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 Control factors of blood pressure Regulation of blood pressure (neural & endocrine pathways) - Regulation of blood pressure: Targets of antihypertensive drugs Sympathetic Endocrine/body fluid Regulation of blood pressure 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 RAAS inhibitors 1. ACEIs 1. ACEIs 2. AT 1 R blockers 2. AT 1 R 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 (AT 1 ) 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 openers: Minoxidil, diazoxide, etc. (9) Vasodilators: Sodium nitroprusside, etc. Diuretics Diuretics 1. Pharmacological effects (1) Reducing plasma volume (cardiac output ) (2) Reducing Na + and promoting 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 ( ) / , 1. 2. Na + -K + -2C1 Na + -K + -2C1 1. 2. Na + -C1 Na + -C1 1. 2. Na + / 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: as diuretic agents, 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 (CCB) 1. Pharmacological effects Relaxing vascular smooth muscles 2. Clinical uses Mild to severe hypertension (usually combined with receptor blockers ) C. Antihypertensive Drugs Nifedipine Use of different CCBs in the treatment of hypertension 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 , enalapril AT 1 receptor antagonists losartan AT 1 receptor antagonists losartan Renin inhibitors: enalkiren Renin inhibitors: enalkiren C. Antihypertensive Drugs Drugs acting on renin, angotensin converting enzyme (ACE) and AT 1 receptor 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. Actions of angiotensin Ang 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 Effects of ACE inhibitors on blood pressure 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 AT 1 (angiotensin II receptor antagonist) (angiotensin II receptor antagonist) C. Antihypertensive Drugs Losartan Action of AT 1 receptor blockers AT 1 receptor antagonists Compared with ACEI 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 enalkiren 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 C. Antihypertensive Drugs 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 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 TG HDL-c TG HDL-c drug withdrawal reactions drug withdrawal reactions worsening asthma & COPD worsening asthma & COPD cardiac depression cardiac depression C. Antihypertensive Drugs 1 Receptor blockers 1 C. Antihypertensive Drugs Prazosin Terazosin Doxazosin Trimazosin 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 / 1 C. Antihypertensive Drugs Labetalol Carvedilol Amosulalol 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 Methyldopa 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 I 1 rilmenidine moxonidine moxonidine C. Antihypertensive Drugs Ganglionic blockers Trimetaphan ( ) Trimetaphan ( ) Mecamylamine Mecamylamine Shor-acting Shor-acting Tolerance Tolerance For controlling hypotension For controlling hypotension C. Antihypertensive Drugs Noradrenergic nerve ending blockers Reserpine ) Reserpine ) Guanethidine Guanethidine Decreasing NE storage in noradrenergic nerve endings Slow and lasting effects Central depression; GI reactions; digestive ulcer C. Antihypertensive Drugs HydralazineDihydralazine Sodium Nitroprusside Vasodilators Vasodilators Hydralazine 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 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 ( ) poisoning. C. Antihypertensive Drugs Potassium channel openers Including minoxidil ( ), nicorandil, diazoxide ( ), 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 ( ), 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 Applications of antihypertensive drugs in various patients 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