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2013.5

Chapter 11 Antihypertensive Agents Weiping Zhang, MD. PhD. Associate professor Dept. Pharmacology, Medical School, Zhejiang University weiping601@zju.edu.cn. 2013.5. Antihypertensive Agents. Overview hypertension & regulation of blood pressure I. Basic pharmacology of antihypertensive agents

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2013.5

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  1. Chapter 11Antihypertensive AgentsWeiping Zhang, MD. PhD. Associate professorDept. Pharmacology, Medical School, Zhejiang Universityweiping601@zju.edu.cn 2013.5

  2. Antihypertensive Agents Overview hypertension & regulation of blood pressure I. Basic pharmacology of antihypertensive agents 1. Drugs that alter sodium & water balance; 2. Drugs that alter sympathetic nervous system function; 3. Vasodilators; 4. Agents that block RAAS; II. Clinical pharmacology of antihypertensive agents

  3. Blood Pressure and Risk for Coronary Heart Disease in Men Age 65-94 Age 65-94 Age-adjusted annualincidence of CHD per 1000 Age 35-64 Age 35-64 Diastolic blood pressure (mmHg) Systolic blood pressure (mmHg) Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease (CHD) at baseline Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.

  4. Twice as likely to progress to hypertension JNC – 7 Definitions (2003) JNC－8 Expected Release Date:  Fall 2011, spring 2012, still coming now

  5. Causes of death in patients with HTN

  6. The goal of treatment: • Lower the blood pressure; • Protect the target organ; • Reduce the morbidity and mortality rates; • Best therapy and minimal risk;

  7. Hypertension & regulation of blood pressure BP CO PVR Normal regulation of blood pressure Arterial blood pressure  Cardiac output  Peripheral Vascular resistance arteriolar tone Blood volume Heart rate Filling pressure Contractility Venous tone Baroreceptors and sympathetic nervous system Renin-angiotention-aldosterol system (RAAS)

  8. Hypertension & regulation of blood pressure Baroreflexes (mediated by autonomic nerves) Humoral mechanisms (include: RAAS system and local release of hormones from vascular endothelium, such as, NO, endothelin 1) Anatomic sites of blood pressure control

  9. Hypertension & regulation of blood pressure A. Postural baroreflex: responsible for rapid , moment to moment adjustments in blood pressure. • Sense the stretch of the vessel walls • from a reclining to an upright posture; • reduction of peripheral vacular resistance; • Reduction in intravascular volume; -

  10. Hypertension & regulation of blood pressure B. Renin-Angiotensin-Adolsteron (RAAS) Angiotensin II Redistribution of renal blood flow This is responsible for long-term blood pressure control.

  11. Basic pharmacology of antihypertension agents

  12. I. Basic pharmacology of antihypertension agents 1. Diuretics:depleting the sodium and reducing blood volume and perhaps by other mechanisms. 2. Sympathoplegic agents:reducing peripheral vascular resistance, inhibiting cardic output, increasing venous pooling. 3. Direct vasodilators:relaxing vacular smooth muscle, dilaing resistance vessels and/or increasing capacitance. 4. Agents that block RAAS:reduce peripheral vacular resistance and blood volume.

  13. 1. Diuretics（利尿药） • Sodium restriction is very preventive in the control of blood pressure. It is a nontoxic and therapeutic measure. 1) Pharmacological roles (1) Diurectic action: In the early stage: reducing blood volume and cardiac output; In the late stage: reduce peripheral vascular resistance (by reducing the Na+; reduce Na+-Ca2+ exchange in vascular smooth muscle cells (Ca2+i , peripheral resistance  ) Ca2+ Sodium channel [Na+]i ↓ ↓ Na+ Low blood [Na+]

  14. 1. Diuretics（利尿药） • Sodium restriction is very preventive in the control of blood pressure. It is a nontoxic and therapeutic measure. • Pharmacological roles • (2) Non diurectic action: • Direct vasodilating, e.g. Indapamide, a non-thiazide sullfonamide diuretic with both diuretic and vasodilator activity; • Amiloride inhibits smooth muscle responses to contractile stimuli.

  15. 1. Diuretics Selection of diuretcs Normally used in severe hypertension, in renal insufficiency and in cardiac failure or cirrhosis. Normally used in mild or moderate hypertension with normal renal and cardiac function. Useful to avoid excessive potassium depletion. Nephron, a functional unit of kidney Be careful increase blood pressure

  16. 1. Diuretics 2) Clinical application: diuretics alone for mild or moderate essential hypertension. Combine with sympathoplegic and vasodilator drugs to control the tendency toward sodium retention caused by these agents. Dosing considerations (thiazide vs. Furosemide) 100 - 200 mg thiazide diuretics are more natriurectic but the same effect of anti-hypertension is the same as 25 – 50 mg thiazide diuretcs. A threshold amount of body sodium depletion may be sufficient for anti-hypertensive efficacy. The blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose.

  17. 1. Diuretics Adverse effects of diuretcs（略） • Hypokalemia: K+ depletion (except for potassium – sparing diuretcs); hypokalemia may be hazardous in persons taking digitalis, who have chronic arrhythmias, acute myocardial infarction or left ventricular dysfunction. • Restriction of dietary Na+ intake will minimize K+ loss. • Mg2+ depletion; • Impair glucose tolerance, induce hyperglycemia; • Increase serum lipid concentrations, induce hyperlipidemia; • Hyperuricemia, precipitate gout;

  18. 2. Sympathoplegic agents Sedation, mental depression, sleep disturbance, dry mouth, analgesia More selective action Inhibition of parasympathetic regulation, profound sympathetic blockade Similar like surgical sympathectomy

  19. 2. Sympathoplegic agents 1) Centrally acting sympathoplegic drugs（略） Methyldopa: metabolize to -methyldopamine and - methylnorepinephrine; Its antihypertensive action appears to be due to stimulation of central  adrenoceptors by  methylnorepinephrine or  methldopamine.

  20. 2. Sympathoplegic agents 1) Centrally acting sympathoplegic drugs （略） • Clonidine: After intravenous injection, it produces a brief rise in blood pressure (direct stimulation of  adrenoceptors in arterioles) and flowed by a more prolonged hypotension (stimulation of  adrenoceptors in medulla). • Clonidine lowers heart rate and cardiac output more than methyldopa. • Pharmacological roles: -methylnorepinephrine and clonidine both bind more tightly to 2 than to 1 adrenoceptors. • They bind to presynaptic 2 adrenoceptor to reduce catercholamine release • Bind to postsynaptic 2 adrenoceptor to inhibit activity of appropriate neurons. • Clonidine also binds to nonadrenoceptor site, the imidazoline receptor, • Guanabenz and guanfacine:stimulat adrenoceptor

  21. 2. Sympathoplegic agents 1) Centrally acting sympathoplegic drugs （略） 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 Toxicity Central and atropine-like side effects Long-term uses: water and sodium retention rebound phenomenon

  22. 2. Sympathoplegic agents 2) Ganglion blocking agents

  23. 2. Sympathoplegic agents 2) Ganglion blocking agents X X X X

  24. 2. Sympathoplegic agents 2) Ganglion blocking agents（略） • The ganglion blocking agents block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. So the toxicities are intolerable. • Trimethaphan: pool the blood in capacitance vessels, the blood pressure due to the posture. • Adverse of trimethaphan: • sympathoplegia: excessive orthostatic hypotension, sexual • dysfunction; • parasympathoplegia: constipation, urinary retention, • precipitation of glaucoma, blurred vision, dry mouth.

  25. 2. Sympathoplegic agents 3) Adrenergic neuron-blocking agents

  26. 2. Sympathoplegic agents 3) Adrenergic neuron-blocking agents （略） Guanethidine: very efficacy but also toxicities like “pharmacologic sympathectomy”, including postural hypotension, diarrhea and impaired ejaculation. Guanadrel, bethanidine, debrisoquin are similar to guanethidine. Mechanism of guanethidine action: inhibit the release of NE from sympathetic nerve endings. EARLY reduce cardiac output due to bradycardia and relaxation of capacitance vessels. Chronic therapy: decrease the peripheral vascular resistance. Na+ and water retention may be marked during guanethidine therapy.

  27. 2. Sympathoplegic agents 3) Adrenergic neuron-blocking agents （略） Reserpine: block the ability of aminergic transmitter vesicles to take up and store biogenic amines. Depletion of peripheral amines and central component. Toxicity: Cerebral amine depletion cause sedation, lassitude, nightmare, mental depression and PD symptoms. Gastrointestinal tract amine depletion cause diarrhea, gastrointestinal cramps and increases gastric acid secretion.

  28.   2. Sympathoplegic agents 4) Adrenoceptor antagonists  receptor: 1 receptor: 2 receptor:  Receptor: 1 receptor: 2 receptor: Vasocontriction Inhibit NE release Strengthen HR and constriction Bronchial spasm

  29. 2. Sympathoplegic agents 4) Adrenoceptor antagonists  Receptor blockers: Propranolol (1) Mechanism & Sites of Action: nonselective –block in brain, kidney and heart etc.

  30. 2. Sympathoplegic agents 4) Adrenoceptor antagonists  Receptor blockers: Propranolol

  31. 2. Sympathoplegic agents 4) Adrenooceptor antagonists  Receptor blockers: Propranolol (2) Clinical uses A. 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 B. Other uses: angina pectoris; arrhythmias

  32. 2. Sympathoplegic agents 4) Adrenooceptor antagonists  Receptor blockers: Propranolol (3) Side effects A. Bradycardia or cardiac conduction disease (over inhibition); B. Asthma (Why); C. Peripheral vascular insufficiency D. Diabetes E. Withdrawal syndrome after prolonged regular use: nervousness, tachycardia, increased intensity of angina (even myocardial infarction), or increase of blood pressure;

  33. 2. Sympathoplegic agents 4) Adrenooceptor antagonists Other  Receptor blockers: (1) Metoprolol: has cardioselectivity, equal potent with propranolol in blocking 1 receptors but 50- to 100-fold less potent than propranolol in blocking 2-receptors. (2) Nadolol and carteolol, nonselective -receptor antagonists and atenolol, a 1-selective blocker are metabolized and are excreted in the urine. Betaxolol and bisoprolol, 1-selective blockers are primarily metabolized in the liver but have long half lives. Patients with reduced renal function or hepatic function should be careful.

  34. 2. Sympathoplegic agents 4) Adrenooceptor antagonists Other  Receptor blockers: (3) Pindolol, Acebutolol, & Penbutolol : partial agonists, ie, -blockers with intrinsic sympathomimetic activity. (4) Esmolol: a 1-selective blocker with very short half life time (~9 min). Rapidly metabolized via hydrolysis by red blood cell esterases. Normally esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia.

  35. 2. Sympathoplegic agents 4) Adrenoceptor antagonists Prazosin & Other 1 Blockers pinacidil, urapidil, and cromakalim. • Mechanism & Sites of Action: • Reduce arterial pressure by dilating both resistance and capacitance vessels. • Without affects on NE release (2 function) • blood pressure is reduced more in the upright than in the supine position. • Retention of salt and water occurs. • The drugs are more effective when used in combination with other agents, such as a -blocker and a diuretic, than when used alone.

  36. 2. Drugs that alter sympathetic nervous system function 4) Adrenooceptor antagonists Prazosin & Other 1 Blockers pinacidil, urapidil, and cromakalim. (2) Pharmacokinetics & Dosage: Although long-term treatment with these -blockers causes relatively little postural hypotension, it appears first-dose phenomenon- precipitous drop in standing blood pressure develops in a number of patients shortly after the first dose is absorbed.

  37. 2. Drugs that alter sympathetic nervous system function 4) Adrenooceptor antagonists Prazosin & Other 1 Blockers (1) Pharmacological effects • Relaxing arterial and venous smooth muscles • Decreasing peripheral resistance • Nonselective  receptor blocker: activation of baroreflex and RAA system; • Selective 1 receptor blocker: activation of baroreflex and RAA system at the beginning. (2) Clinical usage • Hypertension with benign prostatic hyperplasia

  38. 2. Drugs that alter sympathetic nervous system function 4) Adrenooceptor antagonists Prazosin & Other 1 Blockers pinacidil, urapidil, and cromakalim. • (2) Adverse effects : • Infrequent and mild • First dose phenomenon (postural hypotension) • Water and sodium retention  risk for heart failure • Dizziness, palpitations, headache, and lassitude.

  39. 2. Drugs that alter sympathetic nervous system function 4) Adrenooceptor antagonists  and1 Receptor blockers Blocker effect: >1>>2 Labetalol 拉贝洛尔 Carvedilol 卡维地洛 Amosulalol 氨磺洛尔

  40. 2. Sympathoplegic agents 4) Adrenooceptor antagonists  and1 Receptor blockers Labetalol is formulated as a racemic mixture of four isomers (S,S)- and (R,S)-isomers—are inactive (S,R)- is a potent -  blocker (1) (R,R)- is a potent -  blocker (3) Blood pressure is lowered by reduction of systemic vascular resistance without significant alteration in heart rate or cardiac output. Treating the hypertension of pheochromocytomaand hypertensive emergencies.

  41. 2. Sympathoplegic agents 4) Adrenooceptor antagonists Other  Receptor blockers: CarvedilolS(-), S(+), R(-), R(+) • S(–) isomer is a nonselective -receptor blocker • Both S(–) and R(+) isomers have approximately equal -receptor blocking potency. Nebivolol • D –Nebivolol1 blocker • L-Nevivolol causes vasoliating not mediated by  blocked. • Has active metabolites

  42. 2. Drugs that alter sympathetic nervous system function 4) Adrenooceptor antagonists  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: dose-fixed

  43. 2. Drugs that alter sympathetic nervous system function 4) Adrenooceptor antagonists

  44. 3. Vasodilators • Mechanism & Sites of Action • Hydralazine and minoxidil, which are used for long-term outpatient therapy of hypertension • Parenteral vasodilators, nitroprusside, diazoxide, and fenoldopam, which are used to treat hypertensive emergencies; • Calcium channel blockers, which are used in both

  45. 3. Vasodilators

  46. 3. Vasodilators • (2) Hydralazine （略） • Dilates arterioles but not veins. • A hydrazine derivative, dilates arterioles but not veins. • Disadvantage: tachyphylaxis to hypertensive effects developed rapidly. • Combination therapy are now suggested. Especially in severe hypertension. • Pharmacokinetics & Dosage • bioavailability is low (averaging 25%) because of the first pass metabolism and variable among individuals. The half-life of hydralazine ranges from 2 to 4 hours.

  47. 3. Vasodilators • (2) Hydralazine （略） • Adverse effects • Common: headache, nausea, anorexia, palpitations, sweating, and flushing. • In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias. • High dose or in patients with slow acetylate: arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus. • Infrequency but severe: Peripheral neuropathy and drug fever

  48. 3. Vasodilators • (3) Minoxidil: a potassium channel opener （略） • Dilates arterioles but not veins. • Can be used in patients with renal failure and severe hypertension, who do not respond well to hydralazine. • Pharmacokinetics & Dosage • Minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with –blocker and a loop diuretic. • Adverse effects • Tachycardia, palpitations, angina, and edema are observed when doses of -blockers and diuretics are inadequate. • Headache, sweating, and hirsutism, which is particularly bothersome in women,

  49. 3. Vasodilators • (4) Sodium Nitroprusside: （略） • Dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. • Powerful parenterally administered vasodilator • The mechanism: produce NO and stimulate guanylyl cyclase (GC), thus increase cGMP, which relaxes vascular smooth muscle. • Used in patients with hypertensive emergencies or severe heart failure. • In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, while cardiac output does not change or decreases slightly. • In patients with heart failure and low cardiac output, output often increases owing to afterload reduction.

  50. 3. Vasodilators • (4) Sodium Nitroprusside: （略） • Pharmacokinetics & Dosage • Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation. • The drug should be administered by infusion pump and arterial blood pressure continuously monitored via intra-arterial recording. • Sodium nitroprusside in aqueous solution is sensitive to light • Adverse effects • the most serious toxicity is related to accumulation of cyanide. • Thiocyanate may also accumulate, particularly in patients with renal insufficiency. • Rarely, delayed hypothyroidism occurs. • Methemoglobinemia

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