Part 3 Antihypertensive Drugs

Hypertension: The most common disease causing various complications

§Overview §Classification of § antihypertensive drugs §Antihypertensive drugs §Rational application of § antihypertensive drugs Antihypertensive Drugs

A. Overview Hypertension essential hypertension ~ 90% secondary hypertension ~ 10% secondary hypertension ~ 10% §Criterion of hypertension: diastolic blood pressure  90 mmHg diastolic blood pressure  90 mmHg systolic blood pressure  140 mmHg systolic blood pressure  140 mmHg

Major factors influencing blood pressure Arterial blood pressure pressure CardiacoutputPeripheralresistance   Venoustone Bloodvolume Fillingpressure Contractility Heartrate arteriolartone Baroreceptors and sympathetic nervous system Renin-angiotention-aldosterol system (RAAS) A. Overview

Regulation of blood pressure (neural & endocrine pathways)

Regulation of blood pressure: Targets of antihypertensive drugs Sympathetic Endocrine/body fluid

Peripheral resistance and vascular tone and elasticity

Arterial wall hypertrophy and sclerosis

§Diuretics §Sympathetic nervous system inhibitors mainly, adrenoceptor antagonists §Calcium channel blockers §Regin-angiotensin system inhibitors §Others § Central antihypertensive drugs § Vasodilators B. Classification of Antihypertensive Drugs

Noradrenergic nerve ending blockers RAAS inhibitors 1. ACEIs 1. ACEIs 2. AT 1 blockers 2. AT 1 blockers 3. Renin inhibitors 3. Renin inhibitors

Commonly used antihypertensive drugs (1) Diuretics: Hydrochlorothiazide (2) Calcium antagonists: Nifedipine, amolodipine, verapamil, etc. Nifedipine, amolodipine, verapamil, etc. (3) Angiotensin Ⅱ receptor antagonists: Lasartan, etc. (4) Angiotensin-converting enzyme inhibitors: Captopril, enalapril, etc. Captopril, enalapril, etc. (5)  -Blockers: Propranolol, etc. (6)  1 -Blockers: Prazosin, doxazosin, etc. (7) Central sympatholytics: Clonidine, etc. (8) Potassium channel agonists: Minoxidil, diazoxide, etc. (9) Vasodilators: Sodium nitroprusside, etc.

Diuretics Diuretics 1. Pharmacological effects (1) Reducing plasma volume (cardiac output  ) (2) Reducing Na + and Na + -Ca 2+ exchange in vascular smooth muscle cells (Ca 2+ i , peripheral resistance  ) C. Antihypertensive Drugs

Main diuretics Thiazides Loop diuretics K+ sparing diuretics

类 别 ( 主要作用部位 ) 其他分类名作用机制利尿应用非利尿应用 碳酸酐酶抑制药 （近曲小管） /抑制碳酸酐酶 利尿药耐受的病 人, 与袢利尿药合 用 青光眼，高山病， 代谢性碱中毒 渗透性利尿药 （髓袢及其他部 位） 脱水药增高尿液渗透压急性肾功能衰竭脑水肿，青光眼 袢利尿药（髓袢 升支粗段） 1. 高效能利尿药 2. Na + -K + -2C1 — 同 向转运体抑制药 抑制 Na + -K + -2C1 — 同向转运 各种严重水肿， 急性肾功能衰竭 高钙血症，加速 毒物排出 噻嗪类利尿药 （远曲小管） 1. 中效能利尿药 2. Na + -C1 — 同向转 运体抑制药 抑制 Na + -C1 — 同向 转运 各种水肿 高血压，高尿钙 症，尿崩症 保钾利尿药（集 合管、末段远曲 小管） 低效能利尿药 1. 拮抗醛固酮作 用（螺内酯） 2. 抑制上皮细胞 Na + 通道（氨苯蝶 啶，阿米洛利） 水肿（尤其对伴 有醛固酮增高者， 如肝硬化病人） 失钾和 / 或失镁

Na + -Ca 2+ exchange , Ca 2+ i  in vascular smooth muscle cells

2. Clinical uses (1) Hypertension single or combined with other drugs single or combined with other drugs mild to moderate hypertension mild to moderate hypertension particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart failure particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart failure (2) Other uses: diuretic, etc. C. Antihypertensive Drugs

3. Adverse effects plasma levels of renin  hypokalemia hypokalemia hyperuricemia hyperuricemia hyperglycemia hyperglycemia hyperlipidemia hyperlipidemia C. Antihypertensive Drugs

Calcium channel blockers 1. Pharmacological effects §Relaxing vascular smooth muscles 2. Clinical uses §Mild to severe hypertension (usually combined with  receptor blockers ) C. Antihypertensive Drugs Nifedipine 硝苯地平

3. Adverse effects Peripheral edema Peripheral edema Reflex sympathetic activation Reflex sympathetic activation Renin activity  Renin activity  Other calcium channel blockers: amlodipine, etc. C. Antihypertensive Drugs

Renin-angiotensin system inhibitors ACEIs: captopril 卡托普利, enalapril 依那普利 AT 1 receptor antagonists ： losartan 氯沙坦 AT 1 receptor antagonists ： losartan 氯沙坦 Renin inhibitors: enalkiren 依那吉仑 Renin inhibitors: enalkiren 依那吉仑 C. Antihypertensive Drugs

Renin inhibitors

Angiotensin converting enzyme Angiotensinogen Angiotensin I (decapeptide) Angiotensin II ( octapepetide) Angiotension III (heptapeptide) Renin-Angiotensin-Aldosterone system (RAAS) Renin Angiotensinase A Adrenal cortex Aldosterone

Constricting vessels, increase peripheral resistance and returned blood volume.Constricting vessels, increase peripheral resistance and returned blood volume. Increasing sympathetic tension, promoting release of sympathetic transmitter.Increasing sympathetic tension, promoting release of sympathetic transmitter. Stimulating release of aldosterone.Stimulating release of aldosterone. Inducing expression of c-fos 、 c-myc 、 c-jun rapidly.Inducing expression of c-fos 、 c-myc 、 c-jun rapidly. Actions of angiotensin Ⅱ C. Antihypertensive Drugs

ACEIs 1. Pharmacological effects §Inhibiting the production of Ang II §Inhibiting the degradation of bradykinin §Increasing ANP and scavenge free radicals C. Antihypertensive Drugs

Implications of inhibition of RAAS AT 1 blockers (-)(+) ACEIs ACEIs Smooth muscle hypertrophy (vascular remodeling)

2. Clinical uses §Hypertension without reflex increase in the activity of sympathetic system without reflex increase in the activity of sympathetic system effective in the management of patients with CHF, diabetes and ischemic heart disease. effective in the management of patients with CHF, diabetes and ischemic heart disease. C. Antihypertensive Drugs

3. Adverse effects hypotension ( first dose phenomenon ) hypotension ( first dose phenomenon ) renal injury renal injury dry cough dry cough hyperkalemia hyperkalemia angioneuroedema angioneuroedema rashes and altered tastes rashes and altered tastes Contraindications: renal artery stenosis, pregnant and lactational women C. Antihypertensive Drugs

AT 1 receptor antagonists (angiotensin II receptor antagonist) (angiotensin II receptor antagonist) C. Antihypertensive Drugs Losartan 氯沙坦

AT 1 receptor antagonists Compared with ACEI: Blocking actions of angiotensin II directly Blocking actions of angiotensin II directly Not influencing bradykinin metabolism Not influencing bradykinin metabolism Protecting renal function Protecting renal function Used for mild to moderate hypertension Used for mild to moderate hypertension Less adverse effects Less adverse effects C. Antihypertensive Drugs

Renin inhibitors enalkiren 依那吉仑 enalkiren 依那吉仑 Inhibiting whole RAAS Inhibiting whole RAAS Including renin antibody, peptide and nonpeptide renin inhibitors Including renin antibody, peptide and nonpeptide renin inhibitors C. Antihypertensive Drugs

Sympathetic system inhibitors Centrally acting adrenergic drugs §Ganglion blockers §Noradrenergic nerve ending blockers §Adrenoreceptor blockers  receptor blockers  receptor blockers  receptor blockers  receptor blockers  and  receptor blockers  and  receptor blockers C. Antihypertensive Drugs

Sympathetic system: Targets of antihypertensive drugs

Adrenoreceptor blockers  Receptor blockers 1. Pharmacological effects (1) Decreasing cardiac output (2) Decreasing sympathetic outflow from CNS and releasing of noradrenalin from peripheral nerve endings (3) Inhibiting the release of renin from kidney (formation of angiotension and secretion of aldosterone) (4) Increasing production of PGI 2 (5) Increasing sensitivity of baroreceptor C. Antihypertensive Drugs

Main actions of β receptor blockers on blood pressure

3. Clinical uses (1) Hypertension: all kinds of hypertension more effective in young patients than elderly more effective in young patients than elderly useful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine headache useful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine headache (2) Other uses: angina pectoris; arrhythmias C. Antihypertensive Drugs

3. Adverse effects alterations in serum lipid patterns alterations in serum lipid patterns drug withdrawal reactions drug withdrawal reactions worsening asthma & COPD worsening asthma & COPD cardiac depression cardiac depression C. Antihypertensive Drugs

 1 Receptor blockers C. Antihypertensive Drugs Prazosin 哌唑嗪 Terazosin 特拉唑嗪 Doxazosin 多沙唑嗪 Trimazosin 曲马唑嗪

 1 Receptor blockers 1. Pharmacological effects Relaxing arterial and venous smooth muscles Relaxing arterial and venous smooth muscles Decreasing peripheral resistance Decreasing peripheral resistance 2. Clinical uses Hypertension: mild to moderate (single) and severe hypertension (combined with diuretics and  blockers) Hypertension: mild to moderate (single) and severe hypertension (combined with diuretics and  blockers) minimal changes in cardiac output, renal blood flow renin release and glomerular filtration regulation of blood lipid minimal changes in cardiac output, renal blood flow renin release and glomerular filtration regulation of blood lipid C. Antihypertensive Drugs

3. Adverse effects first dose phenomenon (postural hypotension) water and sodium retention water and sodium retention C. Antihypertensive Drugs

 and  1 Receptor blockers C. Antihypertensive Drugs Labetalol 拉贝洛尔 Carvedilol 卡维地洛 Amosulalol 氨磺洛尔

 and  1 Receptor blockers §Mild decrease of blood pressure §Minimal changes in cardiac output and heart rate §Used for all kinds of hypertension, including hypertensive emergency §Less adverse effects C. Antihypertensive Drugs

Centrally acting drugs C. Antihypertensive Drugs Clonidine 可乐定 Methyldopa 甲基多巴 Clonidine Methyldopa

Action site of the centrally-acting drugs

1. Pharmacological effects §Diminishing central adrenergic outflow Activating  2 and I 1 receptor in medulla Activating  2 and I 1 receptor in medulla 2. Clinical uses §Hypertension: mild to moderate hypertension that has not responded adequately to treatment with diuretics alone. minimal changes in renal blood flow and glomerular filtration inhibit gastrointestinal secretion and mobility minimal changes in renal blood flow and glomerular filtration inhibit gastrointestinal secretion and mobility C. Antihypertensive Drugs

3. Adverse effects central and atropine-like side effects central and atropine-like side effects long-term uses: long-term uses: water and sodium retention water and sodium retention rebound phenomenon rebound phenomenon C. Antihypertensive Drugs

I 1 receptor agonists rilmenidine （利美尼定） moxonidine （莫索尼定） moxonidine （莫索尼定） C. Antihypertensive Drugs

Ganglionic blockers Trimetaphan ( 米噻芬 ) Trimetaphan ( 米噻芬 ) Mecamylamine （美卡拉明） Mecamylamine （美卡拉明） Shor-acting Shor-acting Tolerance Tolerance For controlling hypotension For controlling hypotension C. Antihypertensive Drugs

Noradrenergic nerve ending blockers Reserpine （利舍平，利血平 ) Reserpine （利舍平，利血平 ) Guanethidine （胍乙啶） Guanethidine （胍乙啶） Decreasing NE storage in noradrenergic nerve endings Slow and lasting effects Central depression; GI reactions; digestive ulcer C. Antihypertensive Drugs

Hydralazine肼曲嗪Dihydralazine双肼曲嗪 Sodium Nitroprusside 硝普钠 Vasodilators

Vasodilators Hydralazine （肼屈嗪） §Dilating arteries and arterioles §Decreasing peripheral resistance §Reflexly elevating heart rate, cardiac output and renin release. §Combined with  blockers and diuretics. §Adverse effects due to vasodilation and lupus-like syndrome can occur. C. Antihypertensive Drugs

Nitroprusside sodium （硝普钠） §Dilating small arteries and veins §Used for treatment of emergency hypertension, hypertension with CHF, controlled hypotension and obstinate CHF  Adverse effects due to hypotension in excess and sulfocyanate () poisoning.  Adverse effects due to hypotension in excess and sulfocyanate ( 硫氰酸盐 ) poisoning. C. Antihypertensive Drugs

Potassium channel openers §Including minoxidil ( 米诺地尔 ), nicorandil, diazoxide ( 二氮嗪 ), etc. §Dilating arteries (Ca 2+ influx  ) §Reflexly elevating heart rate, cardiac output and renin release §Used for treatment of obstinate and severe hypertension §Adverse effects include sodium retention, palpitation, pilosis ( 多毛 ), etc. C. Antihypertensive Drugs

D. Rational application of Antihypertensive Drugs §Diuretics §Calcium channel blockers §Regin-angiotensin system inhibitors §Sympathetic inhibitors §Vasodilators

1. Prescribe according to the severity degree of hypertension (1) Mild: diuretics,  blockers, ACEI, calcium channel blockers (CCB),  1 blockers, AT 1 blockers, single drug. (2) Moderate: combined with two above drugs (3) Severe: adding centrally acting drugs or vasodilators to the two combined drugs D. Rational application of Antihypertensive Drugs

2. Prescribe according to complications CHF and/or COPD Diuretics, ACEI, CCB, prazosin  Blockers Renal failure ACEI, CCB methyldopa Tachycardia  Blockers GI ulcer ClonidineReserpine Diabetes and gout ACEI, prazosin, CCB Thiazides D. Rational application of Antihypertensive Drugs indicatedcontraindicated

hypertensive emergency:vasodilators (nitroprusside sodium, diazoxide), loop diuretics (furosemide) hypertensive emergency: vasodilators (nitroprusside sodium, diazoxide), loop diuretics (furosemide) elderly patients: avoiding drugs that could induce postural hypotension (  1 blocker, larger dose of diuretics) and influence the cognizant ability (clonidine) Cardiac ischemia: avoiding vasodilators D. Rational application of Antihypertensive Drugs

3. Combination of drugs 4. Avoid blood pressure to decrease too rapidly and excessively 5. Individual therapy D. Rational application of Antihypertensive Drugs