Drugs used in hypertension

For B. Pharm
Refer KD Tripathi

1. ANTIHYPERTENSIVE DRUGS Mr. Goutam Mallik Asst. Professor (Pharmacology) GIST, GUNUPUR

2. Antihypertensive Drugs These are drugs used to lower BP in hypertension. Hypertension Hypertension is a very common disorder, particularly past middle age. It is not a disease in itself, but is an important risk factor for cardiovascular mortality and morbidity. The JNC 7* (2003) and WHO-ISH@ guidelines (2003) have defined it to be 140 mm Hg systolic and 90 mm Hg diastolic, though risk appears to increase even above 120/80 mm Hg. Accordingly cause it is of two types viz: Essential & Nonessential hypertension.

3. Majority of cases are of essential (primary) hypertension, i.e. the cause is not known. Hypertension due to some reason called nonessential (secondary) hypertension, i.e. hypertension due to an identifiable cause. For example, Cushing's syndrome, Hyperthyroidism, Renal artery stenosis (RAS) Coarctation of the aorta’, Pheochromocytoma etc.

4. COMPLICATIONS OF HYPERTENSION Hypertension cause various types of other complications in the body. It increases comorbidity of disease finally mortality rate. It affects various organs including heart, brain, kidney, eye etc.

5. CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS Diuretics 2. ACE inhibitors 3. Angiotensin (AT1 receptor) blockers Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide High ceiling: Furosemide, etc. K+ Sparing: Spironolactone, Amiloride etc. Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan etc.

6. 4. Direct renin inhibitor 5. Calcium channel blockers 6. β Adrenergic blockers 7 . β + α Adrenergic blockers Aliskiren Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine, etc. Propranolol, Metoprolol, Atenolol, etc . Labetalol, Carvedilol

7. 8. α Adrenergic blockers 9. Central sympatholytic 10. Vasodilators Arteriolar Arteriolar + venous 11 . Others Prazosin, Terazosin, Doxazosin Phentolamine, Phenoxybenzamine Clonidine, Methyldopa Hydralazine, Minoxidil, Diazoxide Sodium nitroprusside Reserpine, Guanethidine, Pentolinium, etc.

8. DIURETICS Diuretics have been the standard antihypertensive drugs over the past 4 decades, though they do not lower BP in normotensives. Thiazides (hydrochlorothiazide, chlorthalidone) Chlorthalidone is longer acting (~ 48 hours) than hydrochlorothiazide (< 24 hours) and may have better round-the-clock action. Indapamide is also mainly used as antihypertensive, and is equally effective. Initially, the diuresis reduces plasma and e.c.f. volume by 5–15%. Subsequently, compensatory mechanisms operate to almost regain Na+ balance and plasma volume; c.o. is restored, but the fall in BP is maintained by a slowly developing reduction in t.p.r.

9. The reduction in t.p.r. is most probably an indirect consequence of a small (~5%) persisting Na+ and volume deficit. Decrease in intracellular Na+ concentration in the vascular smooth muscle may reduce stiffness of vessel wall. The fall in BP develops gradually over 2–4 weeks. Thiazides are mild antihypertensives, average fall in mean arterial pressure is ~10 mm Hg. In combination, they are useful in any grade of hypertension. They are more effective in the elderly and maximal antihypertensive efficacy is reached at 25 mg/day dose. Their antihypertensive action is attenuated by NSAIDs.

10. High ceiling diuretics Furosemide, the prototype of this class, is a strong diuretic. Furosemide is a weaker antihypertensive than thiazides: fall in BP is entirely dependent on reduction in plasma volume and c.o. The t.p.r. and vascular responsiveness are not reduced. They are indicated in hypertension only when it is complicated by: 1. Chronic renal failure: thiazides are ineffective, both as diuretic and as antihypertensive. 2. Coexisting refractory CHF. 3. Resistance to combination regimens containing a thiazide, or marked fluid retention due to use of potent vasodilators.

11. Desirable properties of thiazide diuretics as antihypertensives Once a day dosing and flat dose-response curve permitting simple standardized regimens. No fluid retention, no tolerance. Low incidence of postural hypotension and relative freedom from side effects, especially CNS, compared to sympatholytics. Effective in isolated systolic hypertension(ISH). Lessened risk of hip fracture in the elderly due to hypocalciuric action of thiazides. Low cost.

12. Indapamide It is a mild diuretic, chemically related to chlorthalidone; reduces BP at doses which cause little diuresis. Electrolyte disturbances and K+ loss are minimal at antihypertensive doses. It probably has additional vasodilator action exerted through alteration of ionic fluxes across vascular smooth muscle cell. Potassium sparing diuretics Spironolactone, eplerenone and amiloride themselves lower BP slightly. They are used only in conjunction with a thiazide diuretic to prevent K+ loss and to augment the antihypertensive action. Spironolactone is not favored because of its hormonal side effects (gynaecomastia, impotence, menstrual irregularities).

13. ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS The ACE inhibitors are one of the first choice drugs in all grades of essential as well as renovascular hypertension. Most patients require relatively lower doses (enalapril 2.5–10 mg/day or equivalent) which are well tolerated. Used alone they control hypertension in ~50% patients, and addition of a diuretic/β blocker extends efficacy to ~90%. They are the most appropriate antihypertensives in patients with diabetes, nephropathy (even nondiabetic), left ventricular hypertrophy, CHF, angina and post MI case. They appear to be more effective in younger (< 55 year) hypertensives than in the elderly.

14. ANGIOTENSIN RECEPTOR BLOCKERS In a dose of 50 mg/day losartan is an effective antihypertensive. The newer ARBs—valsartan, candesartan, irbesartan and telmisartan have been shown to be as effective antihypertensives as ACE inhibitors. ARBs are remarkably free of side effects . DIRECT RENIN INHIBITORS Aliskiren the only available member of the latest class of RAS inhibitors which act by blocking catalytic activity of renin and inhibiting production of Ang I and Ang II. Aliskiren is an equally effective antihypertensive as ACE inhibitors and ARBs. It is a second line antihypertensive which may be employed when the more established ACE inhibitors or ARBs cannot be used, or to supplement them.

15. CALCIUM CHANNEL BLOCKERS Calcium channel blockers (CCBs) are another class of first line antihypertensive drugs. All 3 subgroups of CCBs, viz. dihydropyridines (DHPs, e.g. amlodipine), phenylalkylamine (verapamil) and benzothiazepine (diltiazem) are equally efficacious antihypertensives. They lower BP by decreasing peripheral resistance without compromising c.o. The onset of antihypertensive action is quick. Monotherapy with CCBs is effective in ~ 50% hypertensives; their action is independent of patient’s renin status, and they may improve arterial compliance.

16. Advantages of CCBs Do not compromise haemodynamics: no impairment of physical work capacity. No sedation or other CNS effects; cerebral perfusion is maintained. Not contraindicated in asthma, angina (especially variant) and PVD patients: may benefit these conditioned. Do not impair renal perfusion. Do not affect male sexual function. No deleterious effect on plasma lipid profile, uric acid level and electrolyte balance. Shown to have no/minimal effect on quality of life. No adverse foetal effects; can be used during pregnancy (but can weaken uterine contractions during labour).

17. Disadvantage of CCBs The negative inotropic/dromotropic action of verapamil/diltiazem may worsen CHF and cardiac conduction defects (DHPs are less likely to do so). By their smooth muscle relaxant action, the DHPs can worsen gastroesophageal reflux. CCBs (especially DHPs) may accentuate bladder voiding difficulty in elderly male. The JNC 7 have considered CCBs to be less suitable for monotherapy in hypertensives with no other risk factors. Because they appear to afford less prognostic benefits than thiazides, β blockers and ACE inhibitors/ARBs.

18. β- ADRENERGIC BLOCKERS They are mild antihypertensives; do not significantly lower BP in normotensives. Used alone they suffice in 30–40% patients—mostly stage I cases. The antihypertensive action of most β blockers is maintained over 24 hr with a single daily dose. Nebivolol reduces t.p.r. by generating NO. The nonselective β blockers slightly reduce renal blood flow and g.f.r., but this is minimal in the β1 selective blockers. All cause mortality has been lowered in long-term trials by β blockers.

19. ADVANTAGE OF β - BLOCKERS Drugs with intrinsic sympathomimetic activity (ISA) e.g. Pindolol cause less/no reduction of HR and c.o. but lower vascular resistance by β2 agonism. Because of absence of postural hypotension, bowel alteration, salt and water retention; a low incidence of side effects, and once a day regimen, β blockers retain their place among the first choice drugs recommended by JNC 7 and WHO-ISH. Especially for relatively young non-obese hypertensives, those prone to psychological stress or those with ischemic heart disease. β blockers and ACE inhibitors are the most effective drugs for preventing sudden cardiac death in postinfarction patients.

20. DISADVANTAGE OF β - BLOCKERS There are several contraindications to β blockers, including cardiac, pulmonary and peripheral vascular disease. The nonselective β blockers have an unfavourable effect on lipid profile (raise triglyceride level and LDL/HDL ratio). They have also fared less well on quality of life parameters like decreased work capacity, fatigue, loss of libido and subtle cognitive effects (forgetfulness, low drive), nightmares and increased incidence of antidepressant use. Atenolol monotherapy may be less effective in preventing hypertension related stroke and coronary artery disease. They are less effective for primary prophylaxis of MI and for preventing left ventricular hypertrophy.

21. β+α ADRENERGIC BLOCKERS Labetalol It is a combined α and β blocker; reduces t.p.r. and acts faster than pure β blockers. It has been used i.v. for rapid BP reduction in hyperadrenergic states, cheese reaction, clonidine withdrawal, eclampsia, etc. Carvedilol This nonselective β + weak selective α1 blocker produces vasodilatation and has additional antioxidant/free radical scavenging properties. Carvedilol is a frequently selected drug for long-term treatment of CHF, and is approved as an antihypertensive as well.

22. α- ADRENERGIC BLOCKERS Prazosin This prototype selective α1 antagonist dilates both resistance and capacitance vessels. The haemodynamic effects, viz reduction in t.p.r. and mean BP accompanied by minor decrease in venous return and c.o. are similar to that produced by a direct acting vasodilator. Prazosin is always started at low dose (0.5 mg) given at bedtime and gradually increased with twice daily administration till an adequate response is produced (max. dose 10 mg BD). It has a small but favorable effect on lipid profile: lowers LDL cholesterol and triglycerides, increases HDL.

23. Terazosin, Doxazosin These are long-acting congeners of prazosin with similar properties but suitable for once daily dosing. Adverse effects Postural hypotension Headache, Drowsiness Dry mouth Weakness, Palpitation Nasal blockade, Blurred vision and Rash. Fluid retention attending prazosin monotherapy may precipitate CHF.

24. Nonselective α blockers Phentolamine, Phenoxybenzamine The nonselective α blockers have been disappointing for routine treatment of hypertension, because fall in t.p.r. is compensated by increased HR and c.o. They block both α1 and α2 receptors—NA release is accentuated. They are reserved for special situations like pheochromocytoma, clonidine withdrawal, cheese reaction, etc., where circulating CAs are responsible for the rise in BP.

25. CENTRAL SYMPATHOLYTICS Clonidine Clonidine is a partial agonist with high affinity and high intrinsic activity at α2 receptors, especially α2A subtype in brainstem. The major haemodynamic effects result from stimulation of α2A receptors present mainly postjunctionally in medulla (vasomotor centre). This decreases sympathetic out flow → fall in BP and bradycardia. Enhanced vagal tone contributes to bradycardia. Plasma NA declines. Clonidine is a moderately potent antihypertensive.

26. VASODILATORS Hydralazine/Dihydralazine It is a directly acting arteriolar vasodilator with little action on venous capacitance vessels; reduces t.p.r. and causes greater decrease in diastolic than in systolic BP. Hydralazine is now used as a second line alternative only in combination with a diuretic and/or β blocker for patients not achieving target BP with first line drugs. It is one of the preferred antihypertensives during pregnancy, especially preeclampsia. Parenterally, it is occasionally employed in hypertensive emergencies. The arteriolar dilator action of hydralazine can be employed in the management of CHF particularly in combination with isosorbide dinitrate.

27. Minoxidil It is a powerful vasodilator, the pattern of action resembling hydralazine, i.e. direct relaxation of arteriolar smooth muscle with little effect on venous capacitance. Oral minoxidil increases growth of body hair. Applied topically (2% twice daily) it promotes hair growth in male pattern baldness and alopecia areata. Diazoxide This K+ channel opener arteriolar dilator was used in the past for rapid reduction of BP in hypertensive emergencies. Administered by rapid i.v. injection it can be employed in place of nitroprusside.

28. Sodium nitroprusside It is a rapidly (within seconds) and consistently acting vasodilator; has brief duration of action (2–5 min) so that vascular tone can be titrated with the rate of i.v. infusion. It relaxes both resistance and capacitance vessels: reduces t.p.r. as well as c.o. (by decreasing venous return). Myocardial work is reduced—ischaemia is not accentuated, as occurs with selective arteriolar dilators (hydralazine). In patients with heart failure and ventricular dilatation, nitroprusside improves ventricular function and c.o. mainly by reducing aortic impedance (afterload), but also by lowering atrial filling pressure (preload).

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