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 ↑↑ Na & H 2 O retention resistance Increased blood pressure

Captopril was the 1 s t 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 mgm/day - ↑ 60 years of age - 5 mgm/day - younger age Given once daily Maintenance – 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 – 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 – 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 mgm/day

Atenolol Given in a dose of 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 mgm/day Hypertensive emergencies- Intravenous bolus 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 st dose 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 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 mgm/day

Nicardipine mgm/day Isradipine 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 – 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 – 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 – 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 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 mgm Can also be given as infusion at a rate of 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: 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 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 ↓ 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 mgm /day Hydrochlorthiazide – 12.5 – 50 mgm/day Furosemide – 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