【正文】 33～ 36 hours) Classification1 Positive inotropic drugs ? Adrenoceptor agonists They are used intravenously in CHF emergencies Example of ? Adrenoceptor agonists : Dobutamine (多巴酚丁胺 ) ? Exciting β1 Adrenoceptor → positive inotropic action →the volume of output↑ ? Exciting β2 Adrenoceptor→dilate the vascular → afterload↓ have benefits within short time Classification1 Positive inotropic drugs PhosphodiesteraseⅢ inhibitors Inodilator / inodilating drugs Inhibiting the activity of PDE Ⅲ → cAMP↑→ causes an increase in myocardial contractility and vasodilatation →total peripheral resistance → cardiac output ↑ Examples: Armirinone（氨力農(nóng)） : Inhibits the excess product of NO, TNF and affects the neurohormone, antithe forming of thrombus milrinone（米力農(nóng)） : stronger 20 time vesnarinone（維司力農(nóng)） : myocardial contract element’s the sensitivity to calcium Classification1 Positive inotropic drugs Calcium sensitizers Pimobendan 匹莫苯 : Inhibit PDE Ⅲ 。 Process of drug through body Drug Absorption rate (%) Proteinbinding (%) Heptoenteralcirculation (%) Biotransformation (%) Kidney excretion (%) T1/2 digitoxin 90~100 97 27 30~70 10 5~7 day digoxin 60~85 30 5~10 60~90 33~36 h Cedilanide 20~40 5 Few Quite few 90~100 33 h Strophanthin K 2~5 5 Few 0 90~100 12~19 h Pharmacologic action I. Action of cardiac glycosides on the heart inotropic action： Increasing contractility of cardiac muscle in heart failure. (1) characteristic: quick contraction, QT period↓ ① rate of force ↑ ② time to peak tension ↓ B. no increase oxygen consumption： the increase in output is not acpanied by an equivalent increase in oxygen consumption Factors of oxygen consumption： 1） Myocardia contractility 2） Heart rate 3） Myocadiac fiber length and tone Factors affect consumption of oxygen I. The force of cardiac contraction II. Heart rate III. Volume of ventricular C. Effect of positive inotropic act ① cardiac output is increased ② pensatory sympathetic tone is reduced ③ cardiac preload and afterload is decreased ④ heart rate is reduced ⑤ myocardiac fiber tone and oxygen consumption is decreased ⑥ increasing stroke volume causes a decrease in endsystolic volume (2) Machanism of cardiac glycoside on positive inotropic action A. Inhibiting Na+K+ATPase in therapeutic dose: B. Increasing of calcium inward and induce the releasing of calcium from sarcoplasmic reticulum ( internal stores, by CICR) α β ↓ ↓ ↓ ↓ ↓ glycoside → Structure changes Enzyme activity ↓ Na+↑ , K+↓ in cell Ca2+Na+exchange↓ in cell) ↓ Na+K+ATPase is a recetor of glycoside Mechanism of pharmacological act Na+K+ATPase is the receptor of cardiac glycosides , so cardiac glycosides act by inhibiting the membrane Na+K+ATPase pump → ? Na+ ? i → ? Na+ ? i Bidirectional exchange ① Na+ enter ↓ → Ca2+ ↓ outer ② Na+ outer ↑→Ca2+ ↑ enter →by Na＋ /Ca 2+exchanger → ?Ca2+ ?i↑ Ca2+ induced Ca2+ release Sarcoplasmic reticulum release Ca 2+ Enhance the increased cytosolic calcium concentration Sarcoplasmic reticulum → ?Ca 2+ ?i↑ chronotropic action A. Continuous effect of positive inotropic action decreasing sinus rate heart rate is decreased Heart rate is decreased, Atropine can antagonize (block) B. Increasing sensibility of myocardia to vagus nerve (increasing of potassium outward and resting potential, reducing of automaticity). 3. Affects of glycosides to conductive tissues A. Increasing conduction of the atrial muscle fibers, because increasing excitation of vagus nerve (increasing of potassium outward). Increasing resting potential. Elevating rate of phase0 depolarization. Acceleration rate of depolarization phase0 and atrial fibers co