PHARMACOTHERAPY OF HYPERTENSION Dr. R. Jamuna Rani MD, Professor & HOD, Department of Pharmacology INTRODUCTION Hypertension is a common disorder if not effectively treated results in coronary thrombosis, stroke, retinopathy and renal failure Blood pressure is intimately related to kidneys – renovascular hypertension. Sympathetic over activity, renin angiotensin, aldosterone system and endothelium derived autocoids play a major role in the development of hypertension NON PHARMACOLOGICAL LINE OF TREATMENT Reduction of body weight. Sodium restriction 5gms/day. Potassium therapy. Physical exercise. Relaxation exercise (meditation and yoga). Avoid smoking and alcohol. AVOID CURRY, HURRY AND WORRY. HISTORY Before 1950 veratrum and sodium thiocyanate were used. 1950 – Ganglion blocker, reserpine and hydralazine 1960 – 1970 – Guanethidine, Beta blockers, Alpha blockers, Alpha methyldopa, clonidine and diuretics 1980 – 1990 – ACE inhibitors and calcium channel blockers 1992 – Angiotensin1 receptor antagonist ACE INHIBITORS Captopril, Enalapril, Lisinopril, Ramipril, Benazepril, perindopril Does not affect the quality of life. First line drug in the treatment of hypertension Safe in asthma, diabetes mellitus and peripheral vascular diseases Renal blood flow is well maintained Prevent left ventricular remodeling, vascular hypertrophy and secondary hyperaldosteronism MECHANISM OF ACTION Angiotensin I ACE inhibitors ACE Angiotensin converting enzyme Angiotensin II ADVERSE EFFECTS Brassy cough, Angiooedema Hypotension Hyperkalemia Acute renal failure Fetopathic potential Proteinuria Loss of taste (dysgeusia) Neutropenia – Common in collagen vascular disease or renal parenchymal disease DRUG INTERACTIONS Antacids reduce the bioavailability of ACE inhibitors NSAIDs reduce anti hypertensive effect of ACE inhibitors K+ sparing diuretics and K+ supplement exacerbate ACE inhibitor induced hyperkalemia (Contd…) ACE inhibitors increase plasma levels of digoxin and lithium (dosage adjustment is necessary) Increase hypersensitivity reactions to allopurinol. Contraindications: Bilateral renal artery stenosis and pregnancy USES Hypertension Left ventricular dysfunction Acute myocardial infarction Patient who are at high risk of cardiovascular events Chronic renal failure Scleroderma renal crisis ANGIOTENSIN ANTAGONIST Losartan potassium, Irbesartan, candesartan, valsartan Angiotensin II receptor antagonist; losartan block the AT1 receptors competitively and the metabolite E3174 irreversibly inhibits AT1 receptor Brassy cough is less common Adverse effects, contraindications and drug interaction are similar to ACE inhibitors USES All angiotensin II receptor antagonist are approved for the treatment of hypertension Irbesartan and losartan are approved for diabetic retinopathy Valsartan is approved for heart failure Losartan is approved for stroke prophylaxis and cirrhosis with portal hypertension CALCIUM CHANNEL BLOCKERS Nifedipine, amlodipine, felodipine They block voltage sensitive L – type calcium channels Side effects: Headache, hypotension, reflex tachycardia and ankle oedema Uses: Idiopathic systolic hypertension , cyclosporine induced hypertension, and in pregnancy – discontinue before labour. BETA BLOCKERS Propranolol, timolol, atenolol, acebutalol and metaprolol First line drug in hypertension Less effective in elderly patients Side effects: Bradycardia, cause rebound hypertension on sudden withdrawal Fatigue sleep disturbances and depression Propranolol mask the hypoglycemic symptoms produced by insulin and oral hypoglycemic agents C/I: Bronchial Asthma ALPHA BLOCKERS Phentolamine, phenoxybenzamine, prazosin, terazosin and doxazosin Side effects: Hypotension, tachycardia, nasal stuffiness, diarrhoea, miosis and impotence Uses: Hypertension with benign enlargement of prostate Pheochromocytoma ALPHA & BETA BLOCKERS Labetalol Carvedilol – also has antioxidant action Uses: hypertensive emergency, idiopathic dilated cardiomyopathy ALPHA METHYL DOPA Drug of choice for hypertension in pregnancy Activate alpha2 receptors (presynaptic) and decrease norephinephrine release Side effects: Sedation, hypotension, hypersensitivity, nasal stuffiness, weight gain Produce positive coomb’s test Tricyclic antidepressants reverse its effect Dose: 250mg – 500mg b.d CLONIDINE Alpha2 agonist used in moderate hypertension. Sudden withdrawal cause rebound hypertension CPZ and TCA abolish antihypertensive action of clonidine Dose: 100mcg b.d THIAZIDES Chlorthalidone, hydrochlorothiazide Used in mild hypertension and effective in elderly patients It potentiate the action of all antihypertensive drugs except calcium channel blockers Side effects: Hypokalemia, hyponatremia, hypomagnesemia, hyperglycemia, hypercalcemia and hyperuricemia VASODILATORS Hydralazine – useful in pregnancy Minoxidil – Alopecia (male type baldness) Diazoxide – In operable insulinomas Sodium nitropruside Balanced vasodilator, produce vasodilatation by activating glutathione and release NO used in hypertensive emergency produce controlled hypotension if it is administered continuously release cyanide and latter converted to thiocyanate and cause psychosis. Also cause palpitation, lactic acidosis, vomiting & pain abdomen. NEW DRUGS Ambrisentan and Bosentan – endothelin receptor antagonist used in pulmonary hypertension Fenoldopam – (I.V infusion) selective D1 receptor agonist for short term management of severe hypertension Moxonidine – Alpha2 agonist produce less sedation Aliskiren – Renin inhibitors