Antihypertensive Drugs

1. Pharmacology for cardiovascular system • 八年制课程 Antihypertensive Drugs 张翔南 xiangnan_zhang@zju.edu.cn

2. Contents: • Overview • Classification of antihypertensive drugs • Antihypertensive drugs • Clinical pharmacology of antihypertensive drugs

3. 1. Overview

4. 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.

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

6. 按危险分层，量化地估计预后

7. The end organ damage of hypertension: Kidney: renal failure Heart: coronary disease, cardiac failure Brain: stroke

8. 1. Overview The goal of treatment: Lower the blood pressure Protect the target organ Reduce the morbidity and mortality rates Best therapy and minimal risk

9. 1. Overview Major factors influencing blood pressure Arterial blood pressure  Cardiac output Peripheral resistance arteriolar volume  Blood volume Filling pressure Heart rate Contractility Venous tone Baroreceptors and sympathetic nervous system RAAS

10. 2. Classifications of hypertensive Drugs • Diuretics • Calcium channel blockers • Renin-angiotensin system inhibitors ACEIs ARBs Renin inhibitors

11. Sympathetic inhibitors Centrally acting adrenergic drugs Ganglion blockers Noradrenergic nerve ending blockers Adrenoreceptor blockers  receptor blockers  receptor blockers  and  receptor blockers • Vasodilators

12. 3. Antihypertensive Drugs 3.1 Diuretics A Actions • Reduce plasma volume(cardiac output ) • Reduce Na+-Ca2+ exchange in vascular smooth muscle cell(peripheral resistance  )

13. NaHCO3 NaCl Na+ Cl- K+ Na+ K+ Cl- H2O 高效能 中效能 低效能

14. 3. Antihypertensive Drugs 3.1 Diuretics B Therapeutic uses: • Hypertension - Single drug or combined with others - Particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart failure

15. Diuretics

16. 3. Antihypertensive Drugs 3.1 Diuretics C Adverse effects: plasma level of renin  hypokalemia (低钾血症) hyperuricemia (高尿酸血症) hyperglycemia (高血糖) hyperlipidemia (高脂血症)

17. 3. Antihypertensive Drugs 3.2 Calcium channel blockers (CCBs) Nifedipine 硝苯地平 A Actions • Relaxs vascular smooth muscle B Therapeutic uses: • Mild to severe hypertension (usually combined with  blockers )

18. 3. Antihypertensive Drugs nifedipine C Adverse effects Peripheral edema Reflex sympathetic activation Renin activity 

19. 3. Antihypertensive Drugs Other calcium channel blockers: Verapamil Diltiazem Nimodipine Amlodipine Felodipine

20. Generations of calcium channel blockers ①First generation: verapamil(维拉帕米), nifedipine(硝苯地平), diltiazem(地尔硫卓). ②Second generation:对血管选择性高. nimoldipine(尼莫地平), felodipine(非洛地平). ③Third generation:同上, 并且 t½长. pranidipine(普拉地平), amlodipine(氨氯地平). 粉防己碱

21. 3. Antihypertensive Drugs 3.3 Renin- angiotensin system inhibitors ACEIs ARBs Renin inhibitors

22. Angiotensin converting enzyme, ACE AT1

23. AngII 在器官损害中作用 中风 Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction 高血压 AngII AT1 receptor LV hypertrophy Fibrosis Remodelling Apoptosis 心衰 心肌梗塞 DEATH GFR Proteinuria Aldosterone release Glomerular sclerosis 肾衰 *Preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

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

25. Angiotensin converting enzyme inhibitors(ACEIs)

26. 3. Antihypertensive Drugs 3.3 Renin- angiotensin system inhibitors ACEIs A Actions • Inhibit the production of Ang II (dilate vessels, decrease sympathetic activity, inhibit release of aldosterone, anti-hypertrophy) • Inhibit the degradation of bradykinin

27. PGI2 NO Actions of ACEIs Inactive peptide Angiotensin II Brandykinin Angiotensin I ACEI (—) B2 receptor ACEI ACE Circulation and local tissues (—) ACE Circulation and local tissues Vasodilation Anti-proliferation, anti-hypertrophy

28. 3. Antihypertensive Drugs ACEIs B Therapeutic uses • Antihypertension - without reflexly increasing the activity of sympathetic system - effective in the treatment of CHF, diabetes and ischemic heart disease.

29. 3. Antihypertensive Drugs ACEIs C Adverse effects Hypotension ( first dose phenomenon ) Renal injury (renal artery sclerosis ) Dry cough and angioneuroedema (bradykinin accumulation) Hyperkalemia (aldosterone inhibition) Rashes and altered taste Fetotoxicity

30. 3. Antihypertensive Drugs ACEIs D Contraindications Renal artery stenosis Pregnant and lactation women

31. 3. Antihypertensive Drugs • ARBs • Compared with ACEIs: • Block actions of angiotensin II directly • No influence on bradykinin metabolism • Protect renal function • Used for mild to moderate hypertension • Less adverse effects

32. 3. Antihypertensive Drugs • Renin inhibitors • Inhibit whole RAAS • Include renin antibody, peptide and nonpeptide renin inhibitors (eg. remikiren)

33. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.1 Adrenoreceptor blockers  receptor blockers A Actions • Decrease cardiac output • Inhibit the release of renin from kidney (formation of angiotension and secretion of aldosterone )

34. 3. Antihypertensive Drugs  receptor blockers A Actions • Decrease sympathetic outflow from CNS and release of noradrenalin from peripheral nerve endings • Increase production of PGs • Increase sensitivity of baroreceptor

35. 3. Antihypertensive Drugs  receptor blockers B Therapeutic uses • 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

36. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.1 Adrenoreceptor blockers 1 receptor blockers A Actions • Relax arterial and venous smooth muscle, decrease peripheral resistance • Alterations in serum lipid patterns

37. 3. Antihypertensive Drugs 1 receptor blockers B Therapeutic 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

38. 3. Antihypertensive Drugs 1 receptor blockers C Adverse effects First dose phenomenon (postural hypotension) sodium retention

39. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.1 Adrenoreceptor blockers  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

41. 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 2 receptor in medulla - activates I1 receptor in medulla

42. 3. Antihypertensive Drugs Clonidine B Therapeutic uses • Hypertension: mild to moderate - minimal changes in renal blood flow and glomerular filtration - inhibits gastrointestinal secretion and mobility

43. 3. Antihypertensive Drugs Clonidine C Adverse effects Atropine-like effects Water and sodium retention (renal filtration ) Rebound phenomenon

44. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.2 Centrally-acting drugs I1 receptor agonists Rilmenidine Moxonidine

45. 3. Antihypertensive Drugs 3.4 Sympathetic system inhibitors 3.4.3 Ganglion blockers Trimetaphan(米噻芬) Mecamylamine（美卡拉明）

46. 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)

47. 3. Antihypertensive Drugs 3.5 Vasodilators Hydralazine (肼屈嗪) • Dilates arteries and arterioles • Decreases peripheral resistance • Reflexly elevates heart rate, cardiac output and renin release. • Administrated with  blockers and diuretics. • Adverse effects due to vasodilation and lupus-like syndrome can occur.

48. 3. Antihypertensive Drugs 3.5 Vasodilators Nitroprusside sodium (硝普钠) • Dilates 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.

49. 3. Antihypertensive Drugs 3.5 Vasodilators Potassium channel openers • Including minoxidil, nicorandil, diazoxide, etc. • Dilates arteries (Ca influx ) • Reflexly elevates heart rate, cardiac output and renin release. • Used for treatment of obstinate and severe hypertension • Adverse effects include sodium retention, palpitation, etc

50. 4. Clinical pharmacology of Antihypertensive Drug 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.