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抗高血压药物 Antihypertensive Drugs

抗高血压药物 Antihypertensive Drugs. Shi-Hong Zhang ( 张世红 ) Pharmacology, Dept. of shzhang713@zju.edu.cn. Outline. Overview of hypertension Classification of antihypertensive drugs Antihypertensive drugs Clinical pharmacology of antihypertensive drugs. 1. Overview of hypertension. Etiology:

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抗高血压药物 Antihypertensive Drugs

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  1. 抗高血压药物Antihypertensive Drugs Shi-Hong Zhang (张世红) Pharmacology, Dept. of shzhang713@zju.edu.cn

  2. Outline • Overview of hypertension • Classification of antihypertensive drugs • Antihypertensive drugs • Clinical pharmacology of antihypertensive drugs

  3. 1. Overview of hypertension

  4. Etiology: • Secondary hypertension (10~15%) • Essential (primary) hypertension (85~90%) High Risk Factors: • Stressful life-style • High dietary intake of sodium • Obesity and hyperlipidemia • Smoking • Hereditary factors (30%)

  5. Kidney Other Failure 2% 15% MI or CHF 50% Stroke 33% The end organ damage of hypertension: Kidney: renal failure Heart: coronary disease, cardiac failure Brain: stroke

  6. 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.

  7. 按危险分层，量化地估计预后 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。

  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 arteriolar volume Cardiac output Peripheral resistance Blood volume Contractility Filling pressure Heart rate Venous tone Baroreceptors and sympathetic nervous system RAAS

  10. Normal regulation of blood pressure:

  11. Actions of angiotensin II • Constricts vessels, increases peripheral resistance and returned blood volume. • Stimulates release of aldosterone. • Increases sympathetic tension, promotes release of sympathetic transmitter. • Induces expression of c-fos、c-myc、c-jun rapidly.

  12. Actions of Aldosterone McMahon EG 2001,

  13. 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)

  14. 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)

  15. 3. Antihypertensive Drugs 3.1 Diuretics Thiazide, loop, potassium-sparing diuretics Hydrochlorothiazide氢氯噻嗪, Chlortalidone氯噻酮, Indapamide吲达帕胺, etc A Antihypertensive actions • Reduce plasma volume (diuretic effect) • Reduce Na+-Ca2+ exchange in vascular smooth muscle cell(peripheral resistance  )

  16. 3. Antihypertensive Drugs 3.1 Diuretics ㈠ Thiazide diuretics （噻嗪类利尿药） ⊕ (+) parathyroid hormone （PTH,甲状旁腺激素）

  17. 3. Antihypertensive Drugs 3.1 Diuretics B Therapeutic uses: • Hypertension - First-line agents - Monotherapy or combined with others - Particularly useful in the treatment of elderly patients (high sodium and water volume, low renin), pure systolic hypertension, hypertension with heart failure • Edema

  18. 3. Antihypertensive Drugs 3.1 Diuretics C Adverse effects: - plasma level of renin - hypokalemia (低钾血症): more excretion of K+ through distal tubules. - hyperuricemia (高尿酸血症): competitive secretion from the proximal tubules - hyperglycemia (高血糖): inhibition of  cells in the islets - hyperlipidemia (高脂血症): inhibition of PDE in the liver

  19. 3. Antihypertensive Drugs 3.2 Calcium channel blockers (CCBs) Nifedipine 硝苯地平, nitrendipine尼群地平 amlodipine氨氯地平,felodipine非洛地平, etc A Actions: Relax vascular smooth muscle, especially in arterioles. B Therapeutic uses: first line, mild to severe hypertension (combined with  blockers when needed) C Adverse effects: peripheral edema, reflex sympathetic activation, and renin activity 

  20. 3. Antihypertensive Drugs 3.3 Renin-angiotensin system inhibitors ACEIs: captopril (卡托普利), enalapril (依那普利), lisinopril (赖诺普利), benazepril (贝那普利), fosinopril (福辛普利), etc. AR1Bs: Losartan (氯沙坦), valsartan (缬沙坦), erbesartan (厄贝沙坦), candesartan (坎地沙坦), telmisartan (替米沙坦), etc Renin inhibitors: renin antibody, peptide and nonpeptide renin inhibitors (eg. Aliskiren阿利吉仑)

  21. 血管紧张素原 激肽原 激肽释放酶 and NO Chymase Vasodilation, anti-proliferation, anti-hypertrophy

  22. 3. Antihypertensive Drugs 3.3 Renin- angiotensin system inhibitors ACEIs A Actions • Inhibit the production of Ang II (dilate vessels, decrease sympathetic activity, protect renal and cardiac function, inhibit release of aldosterone, anti-hypertrophy) • Inhibit the degradation of bradykinin(vasodilation, anti-hypertrophy, myocardial protection, improvement of insulin receptor sensitivity)

  23. 3. Antihypertensive Drugs ACEIs B Therapeutic uses • Hypertension - first line antihypertensive drugs - effective in the treatment of CHF, diabetes and ischemic heart disease. Benazepril is renal protective.

  24. 3. Antihypertensive Drugs ACEIs C Adverse effects Hypotension (first dose phenomenon) Renal injury (in patients with renal artery sclerosis) Dry cough and angioneuroedema (bradykinin accumulation) Hyperkalemia (aldosterone inhibition) Hypoglycemia (insulin sensitivity) Rashes and altered taste (-SH-related) Fetotoxicity (esp. during the second and third trimester, pregnancy category D) Adverse effects in the CNS and GI system

  25. 3. Antihypertensive Drugs ACEIs D Contraindications Renal artery stenosis (pressure-dependent kidney perfusion in these patients) Pregnant and lactation women

  26. 3. Antihypertensive Drugs • AR1Bs • Compared with ACEIs: • Block actions of angiotensin II on AR1 directly, enhance actions on AR2. • No influence on bradykinin metabolism • Renal protection: irbesartan and candesartan. • Avoid combination with ACEI, potassium-sparing diuretics.

  27. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.1 Adrenoreceptor blockers  receptor blockers Propranolol, atenolol, metoprolol, labetalol, carvedilol, etc A Actions • Decrease cardiac output • Inhibit renin release from kidney (formation of angiotensin and secretion of aldosterone )

  28. 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

  29. 3. Antihypertensive Drugs  receptor blockers B Therapeutic uses • Hypertension: mild to severe hypertension - more effective in young patients than elderly - useful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma, anxiety and migraine.

  30. 3. Antihypertensive Drugs  receptor blockers C Adverse effects - Asthma - AV block - Bradycardia - Cardiac inhibition - Hypo- or hyperglycemia - Hyperlipidemia

  31. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 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)

  32. 3. Antihypertensive Drugs 1 receptor blockers B Therapeutic uses • Hypertension: mild to moderate (single) and severe hypertension (combined with diuretics or β blockers) C Adverse effects First dose phenomenon (postural hypotension) Sodium retention (+diuretics)

  33. 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

  34. 3. Antihypertensive Drugs

  35. 3. Antihypertensive Drugs Clonidine B Therapeutic uses • Hypertension: mild to moderate • Abstinence of narcotic drugs C Adverse effects Dry month, sedation, constipation (inhibits gastrointestinal secretion and mobility), angioedema, rebound effect

  36. 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 effects to clonidine without rebound effect

  37. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.3 Ganglion blockers (nAChR blockers) Trimetaphan (樟磺咪芬) Mecamylamine (美卡拉明) Only used for hypertensive crisis, dissecting aortic aneurysm (主动脉夹层), controlled hypotension during surgery.

  38. 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) Only used as a component in compound preparations

  39. 3. Antihypertensive Drugs 3.5 Vasodilators Hydralazine (肼屈嗪) • Increase the release of NO 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.

  40. 3. Antihypertensive Drugs 3.5 Vasodilators Nitroprusside sodium (硝普钠) • Serves as a prodrug of NO • Dilates small arteries and veins • Used by iv injection 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).

  41. 3. Antihypertensive Drugs 3.5 Vasodilators Potassium channel openers • Including minoxidil, nicorandil, diazoxide, etc. • Dilates arteries (K+ efflux Ca2+ influx ) • Reflexly elevate heart rate, cardiac output and renin release. • Used for the treatment of obstinate and severe hypertension • Adverse effects include sodium retention, palpitation, etc.

  42. 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 andrequires treatment and must exclude secondary causes of hypertension that might be treated by definitive surgical procedures.

  43. 4. Clinical pharmacology of antihypertensive drug • 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 and dosages is indicated by the level of blood pressure, the presence and severity of end-organ damage, and the presence of other diseases. Drug combination is recommended for obstinate hypertension. • Educate the patient about the nature of hypertension, the importance of life-long treatment and the achievement of goal blood pressure, the potential side effects of drugs. 4.1 General information

  44. 4. Clinical pharmacology of antihypertensive drugs 4.2 Individualized therapy 1) Prescribe according to the severity of hypertension Mild: monotherapy from first line antihypertensive agents (thiazide diuretics, CCBs, ACEIs/ARBs),  blockers, 1 blockers Moderate: combine two of the above drugs Severe: combine three of the above drugs or add centrally acting drugs or vasodilators on the two combined drugs

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