Section 4 Drugs Acting on Cardiovascular & Urinary System
Chapter 4.2 Antihypertensive Agents
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Cardiotonics (Cardiac Glycosides) dose in given In this condition, drugs like verapamil is more effective Left Ventricular Failure Digitalis is used in chronic pure, left ventricular failure with hypertension and ischemic heart disease OTHER POSITIVE INOTROPIC DRUGS USED IN CHF BIPYRIDINE COMPOUNDS AMRINONE It is a relatively selective inhibitor of cyclic GMP, cyclic AMP-PDE (phosphodiesterase) type III family It causes vasodilatation with a consequent decrease in systemic vascular resistance It increases both the force of contraction and velocity of relaxation of cardiac muscles It is administered IV 0.75 mg/kg/min as a bolus dose followed by 510 µg/kg/min IV infusion and total dose not to exceed 10 mg/kg 173 Side effects include nausea, abdominal pain, diarrhoea, fever, thrombocytopenia (transient and dose related) and hepatotoxicity MILRINONE It is relatively selective inhibitor of peak III cyclic AMP phosphodiesterase isoenzyme in cardiac and vascular muscle In patients with CHF, it produces dose related and plasma concentration related increase in the maximum rate of increase of left ventricular pressure Milrinone has a direct inotropic and direct arterial vasodilator activity It is administrated by IV infusion 0.50 mg/kg over 10 with a maximum daily dose of 1.13 mg/kg Side effects include ventricular arrhythmias, sustained ventricular tachycardia, angina, ventricular fibrillation, headache and hypokalemia Both the compounds are indicated in short term management of CHF in patents unresponsive to digitalis, diuretics or vasodilators This page intentionally left blank tterer p p a h CCh 4.2 1.4 Antihypertensive Pharmacodynamics (ModeAgents of Action of Drugs) Hypertension is the most common cardiovascular disease and pathophysiologically hypertension can be classified into two main groups mmHg with low diastolic blood pressure is termed as ‘isolated systolic hypertension’ commonly seen in elderly person a Essential or primary hypertension, where the cause for rise in blood pressure is not known Responsible for majority of cases b Secondary hypertension, where rise is due to renal disease e.g chronic diffuse glomerulonephritis, pyelonephritis; due to some vascular disease e.g renal artery disease or due to some endocrinal disorders e.g pheochromocytoma, Cushing’s syndrome and primary aldosteronism Systemic arterial blood pressure is determined by cardiac output and total peripheral resistance In most of the cases, rise in BP is due to increase in total peripheral resistance The blood pressure is mainly controlled by two systems Firstly through the baro-receptors and the adrenergic nervous system The baroreceptor reflexes protect the circulation against stresses which shows the changes in the arterial blood pressure Secondly through renin angiotensin system, which is involved in the pathogenesis of some forms of secondary hypertension Renin is a proteolytic enzyme released from the juxtaglomerular cells of kidneys The reaction between renin and plasma protein, serum globulin (angiotensinogen) forms an inactive compound ‘angiotensin I’ (decapeptide), which further changed into ‘angiotensin II’ (octapeptide) by the action of angiotensin converting enzyme (ACE) and is the most powerful vasoconstrictor agent Angiotensin II also stimulates the synthesis and release of aldosterone from adrenal cortex of adrenal gland Clinically, hypertension can be divided into three stages e.g mild, moderate and severe hypertension The diastolic blood pressure between 90-104 mmHg is graded as mild, 105-114 mmHg is graded as moderate and above 115 mmHg is graded as severe hypertension The person having systolic blood pressure more than 160 The drugs used in the treatment of hypertension can be classified as in table 4.2.1 176 Section 4/ Drugs Acting on Cardiovascular & Urinary System Table 4.2.1: Classification of antihypertensive agents I Centrally acting sympathetic inhibitors Clonidine (ARKAMIN) Methyldopa (ALPHADOPA) II Adrenergic neurone blocking agents Reserpine (ADELPHANE) Guanethidine (ISMELIN) III Adrenergic receptor antagonists i Alpha blockers Prazosin (PRAZOPRESS) Terazosin (OLYSTER) Doxazosin (DOXACARD) Phentolamine (FENTANOR) Phenoxybenzamine (FENOXENE) ii Beta blockers Propranolol (CIPLAR) Metoprolol (BETALOC) Atenolol (BETACARD) Sotalol (SOTAGARD) Pindolol (PINADOL) Celiprolol (CELIPRESS) iii Alpha & beta blockers Carvedilol (CARDIVAS) Labetalol (NORMADATE) IV Angiotensin converting enzyme (ACE) inhibitors Captopril (CAPOTRIL) Enalapril (ENCARDIL) Lisinopril (BIDPRIL) Ramipril (RAMIPRESS) Perindopril (PERIGARD) Benzapril (BENACE) Also available omapatrilat, Quinapril, Trandolapril V Angiotensin II receptor (type AT1) antagonist Losartan potassium (LOSACAR) Irbesartan (IROVEL) VI Calcium channel blockers Verapamil (VASOPTEN) Diltiazem (DILZEM) Nifedipine (CALCIGARD) Amlodipine (AMLODAC) Also available Felodipine, Lacidipine, Benidipine, NiImodipine VII Direct vasodilators Hydralazine (NEPRESOL) Sodium nitroprusside (NIPRESS) Nicorandil (ZYMCOR) VIII Diuretics (For details see chapter ‘Diuretics’) 75-225 µg/day 0.5-2 g/day 0.25-0.5 mg OD 10-50 mg OD 0.5 mg BD, maintained at 3-20 mg BD 2-10 mg/day 2-8 mg/day 2-5 mg IV 20-60 mg/day oral, mg/kg IV 10-80 mg TDS, 2-8 mg IV 100-450 mg/day 50-100 mg/day 80-480 mg/day 10-30 mg/day 100-200 mg/BD-TDS 12.5-50 mg OD 100-200 mg TDS, 50 mg IV 25-100 mg TDS 10-20 mg OD-BD 5-20 mg/day 2.5-10 mg OD 4-8 mg OD 10-40 mg OD-BD 25-100 mg OD 150-300 mg OD 40-160 mg TDS 30-60 mg TDS-QID 5-20 mg TDS, oral/SL 5-10 mg OD 2-50 mg BD 0.1-0.3 mg/min IV infusion 5-20 mg BD Antihypertensive Agents CENTRALLY ACTING DRUGS CLONIDINE It is an imidazoline derivative with a partial agonist action It stimulates presynaptic, α2 receptors in vasomotor centre of brain causing decreased sympathetic outflow which results in fall of blood pressure and bradycardia After oral administration the absorption is almost complete and rapid It penetrates easily into CNS Half to two third of oral dose is excreted unchanged in urine Adverse effects include drowsiness, dry mouth, sedation, restlessness, anxiety, nightmares, dizziness, sleep disturbances, skin rash, urticaria, nausea, constipation, indigestion and impotence Abrupt withdrawal may result in severe rebound hypertension, hepatic dysfunction and renal dysfunction It is indicated in hypertension of all grades except pheochromocytoma, glaucoma and migraine It is also useful in opiate, alcohol and nicotine withdrawal It also attenuates vasomotor symptoms of menopausal syndrome METHYLDOPA It is α-methyl analogue of DOPA, the precursor of dopamine and noradrenaline It is converted to alpha methyl noradrenaline which stimulates central alpha2 adrenergic receptors in brain thereby decreasing sympathetic outflow It decreases peripheral resistance more than heart rate or cardiac output After oral administration bioavailability is low because of extensive metabolism It 177 is partly metabolized and partly excreted unchanged in urine Adverse effects include dizziness, postural hypotension, sedation, dry mouth, headache, sleep disturbances, depression, anxiety, impotence, blurred vision, constipation, skin rash, arthralgia, fatigue, anorexia, haemolytic anemia, parkinsonian signs, drug fever and hepatitis It is indicated in mild to moderate hypertension ADRENERGIC NEURONE BLOCKERS RESERPINE It is an alkaloid obtained from the roots of ‘Rauwolfia serpentina.’ It is known to deplete the catecholamines – adrenaline, noradrenaline and dopamine from the various sites in the body It also depletes 5hydroxytryptamine (serotonin) Hypotension develops gradually and is due to depletion of noradrenaline from peripheral adrenergic nerve endings Adverse effects include nasal congestion, flushing, bradycardia, postural hypotension, water and salt retention and CHF may be precipitated It also causes miosis, salivation, increased gastric acid secretion CNS side effects include lethargy, apathy, psychic depression which may result in suicidal tendencies and weight gain Endocrinal disturbances include gynecomastia and impotence Because of its serious side effects and limited efficacy, it is not much used now clinically ... in elderly person a Essential or primary hypertension, where the cause for rise in blood pressure is not known Responsible for majority of cases b Secondary hypertension, where rise is due to renal... pressure Secondly through renin angiotensin system, which is involved in the pathogenesis of some forms of secondary hypertension Renin is a proteolytic enzyme released from the juxtaglomerular... cells of kidneys The reaction between renin and plasma protein, serum globulin (angiotensinogen) forms an inactive compound ‘angiotensin I’ (decapeptide), which further changed into ‘angiotensin