1. Pharmacotherapy of Heart Failure 心衰的药物治疗

2. 1 Introduction Definition of heart failure:
Heart failure is a complex of symptoms (include tachycardia, decreased exercise tolerance, shortness of breath, peripheral and pulmonary edema, and cardiomegaly [,kɑːdɪəʊ'megəlɪ]心脏肥大) that are related to the inadequate perfusion of tissue during exertion [iɡ'zə:ʃən]活动 and often to the retention of fluid.
Its primary cause is an impairment of the heart’s ability to fill or empty the left ventricle ['ventrikl]心室 properly.

4. Peripheral edema in heart failure

5. Pulmonary edema in heart failure

6. Cardiac remodeling

7. Pathophysiologic mechanisms of heart failure

8. 2 Drugs used in heart failure
Diuretics
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Beta receptor blockers
Cardiac glycosides ['ɡlaikəusaid]强心苷类
Vasodilators

9. 2.1 Diuretics
Drugs: Loop diuretics 髓袢利尿药/高效利尿药are widely used; the thiazide diuretics have a more restricted role in the treatment of CHF, but they exhibit synergism with loop diuretics; Effects: To improve the "congestive" symptoms; Mechanism: Reducing extracellular fluid volume and ventricular filling pressure (or "preload"); Adverse Effects: Hypokalemia [,haipəukə'li:mjə]低血钾 should be corrected by potassium supplementation or addition of a potassium-sparing diuretic 留钾利尿药.

10. Take-home messages:
1 Diuretics retain a central role in the pharmacological management of the "congestive" symptoms in patients with heart failure;
2 Despite the efficacy of diuretics in controlling congestive symptoms and improving exercise capacity, the use of diuretics, with the exception of aldosterone [,ældəu'sterəun]醛固酮 antagonists, does not reduce mortality [mɔː'tælɪtɪ] 死亡率 in heart failure.

11. 2.2 Inhibitors of the renin-angiotensin system:
2.2.1 ACE inhibitors：
Pharmacological effects:
1) Reducing peripheral resistance (by reducing Ang II) and thereby reduce afterload;
2) Reducing salt and water retention (by reducing aldosterone secretion) and thereby reduce preload;
3) Reducing sympathetic activity through diminution [,dimi'nju:ʃən]减少 of angiotensin’s presynaptic effects on norepinephrine [,nɔ:repi'nefrin, -ri:n]去甲肾上腺素 release;
4) Reducing the long-term remodeling of the heart and vessels.

12. Take-home messages:
A number of placebo-controlled trials have demonstrated that ACE inhibitors improve survival in patients with overt heart failure due to systolic ventricular dysfunction.
The CONSENSUS Study (Cooperative North Scandinavian Enalapril Survival Study, 1987): a 40% reduction in mortality;
The Studies On Left Ventricular Dysfunction (SOLVD Investigators, 1991) Trial: a 16% reduction in mortality;
The Survival And Ventricular Enlargement trial (SAVE) (Pfeffer et al., 1992): a 20% reduction in mortality and a 36% reduction in the rate of progression to severe heart failure.

13. 2.2.2 AT1 receptor antagonists
AT1 blockers could be used as an alternative to ACE inhibitors in heart failure patients who do not tolerate ACE inhibition;
AT1 antagonists provide a mortality benefit that is similar in magnitude to that achieved with ACE inhibitors.

14. 2.3 β adrenergic receptor antagonists

15. Mechanism of action:
Antiarrhythmic [,æntɪə'rɪðmɪk] 抗心律失常的 and anti-ischemic [ɪ’skemɪk] 抗缺血的 effects: reduction in the incidence of sudden death;
Improvement in left ventricular structure and function with a decrease in chamber size and an increase in ejection fraction.

16. Caveats in clinical use of β adrenergic receptor antagonists in heart failure
1. β Adrenergic receptor antagonists should be initiated at very low doses, generally less than one-tenth of the final target dose.
2. These drugs should be increased slowly, over the course of weeks, and under careful supervision.
3. Although limited experience with NYHA Class IIIB and IV patients suggests that they may tolerate β blockers and benefit from their use, this group of patients should be approached with a high level of caution.
4. There is almost no experience in patients with new-onset, recently decompensated 失代偿的 heart failure. There are theoretical reasons for caution in such patients, and at present they should not be treated with β blockers until after they have stabilized for several days to weeks.

17. Take-home messages:
β antagonists improve symptoms, reduce hospitalization, and decrease mortality in patients with mild and moderate heart failure
Metoprolol: decreased all-cause mortality by 34%;
Carvedilol: 65% reduction in all-cause mortality;
Bisoprolol: 34% reduction in all-cause mortality.

18. 2.4 Cardiac glycosides

19. 2.4.1 Pharmacokinetics of digoxin
Absorption: most digoxin[didʒ'ɔksin]地高辛 tablets average 70% to 80% oral bioavailability; however, approximately 10% of the general population harbors the enteric [en’terɪk]肠的 bacterium [bæk'tɪərɪəm]细菌Eubacterium lentum, which can convert digoxin into inactive metabolites, and this may account for some cases of apparent resistance to standard doses of oral digoxin; Elimination: the elimination half-life for digoxin is 36 to 48 hours in patients with normal or near-normal renal function; Excretion: digoxin is excreted by the kidney with a clearance rate that is proportional to the glomerular [ɡlɔ‘merjulə]肾小球的filtration rate;

20. 2.4.2 Cardiac effects:
1 Positive inotropic [,inə'trɔpik] 影响肌肉收缩力的effect; 2 Electrophysiological actions;

21. 2.4.2.1 Mechanism of the positive inotropic effect:
Inhibition of Na+-K+-ATPase
Inhibition of cellular Na+ pump results in a reduction in the rate of active Na+ extrusion and a rise in cytosolic Na+. This increase in intracellular Na+ reduces the transmembrane Na+ gradient that drives the extrusion of intracellular Ca2+ during myocyte repolarization. With reduced Ca2+ efflux and repeated entry of Ca2+ with each action potential, Ca2+ accumulates in the myocyte: Ca2+ uptake into the sarcoplasmic reticulum (SR肌浆网) is increased; this increased Ca2+ becomes available for release from the SR onto troponin C and other Ca2+-sensitive proteins of the contractile apparatus during the next cycle of excitation-contraction coupling, thereby augmenting myocyte contractility.

23. 2.4.2.2 Electrophysiological actions
Atrial ['eitriəl; 'ɑ:triəl]心房的and ventricular myocytes, sinoatrial [,sainəu‘etriəl]窦房的and atrioventricular [,eitriəuven'trikjulə]房室的 (AV) nodal cells, and conduction fibers exhibit different responses to cardiac glycosides that are summations of direct responses and neurally['njuərəlli]-mediated神经系统介导的 reflex responses.

24. Cardiac toxicity: arrhythmias [ə‘riðmiəs] 心律失常
2.4.3 Digoxin toxicity
Cardiac toxicity: arrhythmias [ə‘riðmiəs] 心律失常
Sinus [‘saɪnəs] 窦房结 bradycardia [,brædɪ’kɑːdɪə]心动过缓, sinoatrial arrest or exit block传导阻滞, and second- or third-degree AV conduction delay: atropine 阿托品;
Ventricular arrhythmias: Lidocaine ['lidəukein] 利多卡因or phenytoin [feni'təuin]苯妥英,

25. Gastrointestinal tract:
Anorexia [,ænə‘reksɪə]厌食, nausea [ˈnɔ:ziə]恶心, vomiting, and diarrhea [,daɪə’riə] 腹泻;
Central nervous system:
Vagal ['veiɡəl]迷走神经的 and chemoreceptor [,keməuri'septə]化学受体 trigger zone stimulation; disorientation [dis,ɔ:rien‘teiʃən]定向障碍 and hallucinations [hə,lu:si’neiʃən] 幻觉, visual disturbances including aberrations of color perception [pə'sepʃ(ə)n]感觉.

26. 2.4.4 Clinical use of digoxin in heart failure
Digoxin is no longer viewed as a first-line agent in the treatment of congestive heart failure;
Digoxin is a therapeutic option in patients who remain symptomatic despite treatment with agents that improve survival;
Digoxin does not have an adverse impact on mortality in CHF.

27. Supplementary reading
Drugs are selected that target the hemodynamic derangements that are thought to be responsible for symptoms. In addition to the use of diuretics and load-reducing therapies for relief of congestive symptoms, antagonism of the renin-angiotensin system and the sympathetic branch of the autonomic [,ɔ:təu‘nɔmik] 自主的 nervous system are indicated to prevent further myocardial injury, thereby attenuating disease progression. In the ambulatory patient 可自主活动的病人 in a compensated hemodynamic state, diuretics and organic nitrates 硝酸酯类 are used to establish and maintain euvolemia [ju’vɔlimiə]正常体液容量; vasodilators are used to reduce the systemic vascular resistance in order to optimize forward cardiac output. While maintenance of forward cardiac output will help to attenuate neurohumoral [,njuərəu'hju:mərəl]神经体液的 activation, agents that antagonize the effects of Ang II and sympathetic stimulation are indicated; ACE inhibitors and AT1 receptor antagonists are the agents of choice. Treatment with β blockers should be undertaken when hemodynamic stability is established and treatment with aldosterone antagonists considered in patients with preserved renal function. Digoxin is now primarily used for persistent symptoms in the ambulatory patient; this drug does have positive inotropic effects and independent effects that are mediated via neurohormonal antagonism. However, there are no data that cardiac glycosides decrease mortality.

28. 大纲要求
掌握强心甙的作用、用途、不良反应及防治。
了解非强心甙类抗心功能不全药的作用特点。