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Antihypertensive drugs

Antihypertensive drugs. Lou haiyan louhaiyan@sdu.edu.cn. Section 1 Introduction. Definition Hypertension is defined as a sustained diastolic blood pressure (DBP) greater than 90mmHg or systolic blood pressure (SBP) greater than 140mmHg. Bp≥ 140/90mmHg. Morbidity: 15%~ 20%.

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Antihypertensive drugs

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  1. Antihypertensive drugs Lou haiyan louhaiyan@sdu.edu.cn

  2. Section 1 Introduction • Definition Hypertension is defined as a sustained diastolic blood pressure (DBP) greater than 90mmHg or systolic blood pressure (SBP) greater than 140mmHg. Bp≥ 140/90mmHg Morbidity: 15%~ 20%

  3. Complication:

  4. The Types of Hypertension • Essential hypertension 90% • Secondary hypertension 10%

  5. Primary (essential) hypertension • Nearly 90% of patientshave no specific cause. • Elevated blood pressure is usually caused by several abnormalities such as genetic inheritance, psychological stress, dietary factors. • Treatment: Such hypertension can be controlled by some combination of antihypertensive drugs and changes in daily habits.

  6. Secondary hypertension • 10% -15% of patientshas a specific cause, such as renal artery constriction, primary aldosteronism or tumors of the adrenal glands (pheochronocytoma). • Treatment:

  7. Pathophysiology of hypertension • Genetic factor • Activation of sympathetic nervous system • Activation of RAAS （renin-angiotensin-aldosterone system） • Na+ • Dysfunction of vascular endothelium

  8. Normal regulation of blood pressure Peripheral vascular resistance (PVR) Cardiac output (CO) Arterial blood pressure ≈ × Heart rate Filling pressure Arterial volume Contractility

  9. Cardiac outrput Activation of β1-R on heart sympathetic activity Peripheral resistance Activation of α1-R on smooth muscle Increase in BP Aldosterone AngiotensinII Renin sodium, water retention blood volume Response mediated by the renin-angiotensin-aldosterone system Response mediated by the sympathetic nervous system

  10. 全国高血压日历年主题 10月8日 1998年：“了解您的血压”。 1999年：“控制高血压，保护心脑肾”。 2000年：“普及高血压知识，减少高血压危害”。 2001年：“控制高血压，享受健康生活”。 2002年：“战胜高血压从社区做起！” 2003年：“保持健康生活方式，控制高血压” 2004年：“高血压与代谢综合征”。 2005年: “血压与卒中”。 2006年: “降压达标”

  11. Treatment of hypertension • Diet • Loss weight • Exercise • Antihypertensive drugs

  12. 高血压的治疗目标 • 确切降压 • 稳定降压 • 阻断RAS,减轻或逆转靶器官损伤，降低并发症的发生率和病死率。 • 抗高血压治疗的目标血压：一般 < 140/90mmHg糖尿病、肾病患者< 130/80mmHg

  13. The classification of antihypertensive agents • 1. Diuretics • 2. Calcium channel blocks • 3. RAS inhibitors: • ACEI( angiotensin converting enzyme inhibitors) • AT1 receptor antagonist (angiotensin Ⅱ typeⅠ receptor antagonist ) • Renin inhibitors

  14. 4. Sympathoplegic agents: • Centrally acting agents • Ganglion-blocking agents • Adrenergic neuron-blocking agents • Adrenoceptor antagonist • β-adrenergic antagonist • α1-adrenergic antagonist • Mixed adrenergic antagonist • 5. Vasodilators • Direct vasodilators • Potassium channel openers

  15. Section 2 Basic Antihypertensive Drugs

  16. Ⅰ. Diuretics 1. Thiazide Diuretics (moderate efficacy diuretics): • Hydrochlorothiazide • Chlorothiazide • Characteristics: Mildness, Lasting, No tolerance. Decrease morbidity and mortality of hypertension complications after long-term use.

  17. The Mechanism for Reduction of BP • 1. Early:↑ Na+ and H2O excretion, ↓extracellular volume and blood volume , ↓ cardiac output • 2. Long:↓ Na+ of vessel wall, ↓ Na+-Ca2+ exchange, ↓ intracellular Ca2+, ↓ sensitivity of VSM to vasoconstrictors (NE). • 3. Dilate VSM directly

  18. Thiazide diuretics initial Long-term sodium, water retention Na+ in vessel wall Na+-Ca2+ exchange blood volume Ca2+ in smooth muscle cell Cardiac outrput Peripheral resistance Decrease in BP The mechanism for reduction of BP of thiazide Diuretics

  19. Clinical Uses and evaluation Low-doseof thiazide diuretic therapy is safe, effective and cheap for hypertension. • Thiazide diuretics are appropriate for most patients with mild or moderate hypertension, particularlyelderly patients. • Low doses of hydrochlorothiazide (25-50mg/d) exert as much antihypertensive effect as do higher doses.

  20. Adverse Effects 1.Thiazide diuretics induce electrolyte disturbance: hypokalemia, hypomagnesaemia, hyposodium et al 2. Thiazide diuretics can increase TC, TG, LDL level and renin activity, impair glucose tolerance. Therefore diuretics should be avoided in treatment of hypertensive diabetics or patients with hyperlipidemia.

  21. Indapamide(吲哒帕胺） • Increase in renal Na+ excretion diuresis • Dilate the vascular smooth muscle • Have no effect on the serum lipids

  22. 2. Loop diuretics (high efficacy diuretics): furosemide, etacrynic acid. The loop diuretics act promptly and can be used in hypertensive emergencies or hypertension combined with renal function failure.

  23. 3. Potassium-sparing diuretics (low efficacy diuretics): spironolactone, amiloride. Potassium-sparing diuretics are useful both to avoid excessive potassium depletion and to enhance the natriuretic effect of other diuretics.

  24. II.Adrenergic Receptor Blockers 1. β-receptor blockers Propranolol Metoprolol Atenolol

  25. The Mechanism of Action • (1) Blocking β1-Rof heart, ↓ cardiac output . • (2) Blocking β1-R of kidney, inhibit renin release, ↓ RAS activity. • (3) Blocking peripheral sympathetic presynaptic β2- R ,↓ NA release . • (4) Blocking β-R of CNS , ↓ peripheral sympathetic activity. • (5) Increase synthesis of PGI2.

  26. blocken ofβ-R in peripheral and central nervous system Inhibit NA release and vasomotor center blocken of β1-R on heart Cardiac outrput β-R blockers Peripheral resistance Decrease in BP PGI2 synthesis Renin AngiotensinII Aldosterone sodium, water retention blood volume The mechanism for reduction of BP of β-R blockers

  27. Clinical Uses and Evaluation • All types of hypertension , especially in high renin activity and high cardiac output • The β-Blockers are useful in treating conditions that may coexist with hypertension, such as superventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, migraine headache.

  28. Adverse effects • (1) Common effects: CNS side effects: fatigue, lethargy, insomnia; Sexual dysfunction (impotence) can severely reduce patient compliance. • (2) Alteration in serum lipid patterns: decrease HDL and increase plasma triacylglycerol (TG). • (3)Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of β receptor.

  29. Application Attention • (1) Be avoided in treating patients with (Contraindication) serious AV conduction block, bradycardia, bronchial asthma, peripheral vascular disease, et al. • (2) Beginning with small dose: (individual variation is larger) • (3) Combining with diuretics

  30. 2.α1-adrenoreceptor antagonist • Prazosin (哌唑嗪) • Terazosin (特拉唑嗪) Pharmacological Action : • Blocking α1-R selectively Dilate A and V vessel BP↓

  31. Merit : • Do not reduce the renal blood flow • Do not increase renin activity • Do not reflex increase in heart rate • ↓TG, TC, LDL-c, ↑ HDL-c

  32. Clinical uses • All types hypertension , be united with β-R blockers and diuretics. • Prostate hypertrophy Untoward Reactions • 1. First dose phenomenon • 2. Retention of salt and fluid

  33. 3. αandβ-Receptor Antagonist Labetalol (拉贝洛尔） Carvedilol (卡维地洛） Blocking β1= β2 > α1 • Blocking α1 and β-R ,↓ BP • Light effect on heart rate and cardiac output • Used for all types of hypertension

  34. III. Calcium Channel Blockers • Nifedipine (硝苯地平） • Amlodipine（氨氯地平） • Verapamil （维拉帕米） • Diltiazem （地尔硫卓）

  35. Mechanism of Antihypertension: • Calcium antagonists block the entry of calcium into the smooth muscle of the blood vessels, causing it to dilate. • Certain types such as verapamil and diltiazem can also slow the heart rate and inhibit cardiac contractility.

  36. Therapeutic uses Calcium channel blockers are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

  37. Nifedipine • 1. Action of dilating vessel is stronger than other calcium antagonist. • 2. Treatment of all types hypertension. • 3. Reflex increase in sympathetic activity: tachycardia, ↑CO ,↑renin activity • 4. Short action , can increase mortality if used for long time.

  38. Amlodipine Amlodipine belongs to long-acting calcium channel blockers which are better than nifedipine. • (1) It takes effect slowly (1--2w), lower BP steadily and continuously • (2) It does not affect heart obviously. • (3) It can reverse myocardial hypertrophy.

  39. Ⅳ . Inhibitors of RAS

  40. Angiotensinogen Bradykinin Renin AngiotensinI Increased prostaglandin synthsis ACE ACE inhibitors AngiotensinII inactive ARB vasodilation vasoconstrition Aldosterone Peripheral resistance Peripheral resistance sodium, water retention Decrease in BP Increase in BP RAAS and its inhibitors

  41. 1. Angiotensin Converting Enzyme Inhibitors(ACEI) • Catopril (卡托普利) • Enalapril (依那普利) • Cilazapril (西拉普利) • Benazapril (贝那普利) • Ramipril (雷米普利)

  42. The Mechanism of Action • 1. Inhibit ACE that cleaves Ang I to form the potent vasoconstrictor Ang II both in circulating system and local tissue. • 2. diminish the degradation of bradykinin---increase bradykinin levels----increase the release of NO, PGI2 • 3.inhibit NA release, inhibit RAS in CNS, and decrease central and peripheral sympathetic nerve activity

  43. The Mechanism of Action • 4. Inhibit generation of AngII in local tissue, inhibit or reverse myocardial and vascular remodeling • 5. Decrease the secretion of aldosterone, result in decreased sodium and water retention. • 6. Protect vascular endothelial cell

  44. The Merits of Treatment of Hypertension • 1. Have no tachycardia • 2. Prevent or reverse proliferation and hypertrophy of VSMC and myocardial cells • 3. Increase renal blood flow and protect renal function. • 4. Have no electrolyte disturbance and lipid metabolism disturbance • 5. Improve life quality , ↓ mortality

  45. Clinical Use • 1. The ACE inhibitors are appropriate for most patients with mild or moderate hypertension, particularly hypertension with high renin activity. • 2. The ACE inhibitors are useful in treating conditions that may coexist with hypertension, such as CHF, myocardial ischemia, diabetes.

  46. Adverse Reactions • hypotension (2%), • dry cough (5-20%), • angioedema, • hyperkalemia, • influence on development of fetus.

  47. 2. Angiotensin II Receptor Antagonist (AT1- Receptor Blocking Agents) • Losartan (氯沙坦） • Valsartan（缬沙坦） • Irbesartan（厄贝沙坦）

  48. Pharmacological Actions Arrest Ang II combine with AT1R • 1. More selective blockers of AⅡ effects than ACEI • 2. No effect on bradykinin metabolism Clinical Use and Evaluation • 1. The action is similar to that of ACEI • 2. Does not cause cough and angioedema .

  49. Section 3 Other Hypotensors 1.Centrally-acting sympathoplegic drugs 2. Vasodilators

  50. 1.Centrally-acting sympathoplegic drugs

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