Antihypertensive Drugs Definition: Systolic BP≥140mmHg or Diastolic BP≥90mmHg 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
1 Antihypertensive Drugs Definition: Systolic BP ≥ 140 mm Hg or 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
Classification and management of BP for adults Category Systolic Diastolic Lifestyle Initial drug modification therapy Normal <120 and <80 Encourage Not needed No,or treat Pre-hypertension 120-139 or 80-89 Yes Compelling indications Stage 1 hypertension 140-1590r 90-99 Yes Diuretic,ACEl,ARB.B-blocker.CCB. Combination;+compelling indications Stage 2 hypertension ≥160 or 2100 Yes Two-drug combo (diuretic and ACEl. or ARB or B-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;ACEl,ACE inhibitor;ARB,angiotensin receptor blocker;B-blocker,B-adrenergic receptor blocker,CCB,calcium channel blocker Hypertension is a leading global risk factor for mortality 8000- 7000 High-mortality,developing region Lower-mortality.developing region 6000- ▣Developed region 5000 4000 3000 2000 1000 0- LO* The Lancet,360:1347(2002) 2
2 Normal Pre-hypertension Stage 1 hypertension Stage 2 hypertension Category Systolic Diastolic < 120 120-139 140-159 ≥ 160 and or or or < 80 80-89 90-99 ≥ 100 Classification and management of BP for adults Based on 7th Report of the Joint National Committee on Detection, Evaluation, and Treatment of High BP (JNC 7) Lifestyle modification Encourage Yes Yes Yes Initial drug therapy Not needed No, or treat Compelling indications Diuretic, ACEI, ARB, β-blocker, CCB, Combination; + compelling indications Two-drug combo (diuretic and ACEI, or ARB or β-blocker or CCB; Also treat compelling indications Diuretic here means thiazide-type; ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; β-blocker, β-adrenergic receptor blocker; CCB, calcium channel blocker Hypertension is a leading global risk factor for mortality The Lancet, 360:1347 (2002)
BP=CO×PVR CNS/sympathetic nerves Baroreceptor reflex arc Heart rate Aortic arch contractility carotid sinuses 81-AR Peripheral a1-AR Arterial Cardiac Blood output resistance Pressure Stroke Na'/Ca2 volume exchange Renin- angiotensin- Venules aldosterone Sodium/ capacitance volume Factors affecting drug treatment of hypertension: Accuracy of diagnosis;severity of hypertension Etiology:Primary(essential hypertension)vs.secondary(10-15%patients) Identifiable causes of hypertension:Pheochromocytoma,renal artery constriction,Cushing's syndrome(hypercorticism)and Cushing's disease (over-production of ACTH).primary aldosteronism,thyroid or parathyroid disease,coarctation of the aorta 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) 3
3 Peripheral resistance Baroreceptor reflex arc Sodium/ volume Venules capacitance Stroke volume Heart rate contractility Na+/Ca2+ exchange Reninangiotensinaldosterone Cardiac output Arterial Blood Pressure CNS / sympathetic nerves BP = CO × PVR Aortic arch carotid sinuses β1-AR α1-AR Baroreceptors Factors affecting drug treatment of hypertension: • Accuracy of diagnosis; severity of hypertension • Etiology: Primary (essential hypertension) vs. secondary (10-15% patients) • Identifiable causes of hypertension: Pheochromocytoma, renal artery constriction, Cushing’s syndrome (hypercorticism) and Cushing’s disease (over-production of ACTH), primary aldosteronism, thyroid or parathyroid disease, coarctation of the aorta • 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)
Pharmacological mechanism-based classification Diuretics: Thiazide-Hydrochlorothiazide Loop-furosemide,torsemide,ethacrynic acid Potassium-sparing-amiloride,spironolactone,triamterene Sympathoplegic agents Adrenergic synthesis/release blockers-reserpine,granethidine Central a-adrenergic agonists-a-methodopa,clonidine a-blockers-prazosin,tetrazosin,doxazosin B-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-lI antagonists ACE inhibitors: ACE inhbitors-captopril,enalapril,enalaprilat,lisinopril,benazepril AT-lI receptor antagonists-losartan 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. 4
4 Pharmacological mechanism-based classification Diuretics: Thiazide - Hydrochlorothiazide Loop - furosemide, torsemide, ethacrynic acid Potassium-sparing - amiloride, spironolactone, triamterene Sympathoplegic agents : Adrenergic synthesis / release blockers - reserpine, granethidine Central α-adrenergic agonists – α-methodopa, clonidine α−blockers - prazosin, tetrazosin, doxazosin β−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 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噻嗪类利尿剂，such as hydrochlorothiazide氢氯 噻嗪，act on distal convoluted tubule and inhibit Nat-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 also 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. Loop diuretics亨利氏环类利尿剂，including furosemidei速尿， torsemide:托拉赛米，and ethacrynic acid:利尿酸，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氨苯蝶呤，amiloride阿米洛利 (both are Na+channel inhibitors),and spironolactone安体舒通 (aldosterone antagonist).Used for treating hypertension in patients who also take digitalis.This class of drugs enhance the natriuretic effects of other diuretics(e.g.,thiazides)and counteract the K+ depleting effect of these diuretics
5 Therapeutic use: Thiazide diuretics 噻嗪类利尿剂, such as hydrochlorothiazide 氢氯 噻嗪, 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 also 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. Loop diuretics 亨利氏环类利尿剂, including furosemide速尿, torsemide托拉赛米, and ethacrynic acid利尿酸, 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氨苯蝶呤, amiloride阿米洛利 (both are Na+ channel inhibitors), and spironolactone安体舒通 (aldosterone antagonist). Used for treating hypertension in patients who also take digitalis. This class of drugs enhance the natriuretic effects of other diuretics (e.g., thiazides) and counteract the K+ depleting effect of these diuretics