Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

FREQUENCY of arterial hypertension (AH) FREQUENCY of arterial hypertension (AH) AP > 140/90 mm Hg  % in population  At elderly people %

Principles of treatment of arterial hypertension 1. Treatment should be started as soon as possible and should be hold till the end of life. Canceling antihypertensive drugs administration causes relapse of AH. 2. All the individuals with increased arterial pressure should obtain drugless treatment (modifying lifestyle): -rejection from smoking and alcohol; -increasing of physical activity; -restriction of salt consumption (less than 6 g per day); -decreasing of body weight in a case of obesity. 3. Scheme of drug treatment should be the most availably simple – 1 tablet per day if possible; it is better to use drugs with long duration of action (prophylaxis of considerable fluctuation of blood pressure during the day). 4. Rapid decreasing of blood pressure to low figures is dangerous, especially for elderly patients. 5. Main aim of the treatment is to decrease blood pressure to 140/90 mm Hg. To improve life prognosis is the aim that has a more significant meaning than character of drugs used to reach this aim. It is better to prescribe cheap and “non modern” drugs than don’t treat the patient at all.

Treatment of arterial hypertension Drugs of first row -diuretics (furosemid, dichlothiazide, spironolacton) -inhibitors of ACE (captopril, enalapril, ramipril) -antagonists of angiotesine II receptors (АRА ІІ) (losartan) -β-adrenoblockers (anaprilin, atenolol, thymolol) -α-adrenoblockers (prasosine, terasosine) -α-, β-adrenoblockers (labetolol, carvedilol) -Ca ions antagonists (niphedipine, amlodipine, verapamil) Drugs of second row : -agonists of α 2 –adrenoreceptors of central action (clopheline, methyldopa) -sympatholytics (reserpin, octadin) -direct vasodilators (molsidomin, hydralasin) New drugs: -imidasolines (moxonidine, rilmenidine) -serotonin receptors blockers (ketanserin) -monateril (calcium antagonist, α 2 -adrenoblocker) Treatment of arterial hypertension Drugs of first row -diuretics (furosemid, dichlothiazide, spironolacton) -inhibitors of ACE (captopril, enalapril, ramipril) -antagonists of angiotesine II receptors (АRА ІІ) (losartan) -β-adrenoblockers (anaprilin, atenolol, thymolol) -α-adrenoblockers (prasosine, terasosine) -α-, β-adrenoblockers (labetolol, carvedilol) -Ca ions antagonists (niphedipine, amlodipine, verapamil) Drugs of second row : -agonists of α 2 –adrenoreceptors of central action (clopheline, methyldopa) -sympatholytics (reserpin, octadin) -direct vasodilators (molsidomin, hydralasin) New drugs: -imidasolines (moxonidine, rilmenidine) -serotonin receptors blockers (ketanserin) -monateril (calcium antagonist, α 2 -adrenoblocker)

Mechanism of action of thiaside diuretics in case of arterial hypertension Dychlothiaside (hypothiaside) Oxodolin (chlortalidon, hygroton) Thiaside diuretics Holding sodium and water Volume of circulating blood Cardiac output Peripheral vascular resistance Decreasing of arterial pressure

FUROSEMIDE  High ceiling (loop) diuretic  Properties : 1. diuretic action 1. diuretic action 2. dilation of peripheral venous 2. dilation of peripheral venous 3. decrease left ventricular filling pressure 3. decrease left ventricular filling pressure 4. potent anti-inflammatory effect (similar to indometacine and other NSAID) 4. potent anti-inflammatory effect (similar to indometacine and other NSAID)  Administration: hypertensive emergencies, long-term treatment of arterial hypertension  Adverse reactions: dehydration, hypokalemia, hearing loss - deafness, hypocalcaemia

THIAZIDES and RELATED DIURETICS  Medium efficacy diuretics  Benzothiadiazines (chlorothiazide, hydrochlorothiazide, clopamide), related thiazide like (chlorthalidone, indapamide)  for long-term treatment of arterial hypertesion (oral administration)  Duration of action (6-12 hours for hydrochlorothiazide, hours for clopamide, hours for chlorthalidone)  Adverse reactions: dehydration, hypokalemia, hyperuricaemia (rise of blood urate level)

Furosemid (diuretic)

Triampur (triamteren + hydrochlorthiaside) diuretic

Mechanism of action of beta-adrenoblockers (anaprilin, atenolol, methoprolol etc.) in case of arterial hypertension β- adrenoblockers activation of β 1 -adrenoreceptors of heart Cardiac output Angiotensine ΙΙ Renin Aldosterone Holding sodium and water Peripheral resist- ance of vessels Volume of blood circulation Decreasing of blood pressure

β-adrenoblockers  Used for mostly mild to moderate cases of AH (frequently in combinations with other drugs)  Stable hypotensive response develops over 1-3 weeks  Titration the effective dose  Antihypertensive action is maintained over 24 hr after single daily dose  Withdrawal syndrome if discontinue quickly  Contraindications: bronchial asthma, peripheral vascular disease, diabetes

Atenolol β - adrenoblocker

Anaprilin β 1 - β 2 adrenoblocker

Vasocardin 100 mg Methoprolol tartrate

Nadolol ( β 1, β 2 - adrenoblocker )

Tenoretic (atenolol + chlortalidon)

α 1 -adrenergic blockers (prazosin, terazosin, doxazosin)  Do not block presynaptic α 2 -adreno- receptors, so do not cause reflex cardiac stimulation (as compared to nonselective α-adrenoblockers)  Dilate resistance and capacitance vessels  Adverse effects: postural hypotension (“effect of first dose”), tolerance gradually develops with monotherapy

Prasosine (α 1 –adrenoblocker)

α, β – adrenoreceptors blockers (labetalol, carvedilol)  Labetalol is used for long-term treatment of AH and for emergencies (i. v. - hypertensive crisis, clonidine withdrawal, cheese reaction)  Carvedilol – produces vasodilatation, antioxidant/free radical scavenging properties, it is used for HD and for CHF

MECHANISM OF ACTION OF IACE Decrease of arterial pressure sympathetic tone peripheral vessels tone retention of Na+ and H 2 O bradicinine ANGIOTENSINOGEN ANGIOTENSIN (inactive) IACE Decrease angiotensine II production Decrease aldosterone production - ACE Renin (kidneys)

IACE (ANGIOTENSIN CONVERTING ENZYME INHIBITORS)  Captopril, enalapril, ramipril, perindopril etc.  Decrease the levels of mortality and morbidity  When used for monotherapy control AP in 50% of patients  Frequently combined with diuretics (not with potassium-sparing diuretics !) and β- adrenoblockers - the effectiveness of therapy grows to 90%  Adverse effects: cause the retention of potassium ions, dry persistent cough (requires discontinuation of IACE or treatment with NSAID)  Contraindicated for the patients with bilateral renal artery stenosis)

Captopril (IACE)

KOZAAR (Losartan) АRА ІІ

CALCIUM CHANNEL BLOCKERS (dihydropyridines – DHPs)  Short acting DHPs (nifedipine) can increase mortality as a result of reinfarction (long term controlled trials)  Retard forms of DHPs (Amlodipine) are used widely for AH  Do not contraindicated in asthma, do not impair renal perfusion, do not affect male sexual function  Can be used during pregnancy  Can be given to diabetics  Adverse reactions: ankle edema, slight negative inotropic / dromotropic action, nifedipine decreases insulin release (diabetes accentuating)

NIFEDIPINE (calcium channels blocker)

NORVASC (AMLODIPINE) (calcium channels blocker)

Arterial hypertension VerapamilDilthiasemNiphedipinFelodipinAmlodipin Ischemic heart disease DilthiasemNiphedipinAmlodipinVerapamil SupraventriculetachicardiaVerapamilDilthiasem Possibility to combine with beta-blockers DilthiasemДилтіаземNiphedipinAmlodipin recommended drug to use carefully diseases DRUGSFelodipin Calcium channels blockers administration

CLOPHELINE  α 2 - adrenergic receptors agonist (in brainstem stimulates α 2 - adrenergic receptors and imidazoline receptors)  decreases vasomotor centers tone - reduces sympathetic tone - fall in AP  Increases vagal tone - bradycardia  Has analgesic activity  For hypertensive emergencies (i. v. dropply or very slowly)  Side effects and complications: postural hypotension, sedation, mental depression, sleep disturbance, dry mouth, constipation, withdrawal syndrome

CLOPHELINE (decreases vasomotor centers tone)

SINEPRESS (dihydroergotoxine + reserpine + hydrochlorthiaside)

TRIRESIDE ( reserpine + hydralasine + hydrochlorothiaside)

CRISTEPIN (clopamide + dihydroergocristine + reserpine)

MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously) DrugDoseOnsetSide effects Sodium nitroprussid 0,5-10 mcg/kg/min (dropply) immediate ly nausea, vomiting, fibrillation of muscles, sweating Nitroglyceri -num 5-10 mcg/kg (dropply)2-5 mintachicardia, flushing, headache, vomiting, Diazoxidum mg (quickly) 300 mg (during 10 min) 2-4 minnausea, vomiting,, hypotension, tachicardia, flushing, redness of skin, chest pain Apressinum mg10 minflushing, redness of skin, headache, vomiting Furosemidu m mg during sec2-3 minhypotension, fatigue Clophelinum 0,5-1 ml 0,01 % solution (in ml 0,9 % solution NaCI slowly) min somnolence Anaprilinum 5 ml 0,1 % solution (in 20 ml 0,9 % NaCI solution slowly) min bradicardia Magnesium sulfas ml 25 % solution (i. v. very slowly or dropply) minredness of skin Labetololum mg (slowly – 10 min) or 2 mg/kg (dropply); the whole dose – mg 5-10 minnausea, vomiting,, hypotension, dizzeness

Factors which promote development of INTOXICATION WITH HEART GLYCOZIDES DECREASING OF TOLERANCE TOWARDS HG – in case of considerable damage of myocardium with pathological process DECREASING OF TOLERANCE TOWARDS HG – in case of considerable damage of myocardium with pathological process (acute MI, myocarditis, chronic lung heart) “Patients which need HG the most are the most sensitive of diuretics (furosemis, dychlothiazide), GCS, glucose with to them” HYPOPOTASSIUMEMIA, HYPOPOTASSIUMHISTIA OF MYOCARDIUM, HYPOMAGNESIUMEMIA HYPOPOTASSIUMEMIA, HYPOPOTASSIUMHISTIA OF MYOCARDIUM, HYPOMAGNESIUMEMIA - administration insuline, amphotericine B - secondary hyperaldosteronism, vomiting, diarrhea HYPERCALCIUMEMIA, KIDNEY, LIVER INSUFFICIENCY HYPERCALCIUMEMIA, KIDNEY, LIVER INSUFFICIENCY

Factors which promote development INTOXICATION WITH HEART GLYCOZIDES  Digitoxin is a choice drug when HI is combined with kidney insufficiency, but contraindicated if liver is damaged (it is metabolized by liver)  Digoxin is not contraindicated even in case of liver cirrhosis (it is not metabolized in liver), but contraindicated in case of kidney insufficiency (it is excreted by kidneys)

Intoxication with heart glycosides

Treatment of intoxication with heart glycosides  Immediate quitting of HG introduction  Correction of hypopotassiumemia (KCl, panangin)  Introduction of unitiol (1 ml of 5 % solution / kg of weight i.m times per day)  Clearing of GI tract (vaseline oil, cholestyramin, magnesium sulfate)  Treatment of arrhythmias (anaprilin, verapamil, difenin, lidokain, atropine)  Na ЕDTA (trilon B), Na citrate  Calcitrin  Antibodies towards digoxin (Digibind)  Oxygen therapy

NONGLYCOSIDE CARDITONIC DRUGS  Xantins, derivatives of isoquinoline (ethophiline)  Pyridines, and bipyridines (amrinon, milrinon)  Derivatives of imidazole (vardax)  Derivatives of piperidine (buquineran, carbazeran)  Polypeptides (glucagon)  Carboxyl antibiotics (lasolacid, calcimycin)  Derivatives of other chemical groups: L- carnitin, heptaminol, creatinol-o- phosphate, trapidil, etc.

NONGLYCOSIDE CARDIOTONIC DRUGS  Dobutamin – beta 1 -adrenomimetic - in case of acute and chronic heart insufficiency – intravenously dropping – 2, mcg/(kg.min); in case of constant infusion tolerance develops after 3-4 days; in case of increasing of dose – heart arrhythmias  Amrinon, milrinon – inhibitors of phosphodiesterase – for temporary improvement of patient’s condition in terminal stage of HI

INHIBITORS OF ANGIOTENSINE TRASFORMING ENZYME (IATE) Captopril, enalapril, ramipril, lysinorpil In case of HI they brake pathological consequences of activation of renin- angiotesine system by inhibiting ATE:  production of angiotensine II decreases (vasoconstrictor, inductor of aldosterone, norepinephrine, endothelin secretion, myocardium hypertrophy)  Accumulation of bradikin (inductor of prostacycline and nitrogen oxide synthesis)

INHIBITORS OF ANGIOTESINE TRANSFORMING ENZYME (IATE)  Increase duration and improve quality of life of patients with HI  Increase tolerance towards physical loads  Decrease risk of recurring MI  Brake development of miocardium hypertrophy

CAPTOPRIL (CAPOTEN)  Dose titration: from 6,25-12,5 mg per day to 12,5-50 mg 3 times a day until appearance of effect  Side effects: dry cough (can be decreased by nonsteroid antiinflammatory), considerable decreasing of AP, worsening of kidneys’ function, hyperpotassiumemia, tachycardia, neutropenia, aphtose stomatitis  Contraindicated in case of bilateral stenosis of kidney arteries, should not be combined with potassium drugs

ANTAGONISTS OF ANGIOTESINE II RECEPTOS (АRА II) LOSARTAN (cosaar) Blocks receptors of angiotensine II Decreases mortality of patients with HI on 50 % Breaks development of myocardium hypertrophy It is approved to combine IATE with АRА II

DIURETICS Dichlotiazide, hyhrotone (oxodoline), clopamide (brinaldix) Furosemid, etacrine acid Spironolacton improve currency of the disease, increase tolerance of patients towards physical loads, improve currency of the disease, increase tolerance of patients towards physical loads, spironolacton decreases quantity of relapses and mortality spironolacton decreases quantity of relapses and mortality

PERIPHERAL VASODILATORS  Arterial: hydralasin, calcium ions antagonists, minoxydil  Venous: nitrates, molsidomin  Of mixed action (influence on tone of arterioles and venules): sodium nitropruside, prasosine, inhibitors of ATE, ARA II Isosorbide dinitrate ( mg/day) + Isosorbide dinitrate ( mg/day) + hydralasin ( mg/day) – for patients which have contraindications towards administration of IATE hydralasin ( mg/day) – for patients which have contraindications towards administration of IATE

PERIPHERAL VASODILATORS Unfavorable action in case of HI: They activate sympatic-adrenalsystem and intermediately renin-aldosterone system

BETA-ADRENOBLOCKERS Carvedilol, methoprolol, bisoprolol They decrease mortality, improve disease currency and quality of patients’ lives in case of stagnant HI They decrease mortality, improve disease currency and quality of patients’ lives in case of stagnant HI Mechanism of treatment action in case of HI  Renewing of quantity and sensitivity of beta- adrenoreceptors in heart, which leads to increasing of systolic volume after 8-10 weeks of regular administration (paradox of beta- adrenoblockade)  Prevent calcium overload of myocardium, improve coronary blood circulation  Decrease production of renin  Prevent arrhythmias  Carvedilol – alpha 1 -adrenoblocking and antioxidant action

BETA-ADRENOBLOCKERS Scheme of administration of beta- adrenoblockers in case of HI The treatment is started from a small dose The treatment is started from a small dose (3,175-6,25 carvedilol), every 2-4 weeks it is doubled until obtaining the effect (usually develops after 2-3 months). (3,175-6,25 carvedilol), every 2-4 weeks it is doubled until obtaining the effect (usually develops after 2-3 months). Average effective doses: Average effective doses: carvedilol – 50 mg carvedilol – 50 mg metoprolol – 100 mg bisoprolol – 5 mg Administration of beta-blockers is possible only in case of constant condition of the patient, before development of stabile improvement of condition temporary worsening may develop Administration of beta-blockers is possible only in case of constant condition of the patient, before development of stabile improvement of condition temporary worsening may develop

DRUGS OF METABOLIC ACTION  Vitamins: Е, С, В group  Ryboxin  Mildronate  Phosphaden, ATP  Creatinphosphate  Potassium orotate, anabolic steroids Drugs manifest cardiocytoprotective action, improve energetic metabolism in myocardium

PECULIARITIES OF TREATMENT OF DIASTOLIC DISFUNCTION OF MYOCARDIUM Indicated: IATE, АRА II, Beta-adrenoblockers, calcium ions antagonists Contraindicated: Nitrates, diuretics, heart glycosides

Diuretics

Classifiction of diuretics accordingly to power of action І Strong (slowing down of Na + reabsorbtion for 10-20%) 10-20%) furosemide, etacrynic acid, clopamide, bufenox furosemide, etacrynic acid, clopamide, bufenox ІІ Medial power of action (slowing down of Na + reabsorbtion for 5-8%) ІІ Medial power of action (slowing down of Na + reabsorbtion for 5-8%) dichlothiaside, oxodoline dichlothiaside, oxodoline ІІІ Light (slowing down of Na + reabsorbtion not more than for 3%) ІІІ Light (slowing down of Na + reabsorbtion not more than for 3%) diacarb, spironolactone, amiloride, triamteren, xanthines (theophylline) diacarb, spironolactone, amiloride, triamteren, xanthines (theophylline)

Mannitol 15 % solution rapid intravenous introduction intravenous dropping intravenous droppingintroduction dehydratingactiondiureticaction diuretic action action

Mannitol Indicatoins 1.Brain oedema (in case of maintaining ofHEB permeability) 2.Toxic lung oedema (poisoning with gasoline, gass, formaline, skipidar etc.) 3. Larynx oedema of allergic or inflammatory genesis 4. Holding of forced diuresis (poisoning with barbiturates, salycylates, sulphonamides, PASA, metanole, boric acid, haemolytic poisons, antifreezers; in case of trasfusing of incompatible blood, massive hemoglobinuria etc. 5.In oliguric phase of acute nephral insufficiency 6.Burns, osteomielitis, peritonitis, sepsysContrainidications Acute cardiac insufficiency, skull trauma, intracranial hemorrhages, arterial hypertension

FUROSEMIDE  High ceiling (loop) diuretic  Properties : 1. diuretic action 1. diuretic action 2. dilation of peripheral venous 2. dilation of peripheral venous 3. decrease left ventricular filling pressure 3. decrease left ventricular filling pressure 4. potent anti-inflammatory effect (similar to indometacine and other NSAID) 4. potent anti-inflammatory effect (similar to indometacine and other NSAID)  Administration: hypertensive emergencies, long-term treatment of arterial hypertension  Adverse reactions: dehydration, hypokalemia, hearing loss - deafness, hypocalcaemia

Furosemide (lazix) Furosemide (lazix) Effective even in case of decreased glomerular filtration less than 10 ml/min. (norm – 127ml/min) Indications Indications 1.Acute left ventricular insufficiency, lung oedema 2.Chronic cardiac insufficiency 3.Arterial hypertension, including hypertensive crisis 4.Brain oedema of any etiology 5.Acute nephral insufficiency 6.Performing of forced diuresis 7.For excretion of Calcium ions (hypervitaminosis D)

Side effects of furosemide Side effects of furosemide 1.Hypopotassiumaemia, hypopotassiumhystia 2.Hypovolemia, vascular collapse, hyposodiumaemia, hypocalciumaemia, hypochloraemia, metabolic alkalosis 3.Ototoxic action 4.Contrinsular action (manifestation of latent diabetes mellitus) 5.Formation of oxalate and phosphate stones in urinary tracts 6.Decreasing of secretion of uric acid (acute attack of gout) It should not be combined with antibiotics, aminoglycosides and cephalosporines!

Furosemide (diuretic) Furosemide (diuretic)

THIAZIDES and RELATED DIURETICS  Medium efficacy diuretics  Benzothiadiazines (chlorothiazide, hydrochlorothiazide, clopamide), related thiazide like (chlorthalidone, indapamide)  for long-term treatment of arterial hypertesion (oral administration)  Duration of action (6-12 hours for hydrochlorothiazide, hours for clopamide, hours for chlorthalidone)  Adverse reactions: dehydration, hypokalemia, hyperuricaemia (rise of blood urate level)

Dichlotiaside (hypothiaside) Dichlotiaside (hypothiaside)Indications 1.Oedema in case of chronic cardiac insufficiency 2.Oedema in case of chronic pathology of liver and kidneys 3.Treatment of arterial hypertension 4.Diabetes insipidus Side effects 1.Hypopotassiumaemia, hypopotassiumhystia 2.Hypochloraemic alkalosis 3.Retention of uric acid - artralgy, acute attack of gout, chronic nephropathy 4.Hyposodiumaemia of dilution: nausea, vomitting, diarrhea, weakness 5.Pancreatitis

Indapamide (ariphone – sulphamoil benzamide) Indapamide (ariphone – sulphamoil benzamide)

Drug Way of administration Latent period Duration of action Sulfonyl derivates Oxololin (chlortalidon, hyhroton) peroral 2-4 hours Till 3 days Clopamideperoral 1-3 hours 8-18 (till 24) hours Bufenox (bumetanide) intravenous min. 2-5 min. 4-6 hours 1-3 hours Potassium-, magnesium-sparing Spironolactoneperoral 2-5 days 2-3 days Triamteren (pterophen) peroral min. 6-8 hours Amilorideperoral 2 hours till 24 hour Pharmacokinetics of some diuretic drugs

Spironolactone (aldactone) Spironolactone (aldactone)

Combined administration of diuretics 1.Mannitol + furosemide (etacrynic acid) 2.Dichlotiaside + triamteren (spironolactone) 3.Furosemide + spironolactone 4.Furosemide (excretes Calcium ions) + dichlotiaside (retains Calcium ions) (retains Calcium ions)

Triampur (triamteren + hydrochlorthiaside) Triampur (triamteren + hydrochlorthiaside)

Blue corn-flowers (Flores Centaureae cyani)

Juniper berries (Fructus Juniperi)