anaesthesia, which is used during short-term surgical procedures. The advantages of combined anesthesia is the possibility to decrease each compound concentration (due to potentiation), which limits toxicity and the development of side effects. The modern methods of anesthesia is neurolept- and ataralgesia. Neuroleptanalgesia is realized by neuroleptics (Droperidol) and opioid analgesics (Phentanyl) combined usage. It leads to expressed analgesic action with maintenance of consciousness, during which surgical procedures are possible.

3 Neuroleptanesthesia is also used, when N2O inhalational anesthesia (N2O 65% + O2 35%) is combined with neuroleptanalgesia.

Ataralgesia or tranquiloanalgesia is realized with the combination of phentanyl and benzodiazepins, in which conditions the expressed analgesia is developed.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

For nonsteroidal anti-inflammatory drugs (NSAIDs) the anti-inflammatory, antipyretic and analgesic actions are characteristic. NSAIDs don`t cause euphoria, don`t have hypnotic effect and don`t inhibit coughing and breathing centers. They

don`t cause addiction and are called also non-narcotic analgesics.

These drugs have nonspecific anti-inflammatory effect, which is based on the inhibition of synthesis of prostaglandins /Pg/. Pgs are the components of arachidonic acid cascade metabolism.

Phospholipids of cell membranes under the influence of phospholipase A2 release arachidonic acid (AA) and PAF (platelet activating factor). Arachidonic acid cascade is undergone by 2 pathways: cyclooxygenase and lipoxygenase. The formed eicosanoids are Pg (PgE2, PgF2α, PgD2), prostacycline (PgI2), thromboxane (PgA2), leukotriens.

By participation of cycloxygenase enzyme, from AA there are formed cyclic peroxides (PgG2, PgH2), which are unstable and convert into stable prostaglandins Pg (PgE2, PgF2α, PgD2), prostacycline (PgI2) and thromboxane (PgA2 or TXA2).

Various prostaglandins are synthesized in various tissues and manifest different biologic activities.

 Prostacycline (PGI2) is formed in endothelium, causing vasodilation and decrease of thrombocyte aggregation;

4  PgE2 is formed in macrophages and causes hyperalgesia, fever, inflammation, stimulates myometrium, decreases tonus of bronchi and peripheral vessels;  PgF2α is formed in bronchi, myometrium and causes stimulation of myometrium, increase of smooth muscle tone of bronchi and gastrointestinal tract;  PgD2 is formed in mast cells and causes decrease of tonus of mesenterial, coronary, renal vessels and decrease the thrombocyte aggregation;  PgA2 is formed in thrombocytes and increases thrombocyte aggregation, causes vasoconstriction. At participation of lipoxygenase enzyme various leukotriens and lipoxins are formed, which participate in the processes of сhemotaxis, plasma exudation, immune responses and can increase smooth muscle tone of bronchi and gastrointestinal tract.

It is established that above mentioned eucosanoids` effects are formed due to interaction with specific receptors.

For achievement of the anti-inflammatory effect the following may serve as pharmacologic targets:

 phospholipase A2 inhibition, that will result in suppression of prostaglandins, thromboxane, leukotriens and PAF synthesis;  inhibition of lipoxygenase, that will result in suppression of leukotriens synthesis;  inhibition of cycloxygenase, that will cause suppression of prostaglandins and thromboxane;  blockade of prostanoid, TAF, leukotrienic receptors

The mechanism of action of NSAIDs is the reversible or irreversible inhibition of cycloxygenase (COX).

There are 2 isoforms of COX in normal physiological conditions - COX1 and COX2.

COX-1 (called also constitutive) as a structural enzyme is constantly produced in organism, except erythrocytes. It participates in production of PG regulating physiologic processes in organism: gastroprotection , regulation of renal blood flow, glomerular filtration, removal of ions and water.

COX-2(constitutive) is constitutively present only in brain, kidneys, bones, female reproductive system.

6 COX-2 (induced) is activated in inflammation, which increases the level of PG three- fold in the inflammatory tissue. COX-2 inductors are cytokines – interleukin-1, interleukin-4, tumor necrosis factor /TNF/ etc.

Prostaglandins, produced under the influence of COX-2, promote development of inflammation. PGE2 and prostacycline induce dilation of vessels, increasing flow of blood to the inflammation site, and PGF2α constricts veins deteriorating blood outflow. In result, the capillaries in the inflammatory focus are dilated, their permeability increases, which causes swelling of tissues, hyperalgesia. PGs also have direct action on the vascular wall and increase the effects of other mediators – histamine, serotonine, bradikinine, increase the release of lysosome enzymes.

NSAIDs by the concurrent mechanism bind to COX enzyme, inhibiting it. COX-1 inhibition is accompanied by disturbance of blood coagulation, renal function and undesirable influence on gastrointestinal tract and COX-2 inhibition is accompanied by anti- inflammatory effect.

Based on the above mentioned “COX2 “ hypothesis was offered. According to this ideal medication must inhibit COX-2 production, which should be suppressed as selectively as possible in conditions of developed inflammation, not influencing significantly COX-1, leading to less side effects.

The correlation of the activities of NSAIDs in blocking COX-1/COX-2 allows judging about their potential toxicity. The less is its value, the more selective is the preparation in respect to COX-2; thus, it is less toxic. All NSAIDs block COX-1 and COX-2. Some drugs have selectivity toward one isoform of COX. Different tissues` COX has different sensitivity toward NSAIDs.

Nowadays the 3-rd isoform of COX (COX-3) is investigated, which is mainly located in brain tissue and heart.

Classification of NSAIDs

NSAIDs are classified according to their: 7 1. degree of selective inhibition of COX 2. chemical structure Classification of NSAIDs according to their chemical structure

 Salicylates - Acetylsalicylic acid (Aspirin)  Pyrazolones - Butadion, metamisol (Analgin)  Acetates - Indometacine, Sulindac, Diclofenac, Ketorolac  Propionates- Ibuprofen, Ketoprofen, Naproxen  Oxycames – Pyroxicam, Meloxicam, Lornoxicam  Sulfonamides – Celecoxib, Rofecoxib, Nimesulid  Alkanons – Nabumeton  Anthranilates – Mefenamic acid  Paraaminophenols - Paracetamol Classification of NSAIDs according to their selectivity towards various forms of COX

 Expressed selectivity toward COX-1, having very less selectivity for COX-2 - Aspirin (in small doses), Indometacin, Ketoprophen, Sulindac  Primary selectivity toward COX-1, having less selectivity toward COX-2 than COX-1- Ibuprofen, Pyroxicam, Mefenamic acid  Almost equal inhibition of COX-1 and COX-2- Diclophenac Naproxen, Lornoxicam  Expressed selectivity towards COX-2 - Meloxicam, Nabumeton, Nimesulid  Selectivity for COX-2- Celecoxib, Rofecoxib, Valdecoxib  Selectivity for COX-3 – Paracetamol (see analgesics-antipyretics)

8 Pharmacologic effects of NSAIDs

Anti-inflammatory action.

Most of NSAIDs, being organic acids, accumulate in acid medium of the inflammation focus and have a direct impact on biochemical processes. Penetration of the preparations into the inflammation tissue is promoted by heightened permeability of vessels.

NSAIDs suppress mainly exudation phase of inflammation, action on the alteration and proliferation phases is less prominent.

In the exudation phase NSAIDs:

 Inhibit prostaglandins synthesis in the inflammation focus at the expense of COX blockade. As a result, microcirculation normalizes, venous hyperemia disappears, tissues nutrition improves.  Inhibit adhesion molecules. NSAIDs inhibit synthesis and expression of adhesion molecules in the vessel endothelium and blood cells. The adhesion molecules’ inhibition disturbs cells migration in the inflammation focus.  Inhibit activity of hyaluronidase. As it is known hyaluronidase increases vessels’ permeability and degrades intercellular matrix, and inhibition by NSAIDs decrease vessel permeability.  Decrease the content of other mediators of inflammation. NSAIDs decrease the activity of enzymes participating in biosynthesis of histamine, serotonine, bradykinine.  Restrict the bioenergetics of inflammation. Energetic metabolism restricts the biochemical reactions, lying in the base of inflammation, chemotaxis, phagocytosis, proliferation of the connective tissue. NSAIDs disturb the ATP production, as they inhibit glycolysis and aerobic respiration. Most of NSAIDs inhibit ATP-ase of inflammed tissue.

9 In alteration phase NSAIDs

 Decrease formation of oxygen radicals - as the cyclooxygenase pathway is blocked, during which endoperoxides are formed, they decrease the probability of cell membranes` damage.  Stabilize lysosoms and manifest an anti-oxidant action. NSAIDs stabilize lysosomes and prevent release of hydrolytic enzymes (proteases, lipases, phosphatases), inhibit lipid peroxidation in lysosomal membranes. The anti-oxidant action of NSAIDs is conditioned by decreased formation of endoperoxides in cycloxygenase reaction, inhibition of phagocytosis and release of oxidative products from macrophages and neutrophils.

In the proliferation phase NSAIDs:

 Decrease the activity and proliferation of fibroblasts. NSAIDs supress proliferation of connective tissue, as they restrict activity of stimulators of fibroblast division (serotonine, bradykinine) in the inflammation focus and disturb energy production, providing the proliferative process. In a result, they decrease collagen and acid mucopolysaccharides (hyaluronic, chondroitine sulphuric acids) synthesis and prevent disorganization of connective tissue. Analgesic action.

The analgesic action of NSAIDs is manifested by 2 mechanisms: central and mainly peripheral.

Peripheral action

1. elimination of hyperalgesia. They inhibit synthesis of PGs. They are factors which increase the sensibility of nociceptors to chemical and mechanical stimuli. Generally, the analgesic effect of such preparations is especially expressed in inflammation.

2. Decrease of edema, pain is reduced, because of decrease in compression of pain endings in restricted cavities (joints, muscles, periodont, meninges). Thus, NSAIDs decrease 10 pain impulse conduction from the inflammed site to CNS. The above-mentioned mechanisms are peripheral mechanisms of analgesic action.

Central analgesic mechanisms

4. Decrease in formation of PGE in brain structures, participating in conduction and perception of pain. 5. Decrease in P substance release in spinal cord, which is mediated by PgE2. 6. Increase of anti-nociceptive system activity defined by release of endorphins and serotonine. For example Paracetamol has only central analgesic action, which is defined by COX-3 inhibition.

Antipyretic effect.

NSAIDs normalize body temperature at fever, but do not lower normal temperature. Decrease of the heightened temperature is due to increased heat irradiation without significant change in heat production. In this, the antipyretic agents principally differ from other hypothermic agents, which increase heat irradiation as well as decrease heat production (neuroleptics, opioid analgesics).

Fever is of the manifestations of the protective reaction of the organism to infection, inflammation, malignant tumor. In the development of fever they attach importance to versatile factors (exogenous – bacterial, viral, fungous, chemical, etc; endogenous – products of tissue alteration, hematomas). Under their impact, there are activated granulocytes, monocytes, macrophages, which release IL-1, IL-6, TNF, interleukins. In a result, the formation of PGE2 increases in the cerebrospinal fluid, which is the direct cause of functional disturbance of hypothalamic thermoregulating centers. In the thermal center of hypothalamus, PGE2 activates adenylatecyclase, causes accumulation of cAMP and enhancement of the capture of calcium ions’ neurons by mitochondria. It disturbs the normal sodium and calcium ions ratio (the ratio of natrium concentration to calcium

11 concentration in cerebrospinal fluid washing thermo-regulating centers increases), and is accompanied by prevalence of the function of thermo-production center over the activity of the center of heat irradiation.

NSAIDs as COX inhibitors decrease PGE2 synthesis in hypothalamus, and so restore the equilibrium between the centers of heat production and heat irradiation. At the same time there takes place slight inhibition of vasomotor center, dilatation of skin vessels and increase of heat irradiation. Simultaneously, in a result of changed activity of hypothalamus, there is observed increase of perspiration, and sweat evaporation improves heat irradiation.

Beside the main functions NSAIDs have also

1. immunotropic effect, inhibit also non specific immunologic effects.

2. antiaggregant effect, prevent microthrombs formation, by decreasing platelet aggregation.

3. anticancer action /cancer of colon)

4. antigout effect.

Pharmacokinetics

All NSAIDs possess a rather high degree of absorption and bioavailability at enteral rout of administration. All of them are well absorbed in the gastro-intestinal tract. They almost completely bind to plasma albumins, replacing other drugs, and in newborns bilirubin, which may cause development of bilirubin encephalopathy. The most dangerous in this respect are salicylates and phenylbutazon. T1/2 of most of NSAIDs is 2-4 hours. Some preparations due to having a longer T1/2, e.g. naproxen, pyroxycam, are taken 1-2 times daily.

NSAIDs are metabolized as a rule in liver, and kidneys excrete metabolites. The speed of excretion of NSAIDs depends on the urine pH. As many of preparations of this group are weak organic acids, they are excreted faster at alkaline urine.

12 Uses of NSAIDs

 As analgesic agents are more active in peripheral pains such as toothache, headache, neuralgia, myalgia, pain syndrome connected with the injuries of bones, joints, ligaments ruptures and other injuries.  Most of NSAIDs are ineffective during acute visceral pain, e.g. at “acute abdomen”, renal colic, pericarditis or myocardial infarction. Ketorolac is the one in this group, which possesses strong analgesic effect, and in some cases is used instead of morphine at post operation pains of light and moderate degrees.  As spasmolytics during spastic pains (in a combination with spasmolytics). 2. As antipyretic agents 3. As an anti-inflammatory agent, often in case of diseases of locomotor apparatus – myosites, arthrites, arthroses, radiculites, plexites. 4. As desensitizing agents at autoimmune diseases – collagenoses, rheumatoid arthritis, systemic lupus erythematosus. 5. As Inhibitor of platelet aggregation. Aspirin lowers the rate of development of repeated myocardial infarction or stroke. It is also efficient for decrease of rethrombosis development probability after coronary artery angioplasty. 6. For treatment of patent ductus Botally in premature newborns This duct remains patent due to constant formation of PGs, its closing in premature newborns may be enhanced by i/v infusion of indometacin. In this situation, formation of PGs is not the result of an inflammation process, and possibly in greater degree depends on the activity of COX-1, than COX-2. As it has been already stated, indometacin has a relatively selective action on COX-1. In many cases, the application of indometacin allows avoiding surgical intervention. 7. Dysmenorrhea. In its etiology, the role of PGE2 and PGF2α has been demonstrated. They are formed from phospholipids of the perished cell membranes of

13 menstruating endometrium. PGE2 inhibits platelet aggregation and dilates vessels. PGF2α result in pain sensation and promote contraction of smooth muscles.

Side effects of NSAIDs

1. GIT tract – is the most frequent complication of NSAIDs (at any rout of administration). On the background of the treatment, there appear loss of appetite, sickness, epigastral pain, diarrhea, gastric erosion, gastric and duodenal ulcer (ulcerogenic effect. The mechanism of the ulcerogenic effect of NSAIDs is due to the direct irritating effect of the preparations, as well as to inhibition of COX-1 and decreased synthesis of PGs and prostacycline, which have gastroprotective function (stimulate mucine synthesis, inhibit HCl, gastrine, secretine synthesis, increase microcirculation.

2. Bleedings are another serious complication of NSAIDs, conditioned by an antiaggregant, anticoagulant actions .

3. Blood picture disorders (leucopenia up to the agranulocytosis, aplastic anemia, thrombocytopenia and pancytopenia). The action on blood system also deteriorates the condition of peptic ulcer /provoked by NSAIDs/.

4. Bronchospasm – “aspirin asthma”. Its frequency increases at bronchial asthma and allergic background. NSAIDs, inhibiting PGs synthesis in cyclooxygenase cascade of arachydonic acid, provoke their switching of the latter to the lipooxygenase pathway of metabolism, leucotriens accumulation leading to brochospasm.

5. Impairment of renal blood flow. NSAIDs, inhibiting PGs synthesis, may impair renal blood flow, slow down glomerular filtration, resulting in renal dysfunction causing retention of water – edema. This side effect can occur after long treatment by NSAIDs, has reversible character.

6. Liver damage – can be conditioned by metabolites and also by their hepatotoxicity.

7. Skin and mucous membranes affections -usually appear in 1-3-rd weeks of the treatment, and are manifested by rushes, photosensitization or urticaria. 14 8. Reye’s syndrome. In the recent years there has been established a correlation between aspirin use at viral infection and development of Reye’s syndrome. This syndrome is a combination of encephalopathy and hepatic necrosis, and in 60% of cases brings to the lethal outcome. Thus, should be avoid prescribing aspirin as an antipyretic agent to children during acute viral infections (flu, measles, chickenpox).

9. CVS- that NSAIDs which can penetrate BBB, inhibit vasodilating PGs formation and can lead to hypertension.

SALICYLATES

Aspirin. It is rapidly converted in the body to salicylic acid which is responsible for most of the actions. Many effects are dose-dependent.

PHARMACOLOGICAL ACTIONS

1. Analgesic, antipyretic, anti-inflammatory actions. Analgesic, antipyretic effects are developed in therapeutic dosages (0.5x3). Antiinflammatory action is exerted at high doses (3-6 g daily).

2. GIT: In therapeutic concentrations Aspirin and salicylic acid released by Aspirin irritate the mucous membrane of stomach leading to epigastral dicomfort, nausea and vomiting, which is defined not only by direct irritative action, but also (high dosages) by stimulation of trigger zone of vomiting center. Aspirin in acidic environment is in non- ionized form and has ability to be diffused, but when it enters into mucous membrane cells (pH -7.1), it`s becoming ionized and is converted into non-diffusible form. In this case Aspirin`s irritative action is increased, leading to damage of mucous membrane cell and capillaries as a result formation of acute ulcer, erosive gastritis, microextravasation is occured. The ulcerogenic effect is especially developed in local administration. The hidden blood loss can be noticed in every dosage of Aspirin.

3. Blood: Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis and has antiaggregant effect. It has additional anticoagulant effect.

15 4. Respiratory system- The effects are dose dependent. At anti-inflammatory doses respiration is stimulated bу peripheral (increased СО2 production) and central (increased sensitivity of respiratory centre to СО2 ) actions. Hyperventilation is prominent in salicylate poisoning. Further rise in salicylate level causes respiratory depression; death is due to respiratory failure. 5. Metabolic effects, acid-base and electrolyte balance. These are significant оnlу at high (anti-inflammatory) doses. Сhrоniс use оf large doses cause negative ammonium balance bу increased conversion оf protein into carbohydrates. Plasma frее fatty acid and cholesterol levels are reduced. Anti-inflammatory doses produce significant changes in the acid-base and electrolyte balance of body fluids. Initially in small dosages respiratory stimulation predominates and tends to wash out СО2 despite increased production - compensated respiratory alkalosis. Higher doses cause respiratory depression and cause respiratory acidosis. The reason of acidosis also can be accumulation of lactic, pyruvic, acetoacetic acids leading to uncompensated metabolic acidosis . 6. CVS -Aspirin has nо direct effect in therapeutic doses. Larger doses increase cardiac оutрut to meet increased peripheral 02 demand and cause direct vasodilatation. Toxic doses depress vasomotor centre: ВР mау fall.

Pharmacokinetics Aspirin is absorbed from stomach and small intestines. It rapidly converts to salicylic acid. Its` poor water solubility is the limiting factor in absorption: microfining the drug particles and inclusion of аn alkalin enhances absorption. Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form. Adverse effects. The most common side effects are 1. Disturbances of GIT function 2. Hypersensitivity and allergic reactions

16 3. Idiosyncrasy /hemolysis is possible, which is noted like idiosyncratic reactions/ 4. Anti-inflammatoгy doses (high doses) produce the syndrome called salicylism - dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance. 5. Reye syndrome. Is developed in children during viral infections when Aspirin is administered. This syndrome is determined by encephalopathy and liver necrosis combination which can lead to lethal outcome in 60% of cases. Thus during viral infection (flu, chickenpox) Aspirin is contraindicated.

Uses 1. As analgesic. For headache, backache, myalgia, joint рain, pulled muscle, toothache, neuralgias and dysmenorrhoea. Analgesic doses (0.5x3). 2. As antipyretic It is effective in fever of аnу origin; antipyretic doses (0.5x3)

3. As antiaggregant in Postmyocardial infarction and poststroke patients Ву inhibiting platelet aggregation it lowers the incidence of reinfarction.

Contraindications Aspirin is contraindicated in patients who are sensitive to it and in рерtiс ulcer, bleeding tendencies, in children suffering from chicken pox or influenza. Due to risk of Reye's syndrome pediatric formulations of aspirin are prohibited. In chronic liver disease cases of hepatic necrosis have bееn reported. It should bе avoided in diabetes, due to metabolic changes. Given during pregnancy it mау bе responsible for low weight babies. It should bе avoided bу breast feeding mothers.

17 Pyrazolones

Butadione (Phenylbutazone) and its active metabolite oxyphenbutazone are potent anti-inflammatory drugs. The analgesic and antipyretic action is less. It is more toxic than Asрirin. The other pyrazolone - Metamisol (Analgin) is primarily used as analgesic and antipyretic /central action/, but poor anti-intlammatory. It is frequently combined with spasmolytics /Baralgin/. These drugs have antigout effect. The main side effect is agranulocytosis. Some pyrazolones (antipyrin and amidopyrin aren`t used nowadays).

Indole derivatives

Indomethacin. It is а potent anti-inflammatory drug as Butadion. It has antipyretic and analgesic effects. It appears with high toxicity.

Sulindac It is а prodrug. Its` anti-inflammatory and toxicity is weaker than indomethacin`s. This group has antigout effect.

Propionic acid derivative

Have analgesic, antipyretic and anti-inflammatory effects.

Ibuprofen It is particularly effective in dysmenorrhoea. This drug is comparably safer and is frequently administered in children.

Naproxen: is valuable in acute gout. Has also good anti-inflammatory effect.

Ketoprofen: has analgesic effect and is effective even in angina attacks.

Aryl-acetic acid derivative

Diclofenac. An analgesic-antipyretic anti-inflammatory drug, similar in еffiсасу to Naproxen. It has the all above-mentioned mechanisms of action. Besides Diclofenac has also the following pecularities.

18 a/ inhibition of also lipoxygenase pathway, resulting in decreased production of leukotrienes, particularly the pro-inflammatory leukotriene B4

b/ inhibition of arachidonic acid release

c/ has good penetration especially in synovial fluid

Diclofenac is widely used in arthritis, dysmenorrhea, posttraumatic and postsurgical inflammatory complications.

Anthranilic acid derivative (phenamates)

Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain.

Oxycam derivatives

Pyroxicam It is а long acting potent NSAID with antiinflammatory potency Plasma t1/2 lasts nearly 2 days. It is similar to Indometacin. Is used in arthritis.

Pyrrolo-pyrrole derivative

Ketorolac. Has potent analgesic and modest anti-inflammatory activity. The analgesic activity is equal to Morphine.

Preferential COX-2 inhbitors

Nimesulide. Antiinflarnmatory action mау bе exerted bу

a/ mainly COX-2 inhibition

b/ reduced generation of superoxide bу leucocytes

c/ inhibition оf PAF synthesis and TNFa release

d/ free radical scavenging action

Has expressed hepatotoxic effect.

19 Meloxicam, Nabumetone – prodrug, are also in this group.

SELECTIVE СОХ-2 INHIBITORS

They exerts antiinflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Though efficacy of selective СОХ-2 inhibitors appears to bе similar to other NSAIDs, but it should be taken into consideration that :

• СОХ-1 isoenzyme mау also have а role in inflаmmаtiоn: sеlесtivе СОХ-2 inhibitогs mау nоt hаvе as broad range of efficacy as nonselective СОХ inhibitors.

• СОХ-2 in gastric mucosa contribute to gastroprotective РG synthesis; its inhibition mау also bе ulcerogenic.

• Juxtaglomerular СОХ-2 is constitutive, inhibition of which сan cause salt and water retention; edema, deterioation of CHF and rise in ВР.

• СОХ-2 inhibitors reduce whole body PGI2 production without affecting platelet ТХА2 synthesis. This mау exert prothrombotic influence and еnhаnсе cardiovascular risk.

Para-aminophenol derivatives

The analgesic and antipyretic effects of Paracetamol are determined due to central mechanisms - inhibition of COX-3 enzyme.

Paracetamol has negligible anti-inflammatory action, because it has poor ability to inhibit СОХ in the presence of peroxides which аге generated in the site of inflammation, but are not present in brain.

Pharmacokinetics. In liver Palacetamol is conjugated

with glucuronic acid and sulfuric acid. The metabolites are fastly excreted through urine.

Side effects: It has hepatotoxic and nephrotoxic actions.

20 Acute paracetamol poisoning can occur in high dosages > 10g.

For treatment of poisoning N-acetylcysteine should bе infused. It replenishes the glutathione stores of liver and prevents binding оf the toxic metabolite to other cellular constituents.

Uses: Paracetamol is оnе оf the most соmmonly used analgesic and antipyretic drug. It is combined with other NSAIDs, caffeine.

The main drug list

Aspirin- tablets 0.25 and 0.5

Butadionum- 0.15 tablets, 5% ointment

Paracetamolum – 0.1, 0.2, 0.5 tablets, 0.1 suppositories

Diclofenac-natrium -0.025 tablets

Indometacinum – 0.025 capsules, 0.05 suppositories

21 Tests

1. The analgesic mechanisms of NSAIDs are, except: a) inhibition of peripheral prostaglandins b) stiulation of brain opiate receptors and activation of anti-nociceptive system c) removal of edema d) decrease in brain`s PgE level e) stimulation of endorphin`s release

2. NSAIDs –oxicam derivative is predominantly inhibits COX-2 a) Naproxene b) Mefenamic acid c) Diclofenac-Sodium (Voltarene) d) Meloxicam e) Butadione

3. Indometacine is used in all-above mentioned cases, except a) dismenorrhea b) non-closed Botally ductus c) ataralgesia d) rheumatoid arthritis e) neuralgia, myalgia

4. The effects of Diclofenac are:

1. increase in body temperature

22 2. ulcerogenic effect

3. removal of headache, toothache, muscle ache

4. miosis

5. removal of possible drug dependence a) 2.3.5 b)2.3.4 c)1.3.5 d)1.2.3

5 Side effects of NSAIDs are 1. deterioration of renal blood supply

2. bronchospasm

3. bleedings

4. hypotension

5. ulcerogenic effect a)1.2.3.5 b)1.2.3.4 c)1.3.4.5 d)1.2.4.5

6. The anti-inflammatory action of NSAIDs is defined by:

1. inhibition of Pg synthesis

2. decrease in TXA2 level and inhibition of thromb formation

3. inhibition of hyaluronidase

4. inhibition of leucocyte migration a)1.2.3.5 b)1.2.3.4 c)1.3.4.5 d)1.2.4.5

23 7. During GIT intolerance toward classic NSAIDs as analgesic can be used:

1. aspirin

2. celecoxib

3. indometacine

4. rofecoxib

5. buadione a) 2.5 b) 2.4 c) 1.3 d) 4.5

8. The prominent complication toward Pracetamol is a) agranulocytosis, leucopenia b) hyperglycemia c) tinnitus, dizziness d) hepatotoxicity e) dispeptic disorders

24 Psychotropic drugs

Psychotropic drugs (from Greek psyche-soul and tropos-direction) are mainly acting on psychi functions (emotions, behavior, thinking,memory etc.) are used to treat neuro- psychical diseases –neurosis and psychosis.

Classification of psychotropic drugs, which are used to treat psychic disorders

1. Antipsychotic agents (neuroleptics) are used to treat various psychoses. 2. Tranquilizers (anxiolytics) are used to treat neurosis. 3. Drugs used to treat affective disorders

 Antidepressants  Antimaniac drugs, mood stabilizers 4. CNS stimulants

 Psychostimulants  Nootropic agents 5. Psychosomimetics, psychodisleptics or hallucinogens

Antipsychotic drugs (Neuroleptics)

Psychosis – is a severe psychic disorder, in this case patient can have non adequate behavior. Clinically we have disturbances of perception of surroundings. Schizophrenia is such type of disorder. Affective disorders including other types of psychosis, which have primary expressions like mood changes (depressiom/mania).

Neuroleptics (Greek neuron – nerve, lepticos – able to perceive), antipsychotic agents or big tranquilizers are used to treat acute and chronic psychosis (schizophrenia, organic, intoxication, infantile and senile psychosis), psychopathic disorders and psychomotor activation. All the symptoms of psychosis are divided into 2 groups: “negative” and “positive”.

25 Positive or productive symptoms are result of stimulation of functional systems. The symptoms are delirium or fixed ideas, aggression, thinking disturbances, illusions, hallucinations, psychomotor stimulation,disturbance of motor activity.

Negative or deficient symptoms are result of reduction of certain psychic functions. The symptoms are depression, social isolation, overwhelmed state, emotional sparing. Schizophrenia and other psychosisis a special type of psychosis, characterized by cognitive, emotional, mental and motor disturbances (hallucinations, delirium and other symptoms). Causes of schizophrenia are not clearly detected, genetic factor associated with external factors issupposed. The most argumented theory nowadays is “biochemical or monoamine hypothesis”, which explains the origin of schizophrenia by disturbances of neurotransmission (dopaminergic, serotoninergic, adrenergic and glutaminergic) in several structures of brain tissue. Mostly investigated and proved is the role of dopamine in the pathogenesis of schizophrenia. It is supposed that the origin of psychosis is hyperactivity of dopaminergic structures of brain. Nowadays we differ the following pathways of central dopaminergic system.  mesolimbic-mesocortical pathway is responsible for human emotions and behavior.  nigrosriatal pathway regulates arbitrary motor functions  tubero-hypophyseal pathway regulates some hormone`s secretion. Dopamine inhibits prolactine secretion and stimulates somatotropic, gonadotropic releasing hormones and antidiuretic hormone secretion.  Trigger zone, which can be stimulated by dopamine, leading to nausea and vomiting

26 Transmission of impulse through these pathways is a result of dopamine- receptor interaction. All five types of dopamine receptors are bound with G- proteins and grouped in two families corresponding with transduction mechanism.

1. Activating D1 and D5 receptors, which are coupled with Gs-proteins

2. Inhibiting D2,D3, D4 receptors, which are coupled with Gi-proteins

The most essential role in development of psychosis have dopamine D2 receptors, which hyperactivity mainly in the mesolimbic system is important for development of “positive” symptoms of psychosis (delirium, hallucinations etc). The hypoactivity of dopaminergic system in mesocortical pathway is responsible for “negative” symptoms.

In psychosis because of dopaminergic system hyperactivity receptors` down- regulation is noticed, during “negative symptoms” the opposite condition – up- regulation.

Other mediators also play a big rolein development of psychic disorders.

So, serotonine or 5-hydroxytriptamine(5-HT) participates in adjusting of numerous physiological processes in an organism interacting with serotonine receptors (5-HT1, 5-HT2, 5-HT3, 5-HT5).

Serotoniergic pathways are beginning from the neurons of nucleus raphe magnus and middle part of pon and project to basal ganglia, limbic system, hypothalamus, oblong brain, cerebellum, spinal cord.

Serotonine takes part in regulation of such functions as behaviour, sleep and awareness, control over sensible impulses, pain sensation, temperature of body, appetite, mood, emotions and sexual functions.

Hyperactivity of the serotoninergic system in some structures of cerebrum results in development of “positive” or productive symptoms of psychosis, and decline of activity – to depression.

The decline of concentration of glutamate or blockage of glutamate NMDA-receptors has a key role in the development of “positive” symptoms of psychosis.

It is known that dopamine and glutamate closely co-operate with GABA – ergic ways, forming the so-called “thalamic filter”. The brake function of thalamic filter leads to psychotic state development.

In the development of psychosis other mediator systems also play role: adrenergic, cholinergic, histaminergic etc. The great role have reciprocal relations of these systems.

Classification of neuroleptics :

Typical or classical Not typical neuroleptics neuroleptics(1-rst generation) (2-nd generation) Derivates of phenothiazine Chlorpromazine (Aminazine) Clozapine Levomepromazine Risperidone Fluphenazine Olanzapine Trifluoperazine Sertindole Butirophenonederivates Quetiapine Haloperidol Amisulpride Droperidol Zotepine Tioxanthenederivates Chlorprothixene

Classic or typical neuroleptics

Classic neuroleptics block dopaminergic, histaminergic, serotoninergic (insignificantly) receptors, as well as M- and α- receptors.

Pharmacodynamics

Central effects:

Antipsychoticaction is an elimination of “positive” symptomsof psychosis (delirium, hallucinations etc). Thebasic mechanisms of action of classical neurolepticsare:blockage of pre- and postsynaptic mainly D2dopaminereceptors in the mesolimbic-mesocortical pathways and partially blockade of serotonine receptors. Blockade of dopamine receptors weakens neurotransmission, which leads to pre- and postsynaptic dopamine receptors` up-regulation after 2-3 weeks of administration. In this moment antipychotic action is developed.

Psycho-sedative action is a removal of the state of excitation, anxiety.

This action is a result of blockage of central Н1-histamine, М1- cholinoreceptors, α- and D-receptors. This effect appears soon after administration of the neuroleptic drug. The most expressed psychosedative action has Chlorpromazine (Aminazine), Levomepromazine, Thioridazine, Chlorprothixene and Droperidol. They are psychosedative neuroleptics. Perphenazine, Fluphenazine and Trifluoperazine has antipsychotic action.

Antivomiting action .

Blocking of dopamine receptors of trigger area neurolepticsremove vomiting and hiccup.

Hypothermic action.

Neuroleptics decreasethe temperature of body, because they depress heating center of hypothalamus. Besides these drugs increase heat production because of blockade of α-adrenoreceptors. 29

Antiseizure action.

Neuroleptics (especially derivative butirofenone – droperidol) has also anticonvulsant action and potentiate the action of anti-seizure drugs.

This property is not characteristic to all neuroleptics, some of them can have even vice versa action (aliphaticderivates of fenothiazine and clozapine).

Hypnotic action

Peripheral effects:

Hypotension, mydriasis, constipation are mainly expressed as a peripheral side effects.

Atypical neuroleptics

Atypical neuroleptics moderately block dopaminereceptors, also expressively block different subtypes of serotonine receptors.

In the brain nigro-striatal and tuberohypophyseal pathwaysserotonine and dopamine have reciprocal relationships: serotoninergic nervous fibres form axon- axonal contacts with a presynaptic dopaminergic receptors. Serotonine, acting on the presynaptic 5-НТ2А receptors, decreases dopamine release from the presynaptic membrane.

Unlike classical neuroleptics, atypical neuroleptics also remove “negative” symptoms of psychosis. The primary and secondary deficiency of dopamine (at the prolonged blockade of dopaminereceptors) especially in the meso-cortical pathway can result in an appearanceof “negative” symptoms. Atypical neuroleptics, blocking presynaptic serotonine receptors, increase dopamine release, by that preventsit’s deficiency,accordingly to which, eliminate “negative” symptoms.

Basic differences between atypical and classic neuroleptics are shown in table:

Classical neuroleptics Atypical neuroleptics

Mechanism of anti- Expressed blockade of different Expressed blockage of different psychotic action subtypes of dopamine receptors subtypes of serotonin receptors and (mainly D2), sometimes moderate blockage of different subtypes insignificant blockage of serotonine of dopamine receptors. receptors.

Symptoms of psy- Positive Positive and negative chosis, eliminated by neuroleptics

Extra-pyramidal Often Rarely and in a less degree and hormonal disturbances

Efficiency at Not effective Effective resistance to treatment

Clozapine belongs to atypical neuroleptics, has low affinity toward dopamineD2receptors, blocks stronger D4 dopamineand serotonine 5-НТ2А receptors, blocks also adreno-, M-cholino-, Н1-histamine receptors. Has expressed anti-psychotic andsedativeeffect. Clozapine causes agranulocytosis.

Olanzapine is almost similar with Clozapine on a receptor type, therapeutic efficiency and spectrum of side effects. Compared to Clozapine rarer causes agranulocytosis.

Risperidone and Quetiapine selectively blocks serotonine 5-НТ2А, dopamine D2 receptors, α-adrenoreceptors and also histamine Н1 receptors. Risperidone compared to other not typical neurolepticsmore frequent causes extrapyramidal disturbance.

Pharmacokinetics of neuroleptics

Neuroleptics can be administered parenterally and orally.

Preparations are lipophilic, however absorbed badly from GIT. Bioavailability is 30-60%. Neuroleptics strongly bind to the blood proteins (more than 90%). Neuroleptics, due to their lipophylicy have high volume of distribution.

Biotransformation takes place mainly in the liver. In the process of biotransformation can appear both non active and active metabolites.

Nonprolonged neuroleptics are administered once in a day. Prolonged neuroleptics are administered once in 2 weeks.

Uses

 Psychosis- white fever, schizophrenia, senilepsychosis  Non psychiatric indications  Neuroleptanalgesia  Premedication  Malignant hyperthermia.  Nausea and vomiting of the central genesis  Prolonged proceeding hiccup Side effects

1. A- type side effects of neuroleptics are due to blockade of different receptors both in CNS and periphery:

1. Extrapyramidal disturbances arise up from the block of dopamine receptors in the nigrostriatal pathway. More characteristic is for classical neuroleptics. They are expressed by different types of diskinesias. By the time of development there are early and tardive diskinesias, Parkinsone syndrome.

2. Hormonal disturbances. Prolactine secretion is increased, that can result in gynecomastia, galactorrhea, disorder of menstrual cycle, disturbances of the sexual function-decline of libido and impotence.

Also the secretion of somatotropic and gonadotropic hormones is reduced.

Some neuroleptics diminish also the secretion of insulin and lead to hyperglycemia development.

3. Neuroleptic syndrome is more prominent for classical neuroleptics, which block dopamine receptors for a long time. It is expressed by aggravation of negative symptoms, emotional indifference and aggravation of depression.

4. Increase of body mass and increase of appetite

5. Arterial hypotension, orthostatic collapse

6. Ocular side effects are mydriasis, increase of intraocular pressure

7. Gastro- intestinal tract side effects are: dryness of the mouth cavity, disturbances of swallowing, inhibition of secretory function of the GIT glands, inhibition of motor function, constipation, cholestasis, cholestatic icterus, hepatotoxic action.

8. Genito-urinary tract: distonia of the urinary bladder, dysfunction of the sphincters, disturbances of urination

9. Skeletal muscles: decrease of skeletal muscle tone and motor activity, because they decrease the descending action of reticular formation on the spinal cord.

14. Tolerance and dependence. The prolonged administration of neuroleptics is instrumental in development of tolerance to the sedative effect, and also effects, related to the blockage of M-cholino- and α-adrenoreceptors. To antipsychotic action and extra-pyramidal disturbances tolerance isn`t developed.

Physical dependence development is less typical for neuroleptics. However, acute withdrawal of neuroleptics can lead to the withdrawal syndrome.

B type side effects.

1. Malignant neuroleptic syndrome is a severe complication, arises up rarely with a possible fatal outcome (in 10-20%), is an idiosyncratic reaction.

Manifestations are muscle rigidity, hyperthermia and expressed leucocytosis, that can imitate infectious disease, by disturbances of consciousness, dysfunction of the vegetative nervous system .

2. Agranulocytosis and leucopenia can arise up in the first weeks in 1-2% cases at the treatment with Clozapine.

3. Allergic reactions, photosensibilization

The main drug list

Aminazinum – 0.025, 0.05, 0.1 dragee, 2.5%-1, 2, 5, 10 ml ampules

Triftazinum- 0.001, 0.005, 0.01 tablets, 0.2%-1 ml ampules

Droperidolum- 0.25%-5,10 ml ampules

Haloperidolum- 0.0015, 0.005 tablets, 0.2%-10 ml flacons, 0.5%-1 ml

Related tests

1. Aminazine has the following effects, except

a) hypothermic

b) antipsychotic

c) antivomiting

34 d) hypertensive

2. Phenothiazine derivatives are

1. Triftazine

2. Aminazinum

3. Haloperidolum

4. Ftorfenazinum

5. Droperidolum a) 2.3.5b) 1.2.4c) 1.3.5d) 1.4.5

3. Clozapine, Risperidone, Olanzapine are a) anxiolytics b) atypical neuroleptics c) antidepressants d) classical neuroleptics

4. Neuroleptics usage are

1. psychosis

2. neurosis

3. vomiting of central action

4. neuralgia, myalgesia

5. neuroleptanalgesia a) 2.3.5 b) 2.3.4c) 1.3.5d) 1.4.5

5. Neuroleptics have antipsychotic action blocking

a) M1- cholinoreceptors

b) D2- dopamine receptors

c) A1- adenosine receptors

d) H1- histamine receptors

e) GABA- receptors

Drugs are used for treatment of affective disorders

Affective disorders are mania, depression and bipolar affective disorders - maniac-depressive psychosis.

Mania (greek mania-madness) is expressed by unusual high mood and is accompanied by the below mentioned symptoms combination: self-confidence, overestimation of own abilities, high psychological activity, impulsive behavior, fastening of associative thinking, excessive speech, in some cases overexcitation and aggressive behavior, hallucinations.

Depression (latin` depression- pressure, inhibition)is described by emotional disorders, characterized by pathologically lowered mood (hypotimia), unmotivatied melancholy, apathy, pessimism, low self- esteem, loss of motivation etc.

Somatic symptoms are also revealed: psychomotor inhibition, loss of sexual activity, loss of appetite, sleepiness.

Usually if from the above-mentioned symptoms 5 are existed, in the patient we can diagnose depression.

Monoamine theory of affective disorders

On the basis of this hypothesis the origin of depressions is related to the decline of function of amine neuromediators: noradrenaline (NA), dopamine (DA), serotonine (5-HT) in the certain parts of cerebrum and vice versa, the increase of functions of these mediators is instrumental in the origin of the maniac state. The most important mediator for mood is 5-HT, which is mediator of ”high mood “.

Antidepressants Antidepressants are used for the treatment of depression. Nowadays all antidepressants can increase mediators amount in the synaptic cleft by the different ways and by this way improves the pathological changed mood in patients. Classification of antidepressants

1. Inhibitors of the neuronal reuptake of monoamines Tricyclic antidepressants (TCA), non selective inhibitors of neuronal reuptake of monoamines (mainly inhibiting the reuptake of 5-НТ and NA)Amitriptyline, Imipramine, Clomipramine, Doxepin

 Inhibitors of neuronal reuptake of mainly 5-НТ (5-НТ>НА): Fluoxetine. Fluvoxamine  Inhibitors of neuronal reuptake of mainly NA (NА>5- HT):Maprotiline 2. Inhibitors of monoaminoxidase (MAO)  Non selective inhibitors of MAO (both MAO-A and MAO-B): Nialamid (irreversible inhibitor )  Selective inhibitors of MAO-A: Moclobemide (reversible inhibitors)  Selective inhibitors of MAO-B: Selegiline 3. Atypical antidepressants:Mianserin, Тrazodone, Мirtazapine

Tricyclic antidepressants

Pharmacodynamics of tricyclic antidepressants :

Tricyclic antidepressants are non selective inhibitors of neuronal reuptake of monoamines, which competitively bind and inhibit transport systems of presynaptic membrane (transport systems of NA, 5-HT). As a result of which the reuptake of noradrenaline and serotonine is disturbed. It results in the accumulation of these mediators in synaptic cleft, leading to activation of adrenergic and serotoninergic neurotransmission .

It is necessary to mark that the antidepressive effect appears not immediately, and after 2-3 weeks. At depression, in the conditions of deficit of mediators, there is an increase of amount and sensitiveness of receptors (up regulation) on a postsynaptic membrane by compensative mechanism, the changes of level of receptors affect also presynaptic membrane. At the action of tricyclic antidepressants, the amount of mediators is increased in a synaptic cleft, that gradually leads to reverse process – diminishing of amount and sensitiveness of receptors (down regulation). It takes 2-3 weeks.

The antidepressant effect can be potentiated also by properties of tricyclic antidepressants to block presynaptic α2-adrenoreceptors, which brings to increased secretion of noradrenaline from presynaptic membrane.

Beside the main mechanisms, TCA have also M-, α- and H1- lytic effects, which define drugs` action and more side effects.

Except for the basic antidepressant effect tricyclic antidepressants have also the following actions:

Sedative effect. Bring to the general calming, diminishing of anxiety. These effects are conditioned by properties of tricyclic antidepressants to block central M-cholino, α-adreno-, histamine Н1 receptors. Sedative effect shows up a few

38 hours after adopting antidepressant. To the sedative effect tolerance is developed as a rule.

Psychostimulant action. Shows up the revival of psychomotor activity, renewal of motivations, increase in mental and physical capacity. It is conditioned by the strengthening of the adrenergic neurotransmission.

Not all tricyclic antidepressants have sedative and psychostimulant effects at the same degree. So for Amitriptiline the sedative effect is more expressed, and Imipraminepossesses a potent psychostimulant action, while a sedative effect and property to block M-cholinoreceptors is expressed in a less degree. Modulating action is characteristic for Imipramine, it means that the expressiveness of one or another action depends on the state of patient.

Analgesic action. It is related to property of tricyclic antidepressants to activate the antinociceptive system, and also to activate opioid receptors and inhibit the nociceptive system.

Tricyclicantidepressants have also hypothermic and antivomiting actions.

Pharmacokinetics of tricyclic antidepressants

Tricyclic antidepressants can be used both parenterally and orally. At oral rout of administration absorption is very rapid, firmly binds with plasma albumins. Have expressed affinity to tissue proteins and large volume of distribution. Metabolism takes place mainly in the liver, with formation of possibly active metabolites, also possessing the antidepressant action.

For the people of senile age elimination of antidepressants is prolonged even more, that is dangerous from point of cumulating of preparations and connecting with it side effects.

Side effects of tricyclic antidepressants:

A- type side effects are mainly connected with the blockage of different types of receptors: α –adreno, M-cholino, histamine Н1 receptors.

1. CNS: Expressed sedation: weakness, sense of fatigue, deceleration of thought, somnolence. 2. Eye: mydriasis, increase of intraocular pressure, paralysis of accommodation, inhibition of secretory function of tear glands. 3. Cardiovascular system: orthostatic hypotension, tachycardia, cardiotoxic action, arrhythmias, different degrees of atrioventricular blockages and inhibition of intraventricular conductivity. 4. Gastrointestinal tract:dryness of mouth, difficulties in swallowing, inhibition of secretory function of the digestive glands, constipation, billiary stasis during long-term treatment, hepatotoxic action. 5. Increase of appetite and increase of mass of the body (blockage of the central histamine Н1 receptors) 6. Urinary tract: delay of urination, different types of sexual dysfunctions 7. B-type side effects: Allergic reactions, agranulocytosis, thrombocytopenia (rarely)

Selective inhibitors of neuronal reuptake of serotonine (SIONRS)

Fluoxetine, Fluvoxamine

Parmacodynemics

SIONRS selectively bind with the specific transporter of serotonine, block them, and bring to the accumulation of serotonine in the synaptic cleft strengthening serotoninergic neurotransmission. During usage of these drugs also receptor changes can occur and antidepressant action develops after 3 weeks of administration. 40

It is known that in the conditions of deficiency of serotonine (depressions of the different origin) postsynaptic as well as presynaptic 5-НТ receptors are exposed to the changes on the principle of up regulation. During the treatment with SIONRS increased level of serotonine brings to the process of down regulation of 5-HT receptors. Diminishing of reception to the normal level (in 2-3 weeks) results in the clinical manifestation of the antidepressant (timoleptic) action of SIONRS.

High doses of SIONRS can also block the transporter of noradrenaline.

The distinctive feature of this group of preparations is an absence of properties to block M-cholinoreceptors and insignificant influence on α-adreno and histamine Н1-receptors.

They are safer from the point of overdose.

As compared to other SIONRS Fluoxetine possesses the most expressed psychostimulating effect, it is also an agonist of 5-HT receptors.

Pharmacokinetics of SIONRS

SIONRS are used orally. They are lipophylic, well absorbed from GIT. Bioavailability varies , well bind to the plasma proteins 95-98%, have high volume of distribution up to, biotransformation takes place in the liver, with the formation of active metabolites.

A-type side effects

1. CNS: state of excitation, anxiety, alarm, insomnia, aggression, cruelty, suicide ideas. 2. Hormonal sphere: inhibition of secretion of ADH and hyponatriemia. 3. “Serotonine syndrome”: anxiety, rigidity and spastic constriction of muscles, hyper reflection, promoted perspiration, hyperthermia, tremor, cramps and coma. arises up at combination of

SIONRS with inhibitors of MAO, that results in the excessive increase of amount of serotonine in synapse. 4. Gastrointestinal tract: the dyspeptic disorders are expressed by nausea, vomiting 5. Disturbances in sexual sphere 6. Fluoxetine inhibits Cytochrome P-450 isoenzymes, leading to decrease and/ or increase in some drugs` metabolism (other antidepressants, neuroleptics, barbiturates, antiepileptic drugs, β- adrenoblockers, some antibiotics).

Selective inhibitors of neuronal reuptake of noradrenaline

Maprotiline

Selective inhibitors of neuronal reuptake of noradrenaline bind mainly with the transporter of noradrenaline and depress its activity. As a result the amount of noradrenaline in the synaptic cleft is increased and adrenergic neurotransmission is activated.

By other pharmacological features selective inhibitors of neuronal reuptake of noradrenaline are like tricyclic antidepressants. Property to block M-cholino, α- adreno - and the histamine Н1 receptors, for them is expressed moderately.

Inhibitors of monoaminooxidase (IMAO)

Classification of MAO-inhibitors:

1. Non selective MAO-inhibitors (MAO-A and MAO-B): Nialamid (irreversible inhibitor ) 2. Selective inhibitors of MAO-A: Moclobemide (reversible inhibitor ) 3. Selective inhibitors of MAO-B: Selegiline

Pharmacodynamics of IMAO:

IMAO inhibiting MAO, block inactivation of noradrenaline, serotonine, dopamine, leading to increase of the amount of these mediators in the brain. Exactly the same changes are marked in periphery also: heart, liver, intestine, substantially the concentration of monoamines rises also in plasma.

As a result increase of the amount of mediators in axoplasma of presynaptic part, in the synaptic cleft interact with the proper receptors on the postsynaptic membrane, leading to activation of the following types of neurotransmission- adrenergic, serotoninergic, dopaminergic (though the last one changes in less degree, than the first two ones).

Inhibition of MAO comes immediately after taking these drugs, however the antidepressant action is developed in 2-4 weeks (changes in sensitivity).

Non selective IMAO irreversibly inhibit MAO.

Selective IMAO bind with an enzyme reversibly. Moclobemid possesses a psychostimulating effect.

In the modern medicine is mainly used MAO-A reversible inhibitor Moclobemide.

A- type side effects:

 Excessive excitation (during overdoses): agitation, maniac state, insomnia, fear, panic, hallucinations etc.  Cardiovascularsystem:hypotension up to an orthostatic collapse.  Eye and GIT:as a result of blockade of M- cholinoreceptors  Violation of sexual function –decrease of libido etc.

 “Cheese crisis” or “thyramine syndrome” is mainly typical for non selective IMAO and for selective ones is not characteristic practically. Normally thyramine, which enters the organism with food (cheese, bananas, chocolate, wine, beer) and can be formed in intestines, is inactivated under influence of MAO of the intestine and liver. In conditions of MAO inhibition thyramine is not inactivated and enters to blood stream. Being indirect adrenomimetic, it leads to the increased noradrenaline release to the synaptic cleft. Clinical manifestations are arterial hypertension, tachycardia, arrhythmias etc.

 Increase of appetite and mass of body.

Atypical antidepressants

The antidepressant action of preparations of this group is mainly conditioned by their influence on different receptors.

Мirtazapine (Mianserine derivative) Increases the amount of NE and 5HT, blocks α2 and 5-HT receptors as a result diminishes probability of development of violations of sexual functions and anxiety. Blocks also H1 receptors and can cause sedation , increase of bodymass.

Тrazodoneselectively blocks the neuronal reuptake of 5HT, blocks 5-HT receptors, sedation, anxiety, sexual disturbances are less expressed.

Venlafaxine has dose–depending property to block the neuronal reuptake of serotonine and less noradrenaline.

Antimaniac drugs

Lithium

Lithium is mood stabilizer. During bipolar psychosis (mania-depression) manifests antimaniac and mood stabilizing effect, prevents development of

44 depresssive stage. Lithium is monovalent cation, which is close to Na+ and K+ ions by its` electrochemical features. In therapeutic dosages it penetrates through Na+ channels into neuronal cells and in opposite to Na+ ions isn`t effluxed by the Na+- K+ ATP- ase. It is accumulated, and as a result deteriorates extra- and intracellular exchange of Na+ ions and distribution of K+ ions, influencing depolarization. It deteriorates many intracellular processes, especially it inhibits IP3 resynthesis from IP2.

It also inhibits NA and DA synthesis, accumulation, release and inhibits adenylatecyclase activity.

Pharmacokinetics

Lithium carbonate is administered orally, Lithium oxybutyratei/m. It is excreted by the kidneys. T1/2 is 12 hours, is accumulated in body.

Side effects

Lithium has low therapeutic index. During drug administration the monitoring of Li+ concentration should be realized.

The mood stabilizers are also Valproate (Valproic acid) and Carbamazepine –anticonvulsant drugs.

The main drug list

Amitriptylinum- 0.025 tablets, 1-2% ampoules

Moclobemide -0.15 tablets

Nialamidum- 0.025 tablets

Tests related to topic

1.The antidepressants are a)corazole, imipramine, amitriptilline b)caffeine, moclobemid, maprotiline c)fluoxetine, imipramine, sertraline d)bemegrid, alprazolam, zolpidem e)ethimizole, moclobemide, mianserine

2.For Amitriptilline it is true, except a) inhibits NA and 5-HT neuronal reuptake b) is a TCA c) has sedative action d) decreases CA`s concentration in synaptic cleft e) has M-lytic and antihistaminic effect

3. Maprotilline a) inhibits NA reuptake b) reversibly inhibits MAO-A c) inhibits psychomotor activity d) inhibits metabolism of NA, DA and serotonine e) blocks A1 adenosine receptors

4. Imipramine

1. is TCA

2. selectively blocks MAO-A

3.has modulating action on CNS

4. has M-cholinolytic action

5. selectively inhibits serotonine reuptake

a) 1.3.4 b) 2.3.4 c) 3.4.5 d) 1.4.5

Which of the following mechanisms are underlie in antidepressant effect of tricyclic antidepressants?

1. inhibition of transport system of presynaptic membrane, which transfer noradrenalin and serotonin

2. inhibition of МАО-А

3. selective inhibition of transport system of presynaptic membrane which transfer serotonin

4. accumulation of noradrenalin and serotonin in synaptic cleft

а) 1,3 b) 2,3,4 c) 3,4 d) 1,4

Anxiolytic drugs

Tranquilizers (tranquilo – quietness, calm) or anxiolytics (lat. anxius– excited, anxios, lysis-elimination) are used for treatment of neurotic conditions with expressed anxiety, fear, excitement etc.

Anxiety, which arises as an answer to not certain situation, is a protective reaction and mobilizes the resources of organism for overcoming antisocial behavior and for preparation to future . When anxiety is too much expressed compared to the reason, or there is no reason for anxiety, it is diagnosed as a pathological anxiety.

Pathological anxiety can deteriorate patient normal activity leading to somatic disease. In persons with pathological anxiety the activity of GABA-ergic inhibiting system of prefrontal cortex is decreased, also the quantity ofbenzodiazepine receptors is reduced.

Tranquilizers remove disbalance between the mechanisms of psychical adaptation, as a result agitation, alarm, anxiety, fear, aggression are removed. In addition, tranquilizers promote stability to stress, improve adaptation in extreme situations.

Classification of anxiolytic drugs

We differ the following preparations that have anxiolytic action, which are classified into the following groups:

1. Agonists of benzodiazepine receptors or benzodiazepines (Diazepam, Fenazepam) 2. Serotonine receptor agonists (Buspirone) 3. Barbiturates 4. Drugs with the different action mechanism (Zolpidem, Meprobamate)

Benzodiazepines Pharmacodynamics of benzodiazepines

BDZ are selective agonists of BDZ receptors. BDZ receptors are

associated with GABAА receptors.

GABA-А receptors are hetero-oligomer glycoproteins (200-400 kDA), contain 3 substructures (α, β, γ), each of them can be in 3 isoforms. Also other substructures were found- δ, ε, ρ. In various regions of CNS receptors can have different structure and different interaction with pointed substructures of GABA. GABA by interaction with the modulating receptor area, results in opening of chlorine channels, strengthening of chlorine ions inflow into the cell, in a result of which hyperpolarization is developed. Hyperpolarization inhibits neurotransmission and neuronal cell activity. BDZ binding toBDZ part of

GABA-А receptor complex, by allosteric mechanism open chlorine channels.

BDZ increase GABA affinity toward their receptors. BDZ increase frequency of opening chlorine channels in a presence of GABA. BDZ increase force of GABA action.

BDZ have the following effects.

 Anxiolytic  Sedative  Myorelaxant  Anticonvulsant  Amnestic (amnesia-loss of memory) Anxiolytic effect is stipulated by the action of frontal cortex, limbic system GABA receptors. These CNS parts are responsible for regulation of emotional behavior.

Sedative action is stipulated by decrease ofattention, decrease of thought and motor reactions, somnolence, weakness. It is conditioned by strengthening of

GABA mediated inhibitingaction in the regions of thalamus and reticular formation, BDZ, by decreasing emotional tension, lead to hypnotic effect, shorten time of latent period of the sleep, increase general duration and depth of sleep.

Usually, majority of hypnotic drugs shorten the stage of rapid sleep, but for BDZ this action is comparatively less. BDZ diminish the proportion of slow sleep; the secretion of growth hormone is not disturbed although. Long- term usage of BDZ as hypnotic agents is undesirable as tolerance and dependence can develop to them.

Some BDZ have activating effect, leading to increase in mood, improving memory. These anxiolytics, which have activating component and less sedative, hypnotic, anticonvulsant and myorelaxant effects are called “daily tranquilizers”. These are Mezapam and Tofizopam.

Muscle relaxant action is stipulated by the central action. Benzodiazepines diminish tone, contraction force of skeletal muscles and volume of active movements. This action is conditioned by potentiating of GABA mediated inhibition in the spinal cord and removal of the activating influencing of reticular formationon the spinal cord. The myorelaxant effect isn`t accompanied by the changes in coordination.

Antiseizure action.is conditioned by potentiation of GABAmediated inhibition in hippocampus, spinal cord, cerebellum. Clonazepam has selective anticonvulsant effect, is used in epilepsy.

BDZ cause anterograde amnesia – impossibility to remember actions during the administration of preparation.

By duration of action we differ  Long acting BDZ (T1/2 = 24-48 hours and more) Diazepam, Chlordiazepoxide, Flurazepam

 Middle acting BDZ (T1/2 = 6-24 hours) Oxazepam, Lorazepam, Alprazolam,  Short acting BDZ (T 1/2< 6 hours)Midazolam, Triazolam

Pharmacokinetics of BDZ

At enteral rout of administration absorbtion is very good. Their maximal plasma concentration reaches after 1 hour. They have high affinity to plasma proteins and due to lipophylicy can be accumulated in adipose tissues.

All BDZ are metabolized and excreted by urine as a glucoronide conjugates or oxidates. They differ by their duration of action.

Some representatives are transformed into active metabolites, N- dezmethyldiazepam (Nordiazepam). Its` T1/2 is 60 hours and has ability to accumulate in body leading to “abstinent syndrome”. Short-acting BDZ are conjugated with glucuronic acid and is excreted from body.

Because BDZ have big role in BDZ biotrasformation, in elder patients, children, or patients with liver diseases they can have longer duration of action.

Uses of BDZ

BDZ are used as

 Anxiolytics for treatment of chronic, heavy anxiety conditions  Hypnotic drugs  Antiepileptic drugs: diazepam, clonazepam  Myorelaxants during physical trauma, neurodegenerative diseases accompanied by muscle cramps  General anesthetic drugs in a combination with main anaesthetic drugs for premedication

 Sedative drugs during procedures, which are accompanied with short, nondesirable and acute pains (endoscopy etc.)  In diseases accompanied with affective disorders such as angina pectoris, myocardial infarction, hypertension, peptic ulcer, bronchial asthma etc. Side effects of BDZ

A-type side effects are somnolence, inhibition ofthought and motions, violation of coordination, loss ofmemory, muscle weakness. BDZ potentiate the action of CNS inhibitors (alcohol, sedative and hypnotic drugs). Most ofBDZ have teratogenic effect and contraindicated in pregnancy.

Toleranceanddependence.Almost all BDZ lead to tolerance.BDZ don`t induce euphoria, but long-term usage leads to dependence. If patient interrupt drug administration suddenly, it leads to expressed anxiety, tremor, dizziness, nervousness, loss of appetite, sometimes` convulsions. Short-term BDZ frequently lead to abstinent syndrome.

Toxicity during overdosage. BDZ comparing to the other sedative-hypnotic drugs are less dangerous, but these drugs are frequently used to commit suicide. During overdosage long-term sleep without disturbances of respiratory and cardiovascular systems can be noticed. In a combination with CNS inhibitors, especially with alcohol, heavy, life-threating inhibition of respiratory center can be noticed.

Endogenous BDZ substances

From brain tissue is extracted endogenous substance Diazepam-binding- inhibitor (DBI), which binding to BDZ site of GABA receptors, leads to opposite action of BDZ. This substance has anxiogenicancconvulsant effects.

Barbiturates

Pharmacodynamics

Action mechanism

Strengthen GABA mediated inhibiting effect by allosteric or partially by direct inhibitory effect.Barbiturates bind with barbiturate part of GABA receptor complex,resulting in opening of chlorine channelsby allosteric mechanism. They particularly lengthen duration of opening of chlorine channels and quantity of influx Cl ions. In high doses barbiturates possess ability independently to open chlorine channels, thus having intrinsic sympathomimetic activity toward GABA receptors.

• diminish the processes of excitation because neutralize an action of stimulating amino acid, particularly glutamate, because they block also AMPA receptors, resulting in weakening of depolarization and neuronal excitation.

 In higher dosage block Na + channels and inhibit neurotransmission. Effects of barbiturates

On the CNS barbiturates have dose-dependent action: sedation hypnotic effect anethesia coma

They have anticonvulsant action

3. Muscle relaxant actionis more expressed at high doses, causing anaesthesia and it is related to strengthening of GABA-ergic inhibition in area of spinal cord, reticular formation

4. Respiratory system: Inhibition of respiratory center (high doses)

5. CVS: Decline of arterial pressure due to (-) inotropiceffect (because of depressionof cardio-vascularcenter and ganglion blockingaction). Reflex tachycardia is possible. 53

6. Urogenital system: oliguria, due to increase of ADH secretion.

7. Liver: Under the influence of barbiturates the microsomal enzymes of liver are exposed to induction (are activated), and as a result the metabolism of many preparations, taken simultaneously with barbiturates, and also barbiturates is accelerated.

Drugs have low therapeutic index. Barbiturates are used as general anesthetic and antiepileptic drugs. Their usage as anxiolytic and hypnotic drugs is not recommended, because they disturb the rapid stage of sleep.

Pentobarbitale (Nembutal) has sedative, hypnotic effect, has 6-12 hours duration of action and is used as general anesthetic. In some countries is used to maintain drug coma during brain ischemia, as well as for efthanasia and for death- sentence. Antiepileptic action is less expressed.

Phenobarbitale has strong antiepileptic and minimal sedative effect, is mainly used as antiepileptic drug.

Thiopental is widely used as i/v injections for general anesthesia.

Side effects: Barbiturates are activators of liver metabolic enzymes, particularly are strong stimulators of cytochrome P450 system, that`s why can precipitate different undesirable effects during combined drug usage.

The side effects are also tolerance and physical dependence.

GABA - ergic substances

There are also endogenous benzodiazepine substances – agonists of benzodiazepine receptors, and also not benzodiazepine molecules, having affinityand internal activitytowardsbenzodiazepine receptors. These endozepines also increase GABA mediated permeability of chlorine channels.

From the brain tissue also was taken Diazepam-binding inhibitor (DBI), which binds to GABA receptors BDZ site leading to opposite effect. This substance has anxiogenic and convulsant effect.

It is supposed that endozepins and DBI substances have role in the different anxiogenic effects development.

Inverse agonists of benzodiazepine receptors (substances that have affinity to BDZ receptors, contacting with them, cause an opposite benzodiazepine effect) are β-carbolines. Binding with BDZ receptors, they lead to anxiogenic effect – cause an alarm, anxiety, cramps. Such phenomenon is possible to explain by the special structure of benzodiazepine receptor area. It is assumed that itcan exist in two conformationsA and В. ConformationA results in activating of GABAmediated current of chlorine ions, hyperpolarization and inhibition,conformation B–vice versa, unable to activate the action of GABA. In normal conditions equilibrium between these two conformations is present. BDZ bind to conformation A, move an equilibrium toward this conformation and facilitate the action of GABA.Inverse agonists bind to conformation B and render an opposite effect. The competitive antagonist Flumazenil binds with both conformations, sodoes not disturb conformationequilibrium, but blocks the effects of both substances -BDZ and inverse agonists. During intoxication by BDZ, antagonists of BDZ receptors- Flumazenil is used, which displaces BDZ and recover normal activity of receptors.

Buspirone

Buspirone and the same drugs (Ipraspirone, Gepirone) are partial agonists of

5-НТ1А serotonine receptors. Are used in different anxious states, but are not effective in panic states. Is considered to be daily-tranquilizer.

Activating presynaptic5-НТ1А receptors diminishes release of serotonine and other mediators, resultingin anxiolytic effect. Inhibits adrenergic locus

55 coeruleus and weakens “wakening reaction”. The anxiolytic effect of Buspirone is developed slowly.

Side effects:

Buspirone possesses less and mild side effects, than BDZ. They are expressed by dizziness, nausea, headache, anxiety. Buspirone doesn`t have sedative effect and disturbances in coordination.

Other drugs

Hydroxizine hydrochloride (atarax) – is diphenylmethane derivative. Has expressed sedative and moderate anxiolytic activity, which is due to blockade of H1 receptors in subcortical structure. Hydroxizine has also cholinolytic, spasmolytic, antihistamine and antipsychotic effects. Is administered for the treatment of anxiety, psychomotor excitation, premedication, as sedative and antiprurital drug.

β-adrenoblockers. Some drugs of this group (propranolol) is used for the treatment of anxiety and some forms of panic states, which are accompanied with sweating, muscle tremor and tachycardia.

Psychostimulants

Psychomotor stimulants increase physical and mental activity, arouse interest to environment, lead to cheerfulness, self - confidence, postpone sleep demand.

Classification of psychostimulants:

1. psychomotor stimulants 2. psychostimulants-adaptogens 3. psycho-metabolic stimulants / nootrops /

Psychomotor stimulants

Increase the rate of work, but not volume. In the basis of action of psychomotor stimulants is neurophysiological (emotional-motivated response, brain cheerfulness, motor activity) and psychophysiological (vigilance, memory, decision-making) processes activation.

Their effects are realized by the body`s own energetic storages, which in long-term usage can lead to body`s exhaustion.

Classification of psychomotor psychostimulants

1. Methylxanthines – Caffeine 2. Phenylalkylamines–Amphetamine 3. Sydnonimine derivatives –Sydnocarb

Methylxanthines Caffeine is a 1,3,7-trimethylxanthine, alkaloid, which is contained in tea bush`s leaf, cacao`s seed, cola`s fruits. Pharmacodynamics: Caffeine’s action can be realized by the following mechanisms. 1. adenosine A1 receptor competetive blockade There are purinergic neurons in central and peripheral nervous system. Adenosine and ATP are mediators in these neurons. There are several types of purinergic receptors. The first type – Р1 or A are classified into following subtypes-

А1, А2, А3

Localization А1 receptorss stimulation effects

CNS Inhibition

- Decrease in spontaneous activation of neurons - decrease in motor activity - sedative effect А1 - anxiolytic activity - anticonvulsant effect Adenylatecyclase ↓ - myorelaxation of central origin - respiratory center inhibition -inhibition of mediators’ release (AcH, NA, DA) from cAMP↓, peripheral and CNS presynaptic membranes Heart inhibition of heart activity Са2+ channel inhibition, К+ - negative inotropic effect - negative chronotropic effect channel opening - negative dromotropic effect Kidneys - constriction of afferent arteriol, decrease of primary urine filtration - renin↓ - erythropoetin↓ Adipose Lipolysis inhibition

tissue

Smooth Constriction (especially bronchial smooth muscles)

muscles

Gastric juice Inhibition secretion

Caffeine inhibits phosphodiesterase enzyme. /In higher than therapeutic doses/. Phosphodiesterase inhibition leads to increase in intracellular concentration of cAMP and cGMP.

Central effects.

Caffeine enhances release ofneuromediators Ach, NA, DA. By enhancing dopaminergic neurotransmission, caffeine leads to psychostimulant effect. Increase release of Ach in cortical synapses leads to activation of mental activity, in oblong brain stimulation of respiratory center.

Increasing adrenergic neurotransmission in hypothalamus and oblonged brain caffeine stimulates vaso-motor center. Caffeine activates also vagal center.

Pheripheral effects

1. Cardio – vascular system

Caffeine has positive inotropic effect. Cardiac output is increased which is more expressed in patients with heart failure. The positive inotropic effect of caffeine can be decreased due to the activation of vagal nerve tone.

Heart contraction rate is not unambiguous under the influence of caffeine. On the one hand caffeine has direct cardiostimulant activity, on the other hand increases vagal nerve tone, which inhibits heart function. As a result the end effect depends on the individual personal qualities of CNS activity, dosage of caffeine. Tachycardia or bradycardia is possible.

By peripheral mechanisms caffeine dilates blood vessels, by central mechanism (stimulates vasomotor center) – constricts. As a result some vessels (skin, mucous membranes, visceral organs) are constricted, but skeletal, coronary, renal vessels are dilated.

Caffeine slightly changes normal blood pressure and increases it in non- expressed hypotension.

2. Caffeine relaxes all smooth muscles: bronchial, bile ducts, urine ducts.

3. Caffeine is considered to be slight diuretic, inhibits reabsorption of Na+ and water and increases renal circulation, leading to increase in renal filtration.

4. Caffeine stimulates pepsin and HCL secretion /even in a parenteral way of administration/.

5. Caffeine increases skeletal muscles` contraction both by central and peripheral mechanisms.

6. Caffeine activates lipolysis, glycogenolysis, increases the metabolism rate. Increases free fatty acids level in blood plasma.

7. Caffeine inhibits release of histamine and the other mediators from mast cells.

Pharmacokinetics. Has a good absorption in a case of oral administration, reaches maximal concentration in plasma in 30-60 minutes. Is metabolized rapidly in liver leading to 3 active metabolite formation` theobromine, theophylline, paraxanthine.

Side effects. Caffeine abuse leads to:

Anxiety, sleeplessness, restlessness, tachycardia, psychological dependence.

Indications for psychomotor psychostimulants:

1. Increase in mental activity in healthy individuals. In this case drug is administered in a first half of day. 2. Premature newborns to treat respiratory depression (apnoe) 3. For migraine treatment in combination with analgesics and ergometrine 4. Phenylalkilamine derivatives: Amphetamine. See indirect sympathomimetics. Sydnonimine derivatives Sydnocarb is considered to be mild psychostimulant. Leads to mild CNS stimulant effect after 2-3 days ofadministration.Sydnocarb doesn’t lead to euphoria and further exhaustion. CNS stimulant effect is explained by noradrenaline release and activation of adrenergic neurotransmission. Sydnocarb doesn’t have an action on dopamine and serotonine release, doesn’t have anorexigenic action. Sydnocarb can be administered only one time or as a short time treatment /2-3 days/ to increasemental activity and physical endurance. Sydnocarb should be administered during first half of day to except the action on sleep.

Psychostimulant-adaptogens

Psychostimulant-adaptogens increase body`s nonspecific endurance toward external nondesirable factors.

Psychostimulant adaptogens increase the rate of physical work, but not volume. They postpone fatigue formation, recover inner facilities. Adaptogens doesn’t exhaust organism own reserves and leads to energy formation in spite of psychomotor psychostimulants.

Effects of psychostimulant adaptogens and their action mechanism

1. Increase the mental activity, short-term and long-term memory, concentration, learning process. 2. Promote energy formation, increase glycolysis and lipid oxidation and glycogenolysis in liver and skeletal muscles. 3. Stimulate DNA, RNA, protein, membrane phospholipids synthesis increase, ameliorate regenerative processes. 4. Increase thyroid gland and adrenal medulla secretion leading to prevention of anxiety and exhaustion processes development. In clinical practice are used psychostimulantadaptogens of plant origin

(Zhen-shen, Schizandra, Aralia tinctures, Eleuterococcus, Radiola, Rose extracts) andanimal originPantocrin.

Indications

Are used in apathy, depression, chronic hypotension. Are administered during first half of day. Are indicated to healthy individuals during intensive physical trainings and intensive mental activity if complete rest is not possible.

Adaptogens administration is limited in hypertension, sleeplessness, bleeding and fever.

Nootrop drugs

Nootrop drugs or psycho-metabolic stimulants have mnemotropic effect (greek. Mneme-memory, tropos-direction)- increase intellectual activity, concentration, short-term memory, learning process. The action mechanism is brain metabolic process activation, increase in proteins and phospholipids synthesis, increase in brain blood circulation and antioxidant effect. Most of nootropic drugs are derivatives of GABA, for example Piracetam, Aminalone.

They are mainly used in memory recovery, insults, intoxication, traumas.

The main drugs Coffeini-natrii benzoas-0.1,0.2g tablets, 10%-1,2ml solution in ampules Sydnocarbum-0.005g tablets Pyracetam-0.4 tablets

Tests samples 1. Caffeine by blocking adenosine A1 receptors leads to

a) bradycardia

b) tachycardia

c) vasodilation

d) inhibition of respiratory center

e) decrease in renin secretion

2. Caffeine leads to the following effects, except`

a) constriction of cranial vessels

b) dilation of coronary vessels

c) dilation of renal vessels 62 d) orthostatic collapse e) relaxation of skeletal muscle vessels

3. Amphetamine`s action mechanisms are

1. activation of GABA-A receptors

2. MAO-A inhibition

3. inhibition of neuronal reuptake of monoamines

4. increase release of NA from presynaptic nerve endings

5. blockade of DA receptors a) 1.3.5 b) 2.3.4 c) 3.4.5 d) 1.4.5

4. Phenamine /Amphetamine/ action mechanisms are

1. activation of GABA-A receptors

2. inhibition of MAO

3. inhibition of cathecolamines neuronal reuptake

4. increase in noradrenaline release from presynaptic vesicles

5. dopamine receptors blockade a) 1,3,5 b) 2,3,4 c) 3,4,5 d) 1,4,5