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Antihypertension Drugs Shi-Hong Zhang (张世红) Pharmacology, Dept. of [email protected] 1 Outline Overview Classification of antihypertensive drugs Antihypertensive drugs Clinical pharmacology of antihypertensive drugs 2 1. Overview Criteria of hypertension diagnosis 3 Etiology: Secondary hypertension(10~15%) Essential hypertension(85~90%) High Risk Factors: Stressful life-style High dietary intake of sodium Obesity and hyperlipidemia Smoking Hereditary factors (30%) 4 The end organ damage of hypertension: Kidney: renal failure Heart: coronary disease, cardiac failure Brain: stroke Kidney Failure 15% Other 2% MI or CHF 50% Stroke 33% 5 按危险分层,量化地估计预后 其它危险因素和病史 血压 I级 II级 III级 Ⅰ 无其它危险因素 低危 中危 高危 Ⅱ1~2 个危险因素 中危 中危 很高危 Ⅲ≥3 个危险因素 高危 高危 很高危 Ⅳ靶器官损害或糖尿 病并存的临床情况 很高危 很高危 很高危 低危患者 <15% , 中危患者 15%~20%, 高危患者 20%~30% , 很高危患者 >30%的风险在未来十年发生心血管事件。 6 Age-adjusted annual incidence of CHD per 1000 Blood Pressure and Risk for Coronary Heart Disease in Men 60 60 50 50 40 40 Age 65-94 30 20 Age 65-94 30 Age 35-64 20 10 10 0 0 <120 120- 140- 160- 180+ 139 159 179 Age 35-64 <75 7584 8594 95- 105+ 104 Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease 7 (CHD) at baseline Framingham Heart Study, 30-year Follow-up. NHLBI, 1987. 8 Goals of antihypertensive treatment: Lower the blood pressure Protect the end organ Reduce the morbidity and mortality rates Best therapy and minimal risk 9 Normal regulation of blood pressure: Arterial blood pressure Cardiac output Heart rate Contractility Peripheral resistance Filling pressure Baroreceptors and sympathetic nervous system RAAS arteriolar volume Blood volume Venous tone 10 Normal regulation of blood pressure: 11 2. Classification of antihypertensive drugs Diuretics (氢氯噻嗪) Calcium channel blockers (硝苯地平) Renin-angiotensin system inhibitors - ACEIs (卡托普利) - AR1Bs (缬沙坦) - Renin inhibitors (阿利吉仑) Vasodilators - Direct acting vasodilators (硝普钠) - Potassium channel openers (米诺地尔) 12 Sympathetic inhibitors - Centrally acting adrenergic drugs (可乐定) - Ganglion blockers (樟磺咪芬) - Noradrenergic nerve ending blockers (利舍平) - Adrenoreceptor blockers - receptor blockers (普萘洛尔) - receptor blockers (哌唑嗪) - and receptor blockers (拉贝洛尔) 13 14 3. Antihypertensive Drugs 3.1 Diuretics Thiazide, loop, potassium-sparing diuretics A Actions Reduce plasma volume (cardiac output ) Reduce Na+-Ca2+ exchange in vascular smooth muscle cell (peripheral resistance ) 15 3. Antihypertensive Drugs 3.1 Diuretics B Therapeutic uses: Hypertension - first-line agent - Single drug or combined with others - Particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart failure 16 3. Antihypertensive Drugs 3.1 Diuretics C Adverse effects: plasma level of renin hypokalemia (低钾血症) hyperuricemia (高尿酸血症) hyperglycemia (高血糖) hyperlipidemia (高脂血症) 17 3. Antihypertensive Drugs 3.2 Calcium channel blockers (CCBs) Nifedipine硝苯地平 A Actions: Relaxes vascular smooth muscle B Therapeutic uses: mild to severe hypertension (usually combined with blockers ) C Adverse effects: peripheral edema, reflex sympathetic activation, and renin activity 18 3. Antihypertensive Drugs 3.3 Renin-angiotensin system inhibitors ACEIs: Captopril AR1Bs: Losartan Renin inhibitors: renin antibody, peptide and nonpeptide renin inhibitors (eg. aliskiren) 19 血管紧张素原 激肽原 激肽释放酶 Chymase 20 3. Antihypertensive Drugs 3.3 Renin- angiotensin system inhibitors ACEIs A Actions Inhibit the production of Ang II (dilate vessels, decrease sympathetic activity, inhibit release of aldosterone, anti-hypertrophy) Inhibit the degradation of bradykinin 21 3. Antihypertensive Drugs ACEIs B Therapeutic uses Hypertension - first line drug - without reflex increase in sympathetic activity - effective in the treatment of CHF, diabetes and ischemic heart disease. 22 3. Antihypertensive Drugs ACEIs C Adverse effects Hypotension (first dose phenomenon) Renal injury (renal artery sclerosis) Dry cough and angioneuroedema (bradykinin accumulation) Hyperkalemia (aldosterone inhibition) Rashes and altered taste (-SH-related) Fetotoxicity (esp. the second trimester) 23 3. Antihypertensive Drugs AR1Bs Compared with ACEIs: • Block actions of angiotensin II directly • No influence on bradykinin metabolism • Protect renal function • Used for mild to moderate hypertension • Less adverse effects 24 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.1 Adrenoreceptor blockers receptor blockers A Actions Decrease cardiac output Inhibit renin release from kidney (formation of angiotensin and secretion of aldosterone ) 25 3. Antihypertensive Drugs receptor blockers A Actions Decrease sympathetic outflow from the CNS Decrease the release of noradrenalin from peripheral nerve endings Increase production of PGs Increase sensitivity of baroreceptor 26 3. Antihypertensive Drugs receptor blockers B Therapeutic uses Hypertension: all kinds of hypertension - more effective in young patients than elderly - useful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine. 27 3. Antihypertensive Drugs receptor blockers C Adverse effects - Hyperglycemia - Hyperlipidemia - Asthma - AV block - Bradycardia - Cardiac inhibition 28 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.1 Adrenoreceptor blockers 1 receptor blockers Prazosin哌唑嗪,terazosin特拉唑嗪 A Actions Relax arterial and venous smooth muscle, decrease peripheral resistance Modulate serum lipid patterns (↓ TG, TC, LDL; ↑HDL) 29 3. Antihypertensive Drugs 1 receptor blockers B Therapeutic uses Hypertension: mild to moderate (single) and severe hypertension (combined with diuretics and β blockers) minimal changes in cardiac output, renal blood flow, renin release and glomerular filtration C Adverse effects First dose phenomenon (postural hypotension) Sodium retention (+diuretics) 30 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.1 Adrenoreceptor blockers and 1 receptor blockers Mild decrease in blood pressure Minimal changes in cardiac output and heart rate Used for all kinds of hypertension, including hypertensive emergency (iv) Less adverse effects Include labetalol, carvedilol 31 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.2 Centrally-acting drugs Clonidine (可乐定) A Actions Diminishes central adrenergic outflow - activates 2A receptor in the medulla - activates I1 receptor in the medulla 32 3. Antihypertensive Drugs 33 3. Antihypertensive Drugs Clonidine B Therapeutic uses Hypertension: mild to moderate - inhibits gastrointestinal secretion and mobility (M antagonism) C Adverse effects Atropine-like effects (dry month, sedation, etc), sedation, water and sodium retention (renal filtration ), rebound effect 34 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.2 Centrally-acting drugs I1 receptor agonists Rilmenidine利美尼定 Moxonidine莫索尼定 Similar efficacy to CCBs, ACEIs, beta-blockers. Similar adverse effect to clonidine without rebound effect 35 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.3 Ganglion blockers Trimetaphan(樟磺咪芬) Mecamylamine (美卡拉明) 36 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.4 Noradrenergic nerve ending blockers Reserpine (利舍平,利血平) Guanethidine (胍乙啶) 37 3. Antihypertensive Drugs 3.5 Vasodilators Hydralazine (肼屈嗪) Increase the release of nitric oxide from endothelium Dilates arteries and arterioles Decreases peripheral resistance Reflexly elevates heart rate, cardiac output and renin release. Combined with blockers and diuretics for moderate and severe hypertension. Adverse effects due to vasodilation and lupus-like syndrome can occur. 38 3. Antihypertensive Drugs 3.5 Vasodilators Diuretics β blockers 39 3. Antihypertensive Drugs 3.5 Vasodilators Nitroprusside sodium (硝普钠) Serves as a prodrug of nitric oxide Dilates small arteries and veins Used for treatment of hypertensive emergencies, hypertension with CHF, controlled hypotension and obstinate CHF Adverse effects due to excessive hypotension and sulfocyanate poisoning (硫氰酸盐中毒). 40 3. Antihypertensive Drugs 3.5 Vasodilators Potassium channel openers Including minoxidil, nicorandil, diazoxide, etc. Dilates arteries (Ca2+ influx ) Reflexly elevates heart rate, cardiac output and renin release. Used for the treatment of obstinate and severe hypertension Adverse effects include sodium retention, palpitation, etc. 41 4. Clinical pharmacology of antihypertensive drugs 4.1 General information • The diagnosis of hypertension should be established by finding an elevated blood pressure on at least three different office visits • The physician must establish with certainty that hypertension is persistent and requires treatment and must exclude secondary causes of hypertension that might be treated by definitive surgical procedures. 42 4. Clinical pharmacology of antihypertensive drug 4.1 General information • Consider the level of blood pressure, the age and sex of the patient, the severity of organ damage (if any) due to high blood pressure, and the presence of cardiovascular risk factors must all be considered. ------Initiate the drug treatment or not. • Selection of drugs is dictated by the level of blood pressure, the presence and severity of end-organ damage, and the presence of other diseases. • Educate the patient about the nature of hypertension, the importance of treatment and the potential side effects of drugs. 43 4. Clinical pharmacology of Antihypertensive Drug 4.2 Out-patient therapy In general: • Sodium restriction: A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day (< 6 g NaCl) • Weight reduction; • Regular exercise; 44 Lifestyle modifications to manage hypertension 45 DASH diet 46 47 48 4. Clinical pharmacology of antihypertensive drug 4.2.1 Prescribe according to the severity of hypertension Mild: monotherapy from ACEIs, CCBs, AR1Bs, diuretics, blockers (first line), 1 blockers Moderate: combine two of the above drugs Severe: add centrally acting drugs or vasodilators on the two combined drugs 49 4. Clinical pharmacology of antihypertensive drug 4.2.2 Prescribe according to complications -- hypertensive emergency: vasodilators (nitroprusside sodium, diazoxide), labetalol, loop diuretics -- elderly patients: avoiding drugs that can induce postural hypotension and influence the cognitive ability (clonidine) 4.2.3 Combination therapy 4.2.4 Avoid blood pressure to decrease too rapidly and excessively 4.2.5 Individual therapy 50 4. Clinical pharmacology of antihypertensive drug 4.2.2 Prescribe according to complications 51 Antianginal drugs 52 Outline 1 OVERVIEW 2 ANTIANGINAL DRUGS - Organic nitrates - β-blockers - Calcium channel blockers 3 CLINICAL USE OF ANTIGANGINAL DRUGS 53 1.1 What is angina pectoris? Frequency: in America, about 6.3 million people are estimated to experience angina. An estimated 350,000 new cases of angina occur every year. One million died of angina each year in China A comprehensive approach to diagnosis and to medical management of angina is an integral part of the daily responsibilities of physicians. 54 Leading Sources of Disease Burden* • • • • • • • Ischemic Heart Disease Unipolar Major Depression Cardiovascular Disease Alcohol Use Traffic Accidents Lung and other cancers Dementia and Neurodegenerative Disorders *based on DALY’s (Disability Adjusted Life Years, WHO) which measure 55 lost years of healthy life due to premature death or disability 1.1 What is angina pectoris? Symptoms: Sudden, uncomfortable pressure, fullness, squeezing or severe substernal pain, radiating to the left arm, shoulders, neck, etc. 56 1.2 How does angina pectoris happen? Demand of the myocardium for oxygen Normal Ischemia Oxygen delivery to the myocardium by the coronary circulation 57 1.2 How does angina pectoris happen? Demand Preload (venous return ) Afterload (arteriolar resistance) Heart rate Delivery Atherosclerosis plaque Thrombus Spasm of coronary arteries 58 1.3 Classification of angina pectoris: Stable angina pectoris Unstable angina pectoris initial onset type Caused by atherosclerosis plaque and thrombus formation accelerated type spontaneous type + Variant/Prinzmetal’s angina pectoris Caused by spontaneous spasm of coronary arteries 59 Occurrence of stable and unstable angina pectoris Extreme weather Strong emotion Excessive food intake Exercise Excessive smoking Variant/Prinzmetal’s angina: usually occur when a person is at rest between midnight and 8am 60 1.4 Strategy for angina treatment Decrease the oxygen demand and/or increase the delivery BY - Dilating arteries, especially coronary arteries, including relieving spasm and opening collateral circulation - Dilating veins - Cardiac inhibition: decrease HR, contractility, tensility of myocardium - Anti-platelet coagulation and thrombus formation 61 1.5 Antianginal drugs Nitrates 硝酸酯类 -receptor blockers Calcium channel blockers 62 2. Antianginal drugs 2.1 Nitrates (硝酸酯类) Nitroglycerin硝酸甘油 A Actions Dilate vessels --- pre- and after-load↓ Redistribution of coronary blood flow --subendocardial area心内膜下区域↑ preload, epicardial vessels, collateral circulation, LVFP↓ Cardiac protection against ischemia Inhibit coagulation of platelets 63 B Mechanisms of action Nitrates (prodrug) NO GC activated [Ca2+]i cGMP Dephosphorylation of myosin light chain Vascular smooth muscle relaxation Anticoagulation of platelets 64 C Pharmacokinetics Time to peak effect Duration of action 2 min Nitroglycerin Sublingual 25 min 15 min Isosorbide dinitrate Sublingual 1 hour 硝酸异山梨酯 65 D Adverse effects Symptoms due to vasodilation: headache, increase of intraocular pressure, postural hypotension, facial flushing and tachycardia Allergy Methaemoglobinaemia高铁血红蛋白 (at very high dose) 66 2.1 Nitrates E Tolerance Provision of daily “nitrate-free interval” To supplement -SH E Interactions with other drugs Antihypertensive drugs Alcohol and Viagra 67 2. Antianginal drugs 2.2 β-blockers Catecholamine receptors Na+ influx ↑ during Ca2+ influx ↑ during phase 0 phase 4 K+ efflux ↑ during repolarization Physiological effects of receptors in the heart 68 2. Antianginal drugs 2.2 β-blockers Propranolol, metoprolol, atenolol A Actions - Decrease myocardial oxygen consumption - Increase blood supply to ischemic area - Improve myocardial metabolism (FFA ) and increase oxygen supply to tissues - Inhibit coagulation of platelets 69 2. Antianginal drugs 2.2 receptor blockers B Therapeutic uses: - stable and unstable type, especially associated with hypertension or arrhythmias, even with myocardial infarction. - not suitable for variant type. 70 2. Antianginal drugs 2.2 receptor blockers C Notices: • Begin with small doses • Withdraw gradually (rebound phenomenon) • Better to be combined with nitroglycerin 71 2. Antianginal drugs 2.3 L-type calcium channel blockers: 2.3.1 Classificaiton a:phenylalkylamines(苯烷胺类): verapamil(维拉帕米) b:benzothiazepines(苯硫卓类): diltiazem(地尔硫卓) c:dihydropyridines(二氢吡啶类): nifedipine(硝苯地平) ,nimoldipine(尼莫地平), amlodipine(氨氯地平) d:tetrandrine (粉防己碱) 72 2. Antianginal drugs 2.3.2 Antianginal effect: - Decrease myocardial oxygen consumption - Increase myocardial blood supply - Protect ischemic myocardial cells - Inhibit coagulation of platelets 73 2. Antianginal drugs 2.3.3 Therapeutic uses of CCBs: Angina pectoris - Stable angina: ver, dil - Variant angina: nif - Unstable angina: ver, dil, nif + blockers 74 2. Antianginal drugs Arrhythmias(ver, dil) : - Supraventricular tachycardia - Arrhythmias induced by triggered activity following after-depolarization Hypertension - Severe: nif; - Mild to moderate: ver, dil Cerebrovascular diseases (nif): transient ischemia attack, cerebral thrombosis, and cerebral embolism Other diseases: peripheral vascular spasmodic disease, arteriosclerosis, migraine 75 2. Antianginal drugs Adverse effects: Contraindications A Peripheral edema A Hypotension B Sympathetic excitation (nif) B Severe heart failure C Bradycardia (ver, dil) D Atrioventricular block D Hypotension (nif) C Sinus bradycardia 76 3. Combination of antianginal drugs 受体阻断药 硝酸酯类+ 受体阻断药 作用 硝酸酯类 动脉压 心率 (反射性) 心肌收缩力 (反射性) 抑制或不变 射血时间 不变 舒张期灌流时间 延长 左室舒张末压 不变或降低 心室容积 不变或缩小 Notice: • Hypotension • Cardiac low perfusion 77