Chapter 34 Antihypertensive Drugs

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

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

A. Overview   Major factors influencing blood pressure Arterial blood pressure  Cardiac output  Peripheral resistance arteriolar tone Blood volume Heart rate Contractility Filling pressure Venous tone Baroreceptors and sympathetic nervous system Renin-angiotention-aldosterol system (RAAS)

Peripheral resistance and vascular tone and elasticity

Arterial wall hypertrophy and sclerosis

B. Classification of Antihypertensive Drugs Diuretics Calcium channel blockers Regin-angiotensin system inhibitors Sympathetic inhibitors Vasodilators

Noradrenergic nerve ending blockers

C. Antihypertensive Drugs Diuretics 1. Pharmacological effects (1) Reducing plasma volume (cardiac output ) (2) Reducing Na+-Ca2+ exchange in vascular smooth muscle cells (Ca2+i , peripheral resistance  )

Na+-Ca2+ exchange , Ca2+i  in vascular smooth muscle cells

C. Antihypertensive Drugs 2. Clinical uses (1) Hypertension single or combined with other drugs mild to moderate hypertension 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 hyperuricemia hyperglycemia hyperlipidemia

C. Antihypertensive Drugs

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 ) Nifedipine 硝苯地平

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

C. Antihypertensive Drugs

C. Antihypertensive Drugs Renin-angiotensin system inhibitors ACEIs: captopril 卡托普利, enalapril 依那普利 AT1 receptor antagonists：losartan 氯沙坦 Renin inhibitors: enalkiren 依那吉仑

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

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

C. Antihypertensive Drugs ACEIs

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 Angiotensin II Inactive peptide brandykinin Angiotensin I ACEI (—) ACEI B2 receptor (—) ACE Circulation and local tissues PGI2 NO ACE Circulation and local tissues Vasodilatation, anti-proliferation, anti-hypertrophy

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

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

C. Antihypertensive Drugs AT1 antagonists Losartan 氯沙坦

C. Antihypertensive Drugs AT1 antagonists Compared with ACEI: Block actions of angiotensin II directly Not influence bradykinin metabolism Protect renal funtion Used for mild to moderate hypertension Less adverse effects

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

C. Antihypertensive Drugs

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

C. Antihypertensive Drugs Adrenoreceptor 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 PGs (5) Increasing sensitivity of baroreceptor

Main actions of β receptor antagonists on blood pressure

C. Antihypertensive Drugs 3. Clinical uses (1) 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 headache (2) Other uses: angina pectoris; arrhythmias

C. Antihypertensive Drugs 3. Adverse effects alterations in serum lipid patterns drug withdrawal Cardiac depression

C. Antihypertensive Drugs

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

C. Antihypertensive Drugs 1 Receptor blockers 1. Pharmacological effects Relaxing arterial and venous smooth muscles Decreasing peripheral resistance 2. Clinical uses 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

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

C. Antihypertensive Drugs

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

C. Antihypertensive Drugs  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 Clonidine 可乐定

C. Antihypertensive Drugs 1. Pharmacological effects Diminishing central adrenergic outflow Activating 2 and I1 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

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

C. Antihypertensive Drugs I1 receptor agonists rilmenidine moxonidine

C. Antihypertensive Drugs

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

C. Antihypertensive Drugs

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

C. Antihypertensive Drugs Vasodilators Hydralazine 肼曲嗪 Dihydralazine 双肼曲嗪 Sodium Nitroprusside 硝普钠

C. Antihypertensive Drugs 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.

C. Antihypertensive Drugs Potassium channel openers Including minoxidil, nicorandil, diazoxide, etc. Dilating arteries (Ca2+ influx ) Reflexly elevating heart rate, cardiac output and renin release Used for treatment of obstinate and severe hypertension Adverse effects include sodium retention, palpitation, etc.

C. Antihypertensive Drugs

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

D. Rational application of Antihypertensive Drugs 1. Prescribe according to the severity degree of hypertension (1) Mild: diuretics,  blockers, ACEI, calcium channel blockers, 1 blockers, AT1 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 indicated contraindicated CHF and/or COPD Diuretics, ACEI, prazosin  Blockers Renal failure ACEI, CCB methyldopa Tachycardia GI ulcer Clonidine Reserpine Diabetes and gout ACEI, prazosin Thiazides

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