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Series «Medicine». Issue 27

Lecture

UDC: 616.61:615.031/.036

CLINICAL PHARMACOLOGY OF I. V. Soldatenko V. N. Karazin Kharkiv National University, Ukraine

Clinical pharmacology of diuretics in the international system of ATC (anatomic-therapeutic-chemical) is presented. Classification of this group by the action mechanism and caused effects is provided. and pharmacodynamics features, indications and principles of diuretics usage in clinics are considered. Contraindications, side effects and interaction with other drugs of this group are discussed in detail. KEY WORDS: clinical pharmacology, diuretics

КЛІНІЧНА ФАРМАКОЛОГІЯ СЕЧОГІННИХ ПРЕПАРАТІВ І. В. Солдатенко Харківський національний університет імені В. Н. Каразіна, Україна

Висвітлена клінічна фармакологія сечогінних препаратів у рамках міжнародної системи класифікації лікарських засобів АТХ (анатомо-терапевтично-хімічної). Представлені класифікації даної групи препаратів за механізмом дії та надаваними ефектами. Розглянуті особливості фармакокінетики та фармакодинаміки, показання та принципи використання в терапевтичній клініці сечогінних препаратів. Детально висвітлені протипоказання, побічні ефекти і взаємодія з іншими лікарськими засобами препаратів даної групи. КЛЮЧОВІ СЛОВА: клінічна фармакологія, сечогінні препарати

КЛИНИЧЕСКАЯ ФАРМАКОЛОГИЯ МОЧЕГОННЫХ ПРЕПАРАТОВ И. В. Солдатенко Харьковский национальный университет имени В. Н. Каразина, Украина

Освещена клиническая фармакология мочегонных препаратов в рамках международной системы классификации лекарственных средств АТХ (анатомо-терапевтическо-химической). Представлены классификации данной группы препаратов по механизму действия и оказываемым эффектам. Рассмотрены особенности фармакокинетики и фармакодинамики, показания и принципы использования в терапевтической клинике мочегонных препаратов. Подробно освещены противопоказания, побочные эффекты и взаимодействие с другими лекарственными средствами препаратов данной группы. КЛЮЧЕВЫЕ СЛОВА: клиническая фармакология, мочегонные препараты

next stage in diuretics creation was based on INTRODUCTION the results of acidosis development observation At present diuretics represent first line in patients, who got sulfanilamides, which is medications for arterial [1], not typical for modern sulfanilamide remedies. hyperkalemia [2] and electrolyte disorders [3, Acidosis was clarified to be stipulated for 4] treatment. carbonic anhydrase enzyme inhibition in As far back in the XVI century it was clear kidneys [5]. Further studies caused the creation that organic mercury compounds have of powerful inhibitor of characteristics but as diuretics they have been carbonic anhydrase in 1951 [6]. In 1957 in the used in medicine since 1920 in Vienna. The process of preparations chemically close to

 Soldatenko I. V., 2014 89 Journal of V. N. Karazin` KhNU. № 1108. 2014 acetazolamide study was 3) on distal part of straight tubule – obtained, which weakly inhibited carbonic and thiazide-like diuretics anhydrase, that is why this property could not (, chlorthalidone, indapa- explain their diuretic efficacy [7]. Both mide, etc.); acetazolamide and thiazide structurally are 4) in general in the area of collective and close to sulfanilamides. Their structure distal tubules ( preserving diuretics); modification caused the creation of more 5) onglomerule (aminophylline, teobro- effective diuretics, such as , etacryn mine). acid, as well as potassium Classification depending on natriuretic preserving diuretics such as triamteren and effect , etc. [8]. Diuretics are divided into the groups depending on natriuretic effect, expressed in CLASSIFICATION OF DIURETICS percentage of excelling from general АТС classification amount of sodium, filtered in renal tubules: C: MEDICATIONS, EFFECTING 1) strong organic compounds of mercury CARDIO-VASCULAR SYSTEM (mersalile, at present it is not used in clinical С03 Diuretics practice): С03А Diuretics with moderately – derivatives of sulfamonlantranile acid expressed activity, group (furosemide, bumetanid); С03АА Simple thiazide diuretics – derivatives of phenoxy-acetic acid С03АА03 Hydrochlorothiazide (etacrin acid, indacrinon). С03В Nonthiazide diuretics with 2) With moderately expressed natriuretic moderately expressed activity effect (causing of 5-10 % sodium, С03ВА Sulfanilamides, simple filtered): preparations – derivatives of bensotiathiazine С03ВА03 (thiazides and hydrothiazides). С03ВА04 Chlorthalidone – heterocyclic combinations similar in С03ВА11 mechanism of tubule activity to thiazide С03ВX Other nonthiazide diuretics diuretics (chlorthalione, clopamide, with moderately expressed effect indapamide). С03ВХ10 Herbal preparations with 3) weak (causing excretion of less than diuretic effect 5 % filtered sodium): С03С Highly active diuretics – potassium preserving; С03СА Simple sulfamides preparations – carbonic anhydraze inhibitors; С03СА01 Furosemide – osmotic diuretics. С03СА02 Bumetanide PHARMACOKINETICS С03СА04 Thorasemide С03СЗ Derivatives of aryloxyazinyl Main pharmacokinetic indicators of acid diuretics are presented in table 1. С03СС01 Etacrin acid Loop diuretics nearly completely absorb C03D Potassium preserving diuretics from gastrointestinal tract, though absorption C03DА Aldosterone antagonists individual indices vary greatly. They relatively C03DA01 quickly metabolize in . Classification depending on the scene of Thiazides and thiazide-like diuretics have action in nephron high under intake. Due to suffi- Classification of diuretics depending on cient lipophilicity and moderately expressed their scene of action in nephron is widely link with proteins they deeply penetrate into disseminated in clinical practice: organs and tissues. Hydrochlorothiazide and 1) on proximal part of straight tubule: chlorthalidone poorly metabolize in liver and is a) Carbonic anhydraze inhibitors nearly absolutely excreted by kidneys (acetazolamide). unchanged. Indapamide practically completely b) Osmotic diuretics (, ). metabolize in liver and only a tiny part of 2) on ascending area of Genle loop - active remedy is excreted by kidneys. «loop» diuretics (furosemide, etacrin acid, Carbonic anhydrase inhibitors are practi- etc.); cally completely absorbed from gastrointestinal

90 Series «Medicine». Issue 27 tract. In 95 % of cases they are linked with metabolized in organism and are completely protein in blood plasma. They are mot excreted by kidneys unchanged. Table 1 Main pharmacokinetic indicators of diuretics

Diuretic Bioavailability (%) Т1/2 (h) Main way of elimination

Thiazide diuretics: Hydrochlorothiazide 60-80 10-12 (2,5) Kidneys Indapamide 90-100 15-25 Kidneys + liver (30 %) Clopamide ? 4-6 Kidneys Xipamide 70-90 5-7 (14) Kidneys + liver 50-60 8-14 Kidneys + liver Chlorthalidone 60-65 24-50 Kidneys + liver Chlorthiazide 33-65 15-27 (1,5) Kidneys + liver Loop diuretics: Bumetanide 60-90 0,3-1,5 Kidneys + liver Pyretanide 80-90 0,6-1,5 Kidneys + liver 80-90 0,8-6,0 Kidneys + liver Furosemide 10-90 0,3-3,4 Kidneys + liver (40 %) Etacrin acid 30-35 12 Kidneys + liver Potassium preserving diuretics: Amiloride 50 6-9 (18-22) Kidneys + liver (50%) Spironolactone 60-90 14 (1,5) Kidneys + liver (20%) Triamteren 50 3-5 Kidneys + liver

Note: Т1/2 – semi-ejection period; in brackets – other meanings of Т1/2, if they rapidly differ from the given/

Potassium preserving diuretics have variable PHARMACODYNAMICS absorption. Triamteren is linked with plasma proteins in 56 % of cases, it is relatively quickly Pharmacodynamic effects of diuretics are metabolized by liver enzymes, forming active hypotensive, antianginal, antiatherogenic, metabolite 4-hydeoxytriamteren sulphate, dehydrative and others. which is secreted into proximal area of Hypotensive effect of diuretics is connected tubules opening with the help of active with influence on one of the pathogenic transport mechanism. Amiloride is weakly mechanisms of arterial hypertension deve- linked with plasma proteins, it is not lopment – sodium latency in organism. Two metabolized in organism and is excreted into possible main mechanisms of hypotensive proximal area of kidneys tubules unchanged. activity are discussed: decrease of sodium Aldosterone derivatives are slowly absorbed content and, consequently, liquid volume in from gastrointestinal tract, just during the first organism and effect on vessels regardless transport through liver they are subjected to natriuresis. Thus antihypertensive effect can be expressed biotransformation. In this case some stipulated for initial decrease of liquid volume metabolites are formed, two of which display in organism (first 3-4 weeks of therapy), and the same pharmacological activity as further (after 6-8 weeks) – protractedly sup- spironolactone. The link of spironolactone with ported decrease of vessels reaction on plasma proteins exceeds 90 %. It has a short sympathy nervous stimulation (periphery vaso- period of semi-excretion (1,6 h), though the dilatation), which can be of compensatory period of its active canrenon metabolite character in response to tiny but long term semiexcretion reaches 10-16 h, which lengthens decrease of blood plasma volume. spironolactone biological effect. Arterial pressure decrease is reached on Both liver and renal failure lower diuretics account of both depletion of sodium chloride clearance and can raise their toxicity.

91 Journal of V. N. Karazin` KhNU. № 1108. 2014 reserves and vascular effects regardless elderly patients demonstrated that indapamide natriuresis amount. produced nephroprotective activity. Antianginal effect of diuretics is stipulated Diuretics provide bronchodilatory and for intracellular calcium decrease with mag- spasmolytic effects (aminophylline and nesium content preservation, decrease of teobromine) on the account of bronchial vascular wall stiffness and promote of effective smooth muscles, periphery arteries, cardiomyocytes relaxation into diastole. In this gastrointestinal smooth muscles, biliary tract case prostacyclin synthesis increases, throm- relaxation. They also increase contractility of bocytes aggregation and thromboxane A2 skeleton muscles (including respiratory). ejection decreases, totally exerts positive INDICATIONS AND USAGE PRINCIPLES hemodynamic effect on account of loading decrease on left ventricle. Diuretics improve Main indications to diuretics clinical use microcirculation in kidneys, eliminate micro- are: albuminuria which is the marker of gene- – arterial hypertension (AH): isolated ralized vascularaffection and a predictor of systole AH in elderly persons; cardio-vascular and renal complications. – edematous syndrome, cause by Na delay: Antiatherogenic effect of diuretics (inda- chronic failure (CHF), chronic renal pamide) is stipulated for decrease of low den- failure (CRF), nephritic syndrome, and sity atherogenic cholesterol and triglycerides under hepatocirrhosis; level with simultaneous increase of high – osteoporosis, hypercalcemia (thiazides); density lipoprotein concentration. – (primary) open angle glaucoma, secon- Dehydration effect of diuretics (mannit, dary glaucoma, pre-operative decrease of intra- urea) is stipulated for increase of osmotic ocular pressure (carbonic anhydrase inhi- pressure in tubules and water reabsorption bitors); obstruction. They are filtered by kidneys – pseudohyperaldosteronism – Liddle synd- without further tubular reabsorption which rome (potassium preserving diuretics); causes water retention in tubules and increase – primary and secondary hyperaldo- of urine volume. Simultaneously natriuresis steronism (spironolactone); increases considerably without potassiumuresis – hyperuricemia (spironolactone). sufficient increase. They cause increase of Daily doses and reception frequency of circulating liquid volume (in connection with diuretics are presented in tab. 2. osmotic pressure growth in bloodstream), SIDE EFFECTS decrease of intracranial and intraocular pressure. Oppression of carboanhydrase causes Most side effects of diuretics are connected decrease of intraocular pressure, inhibition of with electrolytic and water balance changes, excessive paroxysmal neurons discharges and urine pH shift into alkaline side and metabolic antiepileptic activity. acidosis development. Such side effects are: Antiepileptic effect (acetozolamide) is Electrolytic: intracellular liquid reserves stipulated for random suppression of carbo- depletion, arterial hypotension, hypocalcaemia anhydrase (enzyme, catalyzing reverse reaction (thiazides), hyperkalemia (aldosterone antago- of carbon dioxide hydratation and further nists, potassium preserving diuretics), nypona- carbonic acid dissociation). tremia, nypochloremia, metabolic alkalosis, According to LIVE trial (Left ventricular hypomagnesaemia, hypocalcaemia, hyperuri- hypertrophy: Indapamide Versus Enalapril) on cemy. the background of long term indapamide Central nervous system (CNS) disorders: therapy - 1,5 mg per day - reliable decrease of dizziness, headache, weakness, parasthesias. mass index of left ventricle was observed Gastrointestinal: anorexia, nausea, vomi- versus enalapril therapy (20 mg per day). ting, colic, diarrhea, constipation, cholecyctitis, According to most experimental and clini- . cal studied diuretics have no sufficient Sexual: impotence, libido decrease. nephroprotective activity. On the contrary, Hematologic (blood dyscrasia): thrombocy- their monotherapy can accelerate renal tepenia, agranulocytosis, thrombocytopenia function decrease in spite of antihypertensive purpura. effect. Though the results of early trial HYVET Dermatologic: skin rush, photosensibili- (Hypertension in the Very Elderly Trial) in zation.

92 Series «Medicine». Issue 27

Other: hyperglycemia, increase of general increase, low density lipoproteins level cholesterol level in blood, triglycerides level increase. Table 2 Daily doses and the reception frequency of diuretics Average Reception Diuretic doses Note frequency (mg/day)

Thiazides Most efficient for AH treatment than loop Hydrochlorotheozide 12,5-50 1 diuretics excluding the patients with more than 177 mcmole/l

Thiazide-like diuretics Chlorthalidone 12,5-25 1 Indapamide-retard 1,5 1 Loop diuretics Torasemide 2,5-10 1-2 The use of big doses is possible in treatment Forisemide 20-80 1-2 of patients with CRF and CHF. Potassium preserving diuretics Amiloride 5-10 1-2 Is not used if creatinine is more than 220 Tiamtеren 50-100 1-2 mcmole/l Aldosteron antagonists Is not used if creatinine is more than 220 Spironolactone 25-50 2-3 mcmole/l

concentration in blood plasma; lower oral CONTRAINDICATIONS hypolipidemic remedies effects. Diuretics , , asymptomatic activity can decrease under simultaneous hyperuricemia, decompensated application together with indomethacin and hepatocirrhosis, sulpha-nilamide derivatives other non-steroid anti-inflammatory drugs intolerance (hypo-glycemic and antibacterial (NSAIDs). preparations), severe respiratory failure, Thiazide and thiazide-like diuretics lower acute renal failure. In high doses thiazide the efficacy of antigout remedies, diuretics are contrain-dicated under sugar sulphonylurea preparations, insulin. They diabetes, especially of the 1st type. Diuretics can reinforce the activity of anesthetics, should be prescribed with great care to the diasoxide, heart glycosides, prepara- patients with ventricular arrhythmias or to tions and loop diuretics.Such remedies as those who get heart glycosides or lithium NSAIDs and cholestyramine lower the salts. efficacy of diuretics therapy, thus ampho- tericin B and corticosteroids can reinforce INTERCONNECTION OF DIURETICS hypokalemic effect of thiazide and thiazide- WITH OTHER REMEDIES like diuretics Loop diuretics are able to interact Carbonic anhydrase inhibitors interact pharmacodynamically and pharmacokine- with lithium preparations which cause tically with many preparations. lowering of diuretics effect. They reinforce the activity of anti- Spironolactone can raise digoxin coagulants, hypotensive remedies, semipola- concentration in blood plasma and increase rizing myorelaxants; raise the side effects the risk of side effects development, development risk of aminoglycosides, heart including arrhythmia. Combined application glycosides and diuretics, excreting potassium of remedies with ACE inhibitors, and GCS; raise propranolol and lithium indomethacin and other potassium preserving

93 Journal of V. N. Karazin` KhNU. № 1108. 2014 diuretics can cause the development of glomerular filtration and diuresis weaken hyperkalemia (especially on the background diuretic activity of spironolactone. of renal failure). NSAIDs, lowering

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