臨床藥理-治療充血性心力衰竭藥物課件

1、治療充血性心力衰竭藥物 Drugs for Congestive Heart Failure 心力衰竭（heart failure）是各種原因引起的心肌舒縮障礙，導(dǎo)致心輸出量不能滿足機(jī)體需求的一組臨床綜合征。充血性心衰是其中最主要的一種。慢性或充血性心力衰竭（congestive heart failure, CHF）是各種病因所引起的多種心臟疾?。ü谛?、高心、肺心、風(fēng)心、心肌病等）的終末階段，當(dāng)靜脈回流足夠的情況下，心臟排出量絕對(duì)或相對(duì)減少，不能滿足機(jī)體組織需求的一種臨床或病理綜合征。 心衰病人運(yùn)動(dòng)耐量下降，壽命縮短。Concept:CHF is a complex clinical syn

2、drome characterized by impaired ventricular performance, exercise intolerance, a high incidence of ventricular arrhythmias, and shortened life expectancy The signs and symptomsThe signs and symptoms of heart failure include tachycardia, decreased exercise tolerance and shortness of breath, periphera

3、l and pulmonary edema, and cardiomegaly. 動(dòng)脈系統(tǒng)缺血- 乏力，氣短，頭暈靜脈系統(tǒng)淤血- 水腫，頸靜脈怒張，肝脾腫大，呼吸困難靜脈淤血所致的癥狀為主。心衰的分級(jí)（NYHA標(biāo)準(zhǔn)）級(jí)：心功能代償完全，體力活動(dòng)不受限，日?；顒?dòng)無乏力，心悸，呼吸困難等癥狀；級(jí)：輕度代償不全，活動(dòng)輕度受限，休息時(shí)無癥狀；級(jí)：中度代償不全，體力活動(dòng)明顯受限，日?；顒?dòng)即可產(chǎn)生癥狀。限于室內(nèi)活動(dòng)；級(jí)：嚴(yán)重代償不全，休息時(shí)亦有癥狀，不能從事任何體力活動(dòng)。心力衰竭不是一種獨(dú)立的疾病，而是由多種原因引起的心肌收縮和/或舒張功能障礙的綜合征。近年來的研究發(fā)現(xiàn)，心力衰竭雖然主要表現(xiàn)為心肌收縮和舒

4、張功能障礙，但神經(jīng)內(nèi)分泌的改變對(duì)其惡性循環(huán)的形成和維持有重要的作用。這些變化導(dǎo)致心臟出現(xiàn)不可逆的重構(gòu)(remodeling)，使衰竭的心臟一步步惡化。Pathophysiology心力衰竭時(shí)機(jī)體的代償機(jī)制:Augmented sympathetic activity Sodium and water retention Myocardial hypertrophy Ventricular dilatation1心臟本身的代償心率加快、心肌收縮加強(qiáng)-快速發(fā)生心臟擴(kuò)大和肥大緩慢發(fā)生是心臟本身儲(chǔ)備功能的動(dòng)員。2 心臟外的代償血容量增加血液重分配及紅細(xì)胞增多等幾方面的心臟外代償作用。機(jī)體的代償機(jī)制雖然

5、有助于維持機(jī)體所需的心輸出量要求，但長(zhǎng)時(shí)間代償機(jī)制的激活可加重心臟的負(fù)擔(dān)。在CHF的長(zhǎng)期發(fā)病過程中，各種代償機(jī)制對(duì)心臟和動(dòng)脈血管等的影響可產(chǎn)生惡性循環(huán)，加重心臟負(fù)擔(dān)，最終加重心力衰竭。實(shí)際上慢性心衰的發(fā)展過程就是在心肌氧供不足和維持機(jī)體循環(huán)血供需求之間不斷平衡的矛盾發(fā)展過程。慢性心衰的藥物治療：應(yīng)減輕負(fù)荷，降低能耗，保護(hù)心臟。達(dá)到改善血流動(dòng)力學(xué)；改善運(yùn)動(dòng)耐量；延長(zhǎng)生命。而不是病馬加鞭，只增強(qiáng)心肌收縮力心衰的血流動(dòng)力學(xué)指標(biāo)：壓力指標(biāo)：LVEDP，dP/dtmax；容積指標(biāo)：SV，CO，CI，EF（正常0.67, 心衰 0.45, 嚴(yán)重心衰0.3 ）時(shí)間指標(biāo)：PEP，LVET，T-dP/dtmax

6、抗心衰藥物的發(fā)展和演變洋地黃時(shí)代（從民間的治療水腫藥物而來）利尿藥（噻嗪類、汞撒利）非苷類強(qiáng)心藥（兒茶酚胺類，磷酸二酯酶抑制劑-氨力農(nóng)、米力農(nóng)）擴(kuò)血管藥物 血管緊張素轉(zhuǎn)化酶抑制劑 ACEIs，ARBs受體阻斷劑醛固酮受體阻斷劑使用抗心衰藥物后心功能曲線的改變(I) 正性肌力藥物 positive inotropic agents (V) 舒血管藥Vasodilators (D) 利尿藥Diuretics ACE inhibitorsfirst-line therapy in all patients with heart failure improve symptoms, slow progr

7、ession of the disease, reduce mortality, and decrease the incidence of hospitalization The most common adverse effects of ACE inhibitors are directly related to lowering angiotensin II concentrations (hypotension and renal insufficiency) and increasing concentrations of kinins (cough and angioneurot

8、ic edema) 血管緊張素原Angiotensin 收縮血管 腎素激肽原緩激肽降解失活A(yù)ng ACEACEIsAng 分泌醛固酮 NO PGI ( - )ACE和ACEIs作用示意圖舒張血管 Captopril第1個(gè)在臨床上廣泛應(yīng)用的ACEI。含巰基，可致味覺異常。Enalapril 前體藥，不含巰基。藥效和作用時(shí)間比cartopril強(qiáng)。ARBs - angiotensin receptor blockersangiotensin receptor antagonists (AT1 Receptor Antagonists) are as effective as ACE inhibit

9、ors in treating heart failure, but it appears that therapeutic efficacy may be comparable losartan, candesartan, valsartan Positive Inotropic Effect （抑制Na+,K+-ATPase ）Electrophysiological Actions （加上增強(qiáng)迷走）Regulation of Sympathetic Nervous System Activity There is evidence that digitalis may act direc

10、tly to sensitization of baroreceptor response and thereby exert some of its beneficial effects through reduction of sympathetic tone The recent Digitalis Investigation Group (DIG) clinical trial indicated digoxin did not reduce overall mortality in patients with heart failure (who were receiving diu

11、retics and ACE inhibitors), but did reduce the rate of hospitalizationOther inotropic agents只適用于急性心衰，長(zhǎng)期應(yīng)用于慢性心衰后，病人死亡率增加。Beta-Adrenergic Agonists dopamine, dobutamine, prenalterol Levodopa and ibopamine Cyclic Nucleotide Phosphodiesterase (PDE-III, cGMP-inhibitable PDE) Inhibitors Bipyridines- amrino

12、ne and milrinone imidazolone derivatives- enoximone and piroximone Beta-Blockers and CHFA number of studies beginning in the 1970s have shown that beta-blockers can improve symptoms and ventricular function in patients with moderate to severe heart failure, and may slow the progression of heart fail

13、ure in some patients (reviewed in Bristow, Circulation 101:558 (2000) Though beta-blockers were widely considered to be contraindicated for patients with heart failure only a decade ago, they are now considered first-line therapy for patients with mild to moderate heart failure 現(xiàn)認(rèn)為脂溶性的效果更好。metoprolo

14、lcarvedilolbisoprololThe adverse effects : worsening of symptoms, hypotension, and bradycardia These symptoms can be minimized by initiating therapy with low doses and gradually increasing dosage until tolerable therapeutic doses are reached Beta-blockers are contraindicated in patients with asthma

15、or severe bradycardiaDiureticsMost pateints with heart failure require treatment with diuretics to relieve symptoms of fluid retention (edema and congestion), but their is no evidence that diuretics slow the progression of the disease or decrease mortality.Loop diuretics (furosemide) are the most ef

16、fective diuretics 多用于嚴(yán)重水鈉潴留和腎功能不全時(shí)。Thiazide diuretics act on the distal loop and are less effective than loop diuretics 用于輕度水鈉潴留。Concurrent use of two diuretics with different sites of action may be needed in patients who do not respond well to a single oral diuretic The most common adverse effect o

17、f diuretic therapy is potassium depletion which can be prevented by use of supplemental potassium, an ACE inhibitor, or a potassium-sparing diuretic (spironolactone or amiloride) Aldosterone AntagonistsRecent clinical trials indicate that adding spironolactone (螺內(nèi)酯)to standard treatment can signific

18、antly decrease mortality in patients with severe heart failure Effect of spironolactone on survival in patients with moderate or severe congestive heart failure in a randomized double-blind clinical study. (Reproduced, with permission, from Pitt B et al: The effect of spironolactone on morbidity and

19、 mortality in patients with severe heart failure. N Engl J Med 1999;341:709 醛固酮受體拮抗劑螺內(nèi)酯降低充血性心衰病人死亡率Other Agents with Therapaeutic Potential Endothelin-1 Antagonists The vasoconstrictor peptide, endothelin-1, is known to be elevated in heart failure and is a predictor of mortality in patients with he

20、art failure. Animal models of heart failure indicate endothelin receptor antagonists such as bosentan may have long-term benefits in reversing myocardial remodeling and improving survival. Short-term, small-scale trials in humans indicate possible beneficial effects on systemic and pulmonary hemodyn

21、amics xanthine oxidase inhibitorBackground: High serum uric acid (SUA) levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. Results and conclusion: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart

22、failure.However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction.Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol 2008;51 (24):2301-9.Steps in the tre

23、atment of chronic heart failure._1. Reduce workload of the hearta. Limit activity levelb. Reduce weightc. Control hypertension2. Restrict sodium3. Restrict water (rarely required)4. Give diuretics5. Give ACE inhibitor and digitalis16. Give b-blockers to patients with stable class II-III heart failure7. Give vasodilators_1Many