Antihypertensive drugs Classification I Centrally acting drugs 2

Antihypertensive drugs

• Classification I. Centrally acting drugs - α 2 agonists Clonidine, methyl dopa - Drugs that deplete the central neurotransmitter amines Reserpine II. Adrenegic neuron blockers Gaunethidine III. α 1 receptor blockers Prazocin, terazocin, doxazocin

IV. ß blockers Propranolol, metoprolol, atenolol V. Vasodilators a) Arteriolar vasodilators - hydrallazine - minoxidil - diazoxide - calcium channel blockers b) Arteriovenus dilators - Na nitroprusside

VI. Potassium channel activators - hydrallazine - minoxidil - diazoxide VII. Drugs that block renin-angiotensin-aldosterone axis a) Angiotensin converting enzyme inhibitors - enalapril, captopril b) Angiotensin II receptor blockers - sarlasin, losartan, telmisartan VIII. Oral diuretics - Thiazides

• Renin-angiotensin-aldosterone axis Angiotensinogen renin ↓ renal arterial pressure sympathetic stimulation Angiotensin I converting enzyme kininase II Angiotensin II vasoconstriction aldosterone secretion ↑↑ peripheral vascular resistance ↑↑ Na & H 2 O retention Increased blood pressure

• Captopril was the 1 st ACE inhibitor to be developed • Lisinopril • Enalapril all are prodrugs • Benazepril & hydrolyzed to • Ramipril active drug • Perindopril in the liver • Trandolapril

Captopril • It is a powerful inhibitor of the effects of angiotensin I • It affects capacitance (veins) & resistance (arterioles) vessels • ACEI do not affect cardiac contractility cardiac output (CO) normally ↑↑ • They act preferentially on angiotensive vascular beds - those of kidney, heart & brain • This selectivity is important in sustaining adequate perfusion of these vital organs in the presence of ↓↓ perfusion pressure

• • Kinetics Captopril is administered in doses of 25 mgm 2 -3 times a day 1 -2 hours before meals It is rapidly absorbed Bioavailability ↓↓ if the drug is taken with food Less than ½ of oral dose excreted unchanged

• • Enalapril It is a prodrug More potent than captopril Its action is slower but lasts longer Food does not interfere with absorption Dose – Initial dose - 2. 5 mgm/day - ↑ 60 years of age - 5 mgm/day - younger age Given once daily Maintenance – 10 -20 mgm/day

Adverse effects • Severe hypotension after initial dose in elderly, patients on diuretics, GI fluid loss • Acute renal failure – in patients of bilateral renal artery stenosis • Hyperkalemia ↑↑ in patients with renal failure • Dry cough & angioedema (bradykinin accumulation)

Clinical uses of ACE inhibitors • Hypertension • Diabetic nephropathy - it stabilizes renal function without lowering blood pressure - ↓ glomerular arteriolar resistance - improved intra-renal hemodynamics - delays diabetic nephropathy • Congestive heart failure • Myocardial infarction Causes better preservation of LV function in post MI cases It ↓↓ post infarction remodelling

Angiotensin receptor blockers • Losartan • Valsartan • Eprosartan • Irbesartan • Telmisartan

• They are more selective blockers of angiotensin effects than ACE inhibitors • They have no effect on bradykinin metabolism • Angiotensin blocking effect is more complete than ACE inhibitors as other enzymes can also generate angiotensin II • Losartan orally effective • ½ life – 2 hours • Active metabolite – 6 -9 hours • Dose – 25 - 100 mgm/day 50 mgm /day

ß blockers • They act by blocking ß 1 receptors • Peripheral resistance lowered during chronic administration • ↓↓ in cardiac output & plasma renin - variable • They ↓↓ elevated blood pressure in hypertensive patients • Both systolic & diastolic blood pressure ↓↓ • They are cardio-protective – particularly in patients with concurrent IHD

Propranolol • It is a nonselective ß blocker • It is very useful in mild – moderate HTN • Acts on both ß 1 & ß 2 receptors • It reduces blood pressure primarily by ↓ cardiac output • It also inhibits stimulation of renin production – ↓↓ renin-angiotensin-aldosterone system Dose – 80 -480 mgm /day – divided doses ADRs • Due to ß blocking effect – bronchoconstriction • Should never be stopped abruptly Myocardial infarction (MI)

Cardioselective ß 1 blockers Metoprolol • Inhibits stimulation of ß 1 receptors in the heart • Broncho-constriction less than propranolol as cardioselectivity is not complete • Asthmatic symptoms exacerbated in asthma patients Dose • 100 -450 mgm/day

• • Atenolol Given in a dose of 50 -100 mgm/day More cardio-selective Dose should be reduced in renal failure Labetalol Has both α & ß blocking actions Used in hypertensive emergencies & treatment of pheochromocytoma Daily dose 200 -250 mgm/day Hypertensive emergencies- Intravenous bolus 20 -80 mgm

Carvedilol • Non selective ß blocker with equal α blocking effect • HTN dose – 6. 25 mgm twice daily

α 1 receptor blockers Prazocin, terazocin, doxazocin • Antihypertensive effect produced by blocking α 1 receptors in the arterioles & venules dilatation of resistance & capacitance vessels • Blood pressure reduced more in upright than supine position • These drugs more effective when given along with other agents - ß blockers, diuretics

• • • Kinetics & dosage Prazocin Well absorbed orally ½ life 3 -4 hours but anti-hypertensive effect longer Dose – 1 mgm thrice daily Treatment should be initiated with a low dose (1 stdose at bedtime) to prevent postural hypotension & syncope Uses In moderate & severe hypertension as an adjunct to other drugs Terazocin – 5 -20 mgm once daily Doxazocin – 1 -4 mgm once daily

Calcium channel blockers • Dihydropyridines – - amlodipine - isradipine - nifedipine - lacidipine - felodipine - cilnidipine - nicardipine - benidipine - nimodipine • Non-dihydropyridines - verapamil - diltiazem

Mechanism of action • Inhibition of Ca 2+ influx into arterial smooth muscle cells • All Ca 2+ channel blockers effectively ↓↓ blood pressure – hemodynamic differences influence the choice of a particular agent • Vasodilatation - ↑↑ with dihydropyridines (nifedipine) - Reflex sympathetic activation tachycardia ↑CO • Cardiac depression - ↑ diltiazem - ↑↑↑ verapamil (SA node)

• • • Nifedipine (depin, calcigard) Dose- 5 mgm three times daily 15 -60 mgm daily dose Short acting nifedipine more likely to cause MI Sustained release preparations – preferred Sublingual preparations used in emergencies Amlodipine Most preferred drug in treatment of HTN Long acting Given once daily - better compliance Cannot be used in emergencies Dose 2. 5 -10 mgm/day

Nicardipine • 20 -60 mgm/day Isradipine • 2. 5 -10 mgm/day • Both similar to nifedipine • Lacdipine • It is a longer acting newer CCB • 2 -6 mgm once daily • Cilnidipine • Recently approved • Claimed to be a renoprotective CCB • Benidipine • Longer acting newer CCB • Claimed to inhibit remodelling

• • Diltiazem Pharmacological properties in between verapamil & nifedipine ↓↓ –ve ionotropic effects than verapamil ↓↓ vasodilatation than nifedipine Dose – 60 -120 mgm/day Verapamil (isoptin, calaptin) It is a potent –ve ionotropic agent Causes suppression of SA node – anti-arrhythmic effect ↓↓ potent coronary & vasodilator Should not be combined with ß blockers & digitalis Contraindicated in CHF Dose – 80 -240 mgm /day

Vasodilators Hydrallazine • Dilates only arterioles not veins • Fall in blood pressure accompanied by compensatory ↑↑ in heart rate, stroke volume & cardiac output (CO) • Well absorbed orally • Metabolized by acetylation – can be fast acetylators & slow acetylators Dose – 40 -200 mgm/day

ADRs • High doses produce a syndrome similar to acute rheumatoid arthritis or disseminated lupus errythematosis (SLE) • In IHD patients reflex tachycardia & sympathetic stimulation angina ischemic arrhythmias • ß blockers combined

Minoxidil • Very effective oral vasodilator • Dilates only arterioles not veins • Acts by opening K+ channels • • • ↓ contractions in smooth muscle Well absorbed orally – metabolized by conjugation ½ life is 4 hours Hypotensive effect lasts due to active metabolite minoxidil SO 4 Associated with reflex tachycardia & sympathetic stimulation ß blockers combined Dose 5 -10 mgm in two divided doses

Sodium nitroprusside • It is a powerful parenterally administered vasodilator • Used in hypertensive emergencies & cardiac failure • Dilates both arterioles & venules ↓↓ peripheral resistance ↓↓ venous return

• It acts by releasing nitric oxide which relaxes smooth muscle • In HTN ↓ in blood pressure due to ↓↓ vascular resistance while CO does not change • In cardiac failure CO ↑↑ due to after load reduction

• Nitroprusside is a complex of Iron Cyanide Nitroso moiety • It is rapidly metabolized by uptake into RBCs with liberation of - cyanide metabolized by mitochondrial enzymes Thiocyanate distributed extracellulary Eliminated by kidneys

• In renal failure thiocyanate accumulates Toxicity - weakness - disorientation - psychoses - muscle spasms - convulsions

• Nitroprusside rapidly lowers blood pressure • Its effect disappears in 1 -10 minutes of discontinuation • Given by infusion • Na nitroprusside in aqueous solution is sensitive to light • Should be made fresh before each administration & covered with opaque foil Dosage - 0. 5 μgm/kg/minute • May be ↑ 10 μgm/kg/minute • Blood pressure monitoring should be continuously done when on Na nitroprusside

ADRs • Most serious toxicity related to accumulation of cyanide metabolic acidosis arrhythmias excessive hypotension Death • Administration of Na thio. SO 4 as sulphur donor facilitates metabolism of cyanide

Diazoxide • It is chemically related to thiazides but has no diuretic activity • It is a parenterally administered arteriolar dilator used in hypertensive emergencies • Acts by opening K+ channels vascular smooth muscle relaxation • Injection of diazoxide Rapid fall in blood pressure associated with tachycardia & ↑ CO • Hypotension occurs within 5 minutes & lasts for 4 -12 hours

Dose • Started with smaller doses 50 -100 mgm • Can also be given as infusion at a rate of 15 -30 mgm/minutes • ß blockers given to prevent reflex tachycardia ADRs • Most significant is excessive hypotension • Reflex tachycardia can provoke angina, ischemia & cardiac failure in IHD patients

Centrally acting drugs • Methyl dopa decrease sympathetic outflow • Clonidine from vasopressor centers in the brain • The two drugs do not have identical sites of action • They act primarily on different populations of neurons in vasomotor centers of the brain stem • Clonidine ↓↓ heart rate & cardiac output more than methyl dopa

• Methyl dopa It is an analog of L-dopa α methyl dopamine stored in adrenergic nerve vesicles released on nerve stimulation false transmitter interacts with adrenergic receptors (α 2 presynaptic – bind more tightly to α 2 than α 1 )

• Methyl dopa is useful in the treatment of mild to moderate HTN • Lowers blood pressure by ↓↓ peripheral resistance • Variable ↓↓ in heart rate & cardiac output • Most cardiovascular reflexes remain intact • Blood pressure ↓↓ not dependent upon maintenance of upright posture • It ↓↓ renal vascular resistance • Postural hypotension is not a problem Dose: 1 -2 g in divided doses in pregnancy

Clonidine • It acts at α adrenoreceptors in the medulla of the brain • It ↓↓ sympathetic tone ↑↑ parasympathetic • • ↓↓ in blood pressure & heart rate It also ↓↓ circulating catecholamines Binds more tightly to α 2 than α 1 It is lipid soluble & rapidly enters brain after oral administration Given twice daily

• Daily dosage: - 0. 2 -1. 2 mgm/day Transdermal patch • It ↓↓ blood pressure for 7 days after a single application • Postural hypotension is not a problem as baroreceptor reflexes are intact • It is usually given with a diuretic

ADRs • • • Drowsiness due to central sedation Dryness of mouth GI disturbances Allergic rash Abrupt cessation rebound HTN Treated with α & ß blockers Should be withdrawn slowly

• • Diuretics Lower blood pressure by depleting body Na+ stores Initially ↓↓ blood pressure by ↓↓ blood volume & cardiac output Peripheral resistance (PR) may ↑↑ After 6 -8 weeks cardiac output returns towards normal Peripheral resistance (PR) ↓↓ Na+ contributes to PR by ↑↑ vessel stiffness & neural sensitivity Possible relation - ↑↑ Na-Ca exchange

• Some diuretics have direct vasodilating activity eg. indapamide, thiazides • Diuretics effectively ↓↓ blood pressure by 10 -15 mm • Mild or moderate HTN can be treated by diuretics alone • In severe HTN they are combined with vasodilators sympathoplegic drugs

• Thiazide diuretics are appropriate for most patients • More potent loop diuretics are used - in severe HTN - when several drugs with Na+ retaining properties are used - when glomerular filtrate is ↓ 30 -40 ml/minute - in cardiac failure where Na+ - cirrhosis retention is marked • K+ sparing diuretics useful to avoid excessive K+ loss particularly in patients taking digitalis

Dose • Chlorthiazide - 100 -250 mgm /day • Hydrochlorthiazide – 12. 5 – 50 mgm/day • Furosemide – 20 -400 mgm/day IV, oral

ADRs • Most common K+ depletion – may be hazardous in - patients on digitalis - cardiac arrhythmias - in acute MI - left ventricular dysfunction • Mg+ depletion Thiazides - ↑↑ serum lipid concentration – hyperlipidemia - ↑↑ uric acid concentration – gout - Impaired glucose tolerance – hyperglycemia - Hypercalcemia