1. Antihypertensive Drugs
Pharmacology for cardiovascular system
八年制课程
Antihypertensive Drugs
张翔南

2. Contents: Overview Classification of 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 annual incidence of CHD per 1000
Age 35-64
Age 35-64
Systolic blood pressure (mmHg)
Diastolic 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%)
High Risk Factors of Hypertension:
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 其它危险因素和病史 血压 I级 II级 III级 Ⅰ 无其它危险因素 低危 中危 高危 Ⅱ1~2 个危险因素
很高危
Ⅲ≥3 个危险因素
Ⅳ靶器官损害或糖尿病并存的临床情况
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。

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. Baroreceptors and sympathetic nervous system
1. Overview
Major factors influencing blood pressure
Arterial blood
pressure 
Cardiac
output 
Peripheral
resistance
arteriolar
volume
Blood
volume
Heart
rate
Contractility
Filling
pressure
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
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. Endothelial dysfunction
AngII 在器官损害中作用
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction 中风
高血压
AngII AT 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-jun rapidly.

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. Actions of ACEIs Angiotensin II Inactive peptide Brandykinin
(—)
ACEI
B 2 receptor
(—)
ACE
Circulation and local tissues
PGI2 NO
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
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
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
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
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
Centrally-acting drugs
I1 receptor agonists
Rilmenidine
Moxonidine

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

46. 3. Antihypertensive Drugs
3.4 Sympathetic system inhibitors
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 and requires treatment and must exclude secondary causes of hypertension that might be treated by definitive surgical procedures.

51. 4. Clinical pharmacology of Antihypertensive Drug
4.1 General information
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 Begin the drug treatment or not.
Selection of drugs is dictated by the level of blood pressure, the presence and severity of end-organ damage, and the presence of other diseases.
Educate the patient about the nature of hypertension, the importance of treatment and the potential side effects of drugs.

52. 4. Clinical pharmacology of Antihypertensive Drug
4.2 Out-patient therapy
In general:
Sodium restriction: A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day
Weight reduction;
Regular exercise;

53. Lifestyle modifications to manage hypertension
BMI:身体质量指数
the Dietary Approaches to Stop Hypertension (DASH) diet

54. Monotherapy Versus Polypharmacy
1Goal blood pressure for patients:
Young and middle-age adults:
< 130 / 85 mmHg;
With diabetes:
With renal disease:
With renal disease and proteinuria:
< 125 / 75 mmHg

55. 4. Clinical pharmacology of Antihypertensive Drug
Prescribe according to the severity of hypertension
Mild: diuretics,  blockers, ACEIs, CCBs, 1 blockers, ARBs (first line, single drug)
Moderate: combine two above drugs
Severe: add centrally acting drugs or vasodilators on the two combined drugs

56. 4. Clinical pharmacology of Antihypertensive Drug
Prescribe according to complications
Complications
Options
Avoidance
Severe CHF and/or
COPD
Diuretics, ACEIs, prazosin
 blockers
Renal failure
ACEIs, CCBs
Tachycardia
GI ulcer
Clonidine
Reserpine
Diabetes and gout
ACEIs, prazosin
Thiazide

57. 4. Clinical pharmacology of Antihypertensive Drug
Prescribe according to complications
hypertensive emergency: vasodilators (nitroprusside sodium, diazoxide), labetalol, loop diuretics
elderly patients:avoiding drugs that could induce postural hypotension and influence the cognizant ability (clonidine)

58. 4. Clinical pharmacology of Antihypertensive Drug
Avoid blood pressure to decrease too rapidly and excessively

59. References Basic & Clinical Pharmacology (10th edition), 2007.
Lipincott’s illustrated reviews - Pharmacology (2nd edition), 2002
《药理学》，杨世杰主编，人民卫生出版社，2005
《基础医学教程各论》，陈季强主编，科学出版社，2004