ANTI-HYPERTENSIVE DRUGS

Hypertension & its drugs Blood pressure (B.P) tends to ↑ with age. Hypertension means B.P. is higher than normal for age . In adults & middle aged , normal BP is <130/80 mm Hg. Mean B.P. = C.O. TPR  blood viscosity. Most cases of hypertension are due to↑TPR (i.e. ↑ diastolic pressure). C.O. is either normal or slightly ↓ or ↑. Isolated systolic hypertension occurs in elderly. Chronic hypertension is associated with high morbidity due to vascular damage (intima hyperplasia, hypertrophy of SM of media) esp.to target vital organs (brain, heart, kidney) & eye, enhancing atherosclerosis, & mechanical effect of very high B.P (HF, cerebral hemorrhage, dissecting aneurysm).

There is also ↑ mortality esp. from strokes, MI, HF and RF. Most cases of hypertension (about 90% of cases) are primary or idiopathic i.e. no organic cause is detected, but may be associated with genetic factors, high salt intake, alcohol & chronic stress. About 10% of cases are secondary to: Renal parenchymal or renovascular disease. Endocrine disease esp. adrenal disorders like Cushing syndrome, Conn syndrome, and pheochromocytoma Toxemia of pregnancy. Drugs e.g. oral contraceptive, NSAIDs.

Severity of hypertension: According to level of both systolic BP and diastolic BP, whichever is higher : Mild: DBP 90-99 mm Hg. SBP 140-159 mm Hg Moderate: DBP 100-109 mm Hg. SBP 160-179 mm Hg Severe: DBP 110-120 mm Hg. SBP 180-210 mm Hg Very severe: DBP >120 mmHg. SBP > 210 mm Hg Treatment of hypertension: Find cause, and treat it if possible. Treat other risk factors for vascular disease: i.e. hyperlipidemia, diabetes, stop smoking. Non-drug treatment for hypertension: Alone for mild hypertension without complication. Reduce salt intake in diet and ↑ K+ (from lemons, oranges). Avoid stress, stop alcohol consumption and tobacco smoking

Drug treatment: A. Diuretics: most commonly used are the thiazides in low dose (Bendrofluazide 2.5-5 mg/day, hydrochlorthiazide 25 mg/d, chlorthalidone 25 mg/d Thiazide diuretics are effective in low doses due to flat anti-hypertensive dose- response curve. They are used in mild to moderate hypertension The ↓ in B.P is initially due to ↓ in blood volume resulting from diuresis. Later, diuresis gets less, and blood volume is partially restored but there is some vasodilation & ↓ TPR; this results from reduced Na+ content in vessel wall leading to ↓ Ca++ in vascular SM↓ vascular tone and vasodilation associated with ↓ vascular reactivity to vasoconstrictors such as NA released from sympathetic nerve endings in BV.

Loop diuretics e.g. Frusemide have more diuretic efficacy; used for: Severe hypertension. Resistant hypertension ( i.e. failed treatment) Renal impairment.

β-blockers: ↓ C.O. due to β-blocking action on heart. B. Sympatholytics: 1. Receptor blockers: β-blockers: ↓ C.O. due to β-blocking action on heart. With time, TPR ↓ due to sensitization of baroreceptors. Also ↓ renin release, so RAA (renin-angiotensin-aldosterone) system is inhibited. Commonly used agents include: Atenolol, Metoprolol, Timolol, Labetalol. Esmolol has short t½ of about 10 min (rapid hydrolysis by RBC esterases); it can be used IV for hypertensive emergency alpha-blockers: e.g. Prazosin, Doxazosin. Cause vasodilation, so ↓ TPR. Employed as 3rd line drug , but they are 1st line for pheochromocytoma .

2. Central Sympatholytics (central alpha-2 adrenoceptor agonists): Clonidine: less used now because of S.E.s which include Dry mouth, sedation, constipation, and rebound hypertension if stopped suddenly in 15%. alpha-methyldopa: as alternative if β-blockers are C/Is, or in pregnancy hypertension. It acts by forming false neurotransmitter(alpha-methyl NA) which acts as alpha-2 agonist centrally to inhibit VMC. 3. Ganglion blockers: decrease BP by blocking sympathetic ganglia e.g. trimethaphan IV infusion may be used for hypertensive emergency. It has short duration of action of about 5 min

C. Angiotensin antagonists: ↓ TPR, so ↓ B.P. 1. Angiotensin Converting Enzyme Inhibitors (ACEIs): Captopril: given tabs 50 mg x 2-3/d. (t½ ~ 4h). Enalapril: converted in liver to the active metabolite enalaprilate that has long t½ (~9 h), so given once daily. Others: Ramipril, Fosinopril, Lisinopril  all have active metabolites with long t½ , so they are given once daily. ACEIs decrease Angiotensin II formation leading to vasodilation, thus ↓ TPR and B.P. Bradykinin becomes also elevated in plasma as a result of ACE inhibition; ↑ in Bradykinin blood level would increase the vasodilation leading to more ↓ in TPR and B.P. ACEIs will ↓ Aldosterone secretion which will lead to ↑ loss of Na+ in urine, so blood volume and cardiac output will also ↓.

ACEIs are among the 1st-line drugs now for hypertension. They are esp. effective when plasma renin activity (and so angiotensin II level) is high as in RF & unilateral renal artery stenosis; they are C/I in bilateral renal artery stenosis since they may induce RF. Besides their action in lowering the BP, these drugs also help to reverse cardiovascular hypertrophy in hypertension. They also help to protect the kidney in hypertension ( and also in diabetes, esp. if used early in diabetic nephropathy). Other uses of ACEIs are in treatment of congestive heart failure, since they help to decrease preload by their venodiltor action and decrease aldosterone blood level, & thus hels to increase SV and CO in CHF patients.

S.E.s : 1. Dry cough: occurs in about 20% due to high bradykinin level. 2. First-dose hypotension in salt-depleted patients e.g. diuretics 3. ↑ plasma K+ level: esp. if K+ supplements are used or in RF 4. Transient disturbance of taste, and rarely angioedema 5. In pregnancy, they may interfere with fetal kidney growth or function (renal hypoplasia or agenesis). So Avoid Note : ACEIs do not cause reflex tachycardia from their vasodilator hypotensive action 2. Angiotensin 2 receptor (AT1) blockers: - Losartan, Velsartan, irbesartan, candesartan - Similar to ACEIs, but less incidence of cough.

D. Calcium channel blockers (CCBs) : Block voltage-gated calcium channels in vascular SM (L-type) and in heart (L-type + T-type) ↓ ↓ (in muscle) (in conducting tissues) e.g. SA node, AV node Heart (T-type) B.V.(L-type) Drug  Cause vasodilation,↓TPR, so ↓B.P. +++ Dihydropyridine (DHPs) : Nifedipine. ↓HR and produce AV block ++ + ii. Non-DHPs: Verapamil Diltiazem

1 .Flushing, throbbing headache, esp. with nifedipine S.E. 1 .Flushing, throbbing headache, esp. with nifedipine 2. Reflex tachycardia: occurs with Nifedipine or nicardipine ( this can be ↓ by slow-release preparation, or by substituting Amlodipine or felodipine, or by adding β-blocker ) . But Bradycardia occurs with Verapamil or Diltiazem. 3. Ankle edema & gingival congestion  with Nifedipine. 4. Constipation esp. with verapamil 5. Avoid concurrent use of cardio-active CCBs (non-DHPs) with β- blockers since their effects on heart summates  HF, heart block or even cardiac arrest in asystole 6. Avoid use in first trimester (T1): may b.e teratogenic., but nifedipine may be used in T2 or T3

E. Direct vasodilators : Less used now. Produce vasodilation; so ↓TPR and ↓B.P. As 3rd line drug for resistant hypertension Oral : Hydralazine Minoxidil : more potent These drugs probably act as activators of ATP- dependent potassium channels in vascular smooth muscle, thus leading to hyperpolarization, which results in vasodilation & decrease in BP. Hydralazine may also be used in pregnancy hypertension.

1. Flushing & throbbing headache. S.E.s: 1. Flushing & throbbing headache. 2. G.I.: nausea, vomiting 3. Reflex tachycardia: ↓ by β-blockers. 4. Salt and water retention : decreased by use of diuretics. If vasodilator are used alone, these mechanisms(3+ 4) cause tolerance to their anti-hypertensive effect within few weeks. Hydralazine: is metabolized in liver by acetylation. In slow hepatic acetylators, there is ↑ incidence of chemical lupus erythematosus (SLE) esp. with large daily doses od 200 mg or more (reversible on stopping drug). Minoxidil: may cause Hirsutism (not recommended for women), and rarely pericardial effusion.

Dilates both arterioles + venules by: IV vasodilators :- used for hypertensive emergency 1. Sodium nitroprusside: Given by i.v. infusion. Immediate effect in ↓ B.P. Given in ICU. If infusion stopped, effect quickly disappears. Must be prepared fresh, and protected from sunlight. Dilates both arterioles + venules by: Spontaneous splitting of NO from its molecules. Can also directly stimulate guanyl cyclase which ↑cGMP level in vascular smooth muscle. Quickly enters RBC where cyanide is released from it. This cyanide is metabolized to thiocyanate (CNS-) in liver which is then eliminated by kidney in urine.

S.Es : Excessive hypotension: treated by ↓ infusion rate. Muscle cramps, confusion, psychosis: due to thiocyanate accumilation in prolonged infusion for days or in RF. Also may cause methaemoglobinemia 2. Fenoldopam: given by IV infusion for hypertensive emergency, or post-operative hypertension. It stimulates vascular D1 receptors resulting in arteriolar vasodilation and natriuresis. It is metabolized rapidly in liver, mainly by conjugation; t½ about 10 min. S.Es include flushing, headache, reflex tachycardia, and increased intra-ocular pressure

3. Diazoxide: Dilates arterioles. Eliminated by liver & kidney. t½ ~ 12h . S.E.s: i. Excessive hypotension following large IV bolus 300 mg can lead to low perfusion effects such as strokes or blindness, angina, MI, RF. Mini-bolus IV infusion (~ 25-50 mg every 5-15 min has replaced large bolus to ↓ incidence of excessive hypotension ii. Flushing, headache iii. Reflex tachycardia, Salt and water retention. iv. Hyperglycemia: due to ↓ insulin release from the beta cells of islets of Langerhans in pancreas .

Treatment protocols of Hypertension: 1. Start with either Diuretic, β-blocker, ACEI or CCB. 2. If single drug fails, then add a second suitable drug: If single drug was diuretic: add β-blocker or ACEI. If single drug was β-blocker : add diuretic or CCB. If single drug was ACEI : add diuretic. If single drug was CCB : add β-blocker. 3. If 2 drugs are not enough, then add hydralazine. 4. If still not controlled (resistant hypertension), then re-investigate esp. kidney and adrenal causes. Substitute Frusemide for thiazide, & alpha-blockers Prazosin or Doxazosin for the vasodilator.

Hypertensive emergency: BP = or > 260/ 150 as in Accelerated or malignant hypertension. A. Without hemodynamic complications: B.P is reduced over several hours . Not more than 20% reduction in BP (not > 20 mm Hg DBP) to avoid low cerebral perfusion due to autoregulation impairment Oral treatment preferred e.g. Labetalol, Nifedipine, + Frusemide. As BP is controlled in 12-24h, Resume & adjust usual oral treatment .

B. With hemodynamic complication : - Reduction of BP over minutes , and not less than 160/100. With stroke: caution as rapid reduction may ↑ infarct size. In hypertensive encephalopathy (classical presentation of malignant hypertension): there is activation of RAA system. Labetalol IV, or vasodilator e.g. Nitroprusside IV or diazoxide or fenoldopam IV , or trimethaphan IV In dissecting aortic aneurysm: Labetalol IV then nitroprusside In pheochromocytoma : phentolamine IV. In eclampsia : IV Hydralazine. oral alpha methyldopa Note : Frusemide is used if there is HF or to prevent fluid retention from vasodilators. As BP is controlled, resume & adjust oral treatment.