Drug Treatment of Hypertension Medical Pharmacology Lectures 36 37 Richard D Ye Department of Pharmacology College of Medicine Tel 312 996 5087 Room 4143 COMRB E mail yer uic edu Definition or Systolic BP 140 mm Hg Diastolic BP 90 mm Hg Diagnosis is based on multiple 3 measurements on different days For patients having diabetes or chronic kidney disease high risk group diagnosis of hypertension is made with BP 130 80 mmHg 1 Classification and management of BP for adults Category Systolic Diastolic Lifestyle modification Initial drug therapy 120 and 80 Encourage Not needed Pre hypertension 120 139 or 80 89 Yes No or treat Compelling indications Stage 1 hypertension 140 159 or 90 99 Yes Diuretic ACEI ARB blocker CCB Combination compelling indications Stage 2 hypertension 160 or 100 Yes Normal Two drug combo diuretic and ACEI or ARB or blocker or CCB Also treat compelling indications Based on 7th Report of the Joint National Committee on Detection Evaluation and Treatment of High BP JNC 7 Diuretic here means thiazide type ACEI ACE inhibitor ARB angiotensin receptor blocker blocker adrenergic receptor blocker CCB calcium channel blocker Present vs optimal systolic BP distribution Increased longevity physical inactivity obesity and unhealthy diet contribute to the right shift of the curve Data from WHO 2003 2 Hypertension is a leading global risk factor for mortality Hypertension affects 65 millions in the U S NIH estimation The Lancet 360 1347 2002 BP CO PVR CNS sympathetic nerves Baroreceptor reflex arc Heart rate contractility Aortic arch carotid sinuses Peripheral resistance 1 AR 1 AR Stroke volume Baroreceptors Na Ca2 exchange Reninangiotensinaldosterone Cardiac output Arterial Blood Pressure Sodium volume Venules capacitance 3 BP CO PVR and MAP CO TPR MAP Mean Arterial Pressure SBP DBP 3 DBP CO Cardiac Output TPR Total Peripheral Resistance Factors affecting drug treatment of hypertension Accuracy of diagnosis severity of hypertension Etiology Primary essential hypertension vs secondary 10 15 patients e g pheochromocytoma renal artery constriction Cushing s syndrome Pre existing risk factors and medical conditions smoking hyperlipidemia diabetes congestive heart failure asthma current medications Individualization age gender ethnicity patient compliance Single drug monotherapy vs multiple drug polypharmacy 4 Development of AHDs Chronology 1930 1940 1950 1960 1970 1980 1990 2000 Veratrum alkaloids affect sensitivity of baroreceptors not currently in use due to toxicity Thiocyanates sodium nitroprusside ganglion blocking agents trimethaphan Catecholamine depletors reserpine vasodilators hydralazine PNS sympathetic inhibitors guanethidine MAO inhibitors pargyline diuretics hydrochlorothiazides CNS 2 agonists clonidine beta blockers propranolol methyldopa Alpha1 blockers prazocin alpha beta blockers labetalol ACE inhibitors captopril Calcium channel blockers nimodipine Angiotensin II receptor antagonists losartan Endothelin receptor antagonists bosentan Mechanism based classification of AHDs Diuretics Thiazide Hydrochlorothiazide Loop furosemide torsemide ethacrynic acid Potassium sparing amiloride spironolactone triamterene Sympathoplegic agents Adrenergic synthesis release blockers reserpine granethidine Central adrenergic agonists methodopa clonidine blockers prazosin tetrazosin doxazosin blockers propranolol nadolol timolol metoprolol acebutolol penbutolol pindolol Ganglion blocker Trimethaphan Direct vasodilators hydralazine minoxidil sodium nitroprusside diazoxide Calcium channel blockers nifedipine amlodipine felodipine diltiazem verapamil AT II antagonists ACE inhibitors ACE inhbitors captopril enalapril enalaprilat lisinopril benazepril AT II receptor antagonists losartan 5 I DIURETICS First line drug for hypertension Relatively safe and effective Suitable for older adults Can be given orally Use alone or with other antihypertensive agents Low cost and mostly available in 3rd world countries Mechanism of action Diuretics lower BP by depleting body sodium stores Full effects take 2 steps 1 initial reduction of total blood volume and hence cardiac output peripheral vascular resistance may increase 2 when CO returns to normal takes 6 8 weeks PVR declines Therapeutic use Thiazide diuretics such as hydrochlorothiazide act on distal convoluted tubule and inhibit Na Cl symport Can counteract the Na and H2O retention effect of direct vasodilators such as hydralazine and therefore are beneficial for combined use Particularly useful for elderly patients but not effective when kidney function is inadequate Thiazides reduce blood K and Mg2 levels and induce hypokalemia It retains Ca2 and decreases urine Ca2 content It is necessary to monitor serum K level in patients with cardiac arrhythmias and when digitalis is in use 6 Loop diuretics including furosemide torsemide and ethacrynic acid are more powerful than thiazides They are often used for treatment of severe hypertension when direct vasodilators are administered and Na and H2O retention becomes a problem Can be used in patients not responding to thiazides Increase urine Ca2 content K sparing diuretics include triamterene amiloride both are Na channel inhibitors and spironolactone aldosterone antagonist Used for treating hypertension in patients given digitalis Also enhance the natriuretic effects of other diuretics e g thiazides and counteract the K depleting effect of these diuretics Adverse effects and toxicity 1 Depletion of K except K sparing diuretics leading to hypokalemia 2 Increase uric acid concentration and precipitate gout 3 Increase serum lipid concentrations Diuretics are not used for treating hypertension in patients with hyperlipidemia or diabetes 4 Gynecomastia with spironolactone 7 II SYMPATHOPLEGIC AGENTS Centrally acting on vasomotor center methyldopa clonidine guanabenz guanfacine acting as 2 agonists Blocking synthesis and or release of NE reserpine guanethidine granadrel Blocking adrenoceptors propranolol metoprolol labetalol etc Blocking sympathetic ganglia trimethaphan Blocking 1 adrenoceptors in vessels prazosin doxazosin tetrazosin Blocking renin release propranolol and other blockers Cranial CNS Pre ganglionic Ganglion Post ganglionic Ach Parasympathetic Nicotinic Ach Sympathetic alpha beta Ach Sympathetic Muscarinic NE Nicotinic Thoracolumbar Ach Cardiac smooth muscles gland cells nerve terminals Cardiac smooth muscles gland cells nerve terminals Ach Sweat glands Nicotinic Sympathetic Sympathetic
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