Drugs for Congestive Heart Failure

Learning Objectives: List classifications of the agents for CHF, their general target and mechanisms of action. Identify the positive inotropic effect of Cardiac glycosides/digitalis List the treatment of the cardiac toxicity of Cardiac glycosides Analyze the mechanism of RAASI on CHF Discuss the therapeutic considerations of β-adrenoceptor blockers for CHF

Pathophysiology of CHF Systolic/Diastolic dysfunction Sympathetic Nerve System activation β-adrenoceptor down-regulation Renin-Angiotensin-Aldosterone System activation Myocardial hypertrophy and remodeling

Strategy for the treatment of CHF Increase the cardiac contraction Decrease the heart load Inhibit myocardial hypertrophy How?

Classification of Drugs for CHF Cardiac glycosides/digitalis RAASI: ACEI/ARB Diuretics β-adrenoceptor blockers CCB PDEI (phosphodiesterase inhibitor) Vasodilators

Ca++ Cardiac Glycosides Ca+-ECC Na + Na+/Ca++ exchanger Positive inotropic effect K+-Na+-ATPase Na + Na+/Ca++ exchanger Ca++ Ca+-ECC

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Cardiac Glycosides Effects on nerve To inhibit sympathetic nerve activity To enhance vagus nerve activity results?

Electrophysiological effects In therapeutic dose on sinoatrial node (negative frequency ): K MDP automaticity In toxic dose on Purkinje fiber: K-Na-ATPase K MDP Intracellular automaticity

Electrophysiological effects Decrease the conduction in atrioventricular node (negative conduction) Shorten the ERP in atrium

强心苷的电生理学作用 负性频率 A 负性传导 C 16 字诀 正性自律 B 缩不应期 D

Cardiac Glycosides Clinic uses ADR CHF Arrhythmia： Atrial fibrillation, Atrial flutter ADR Gastrointestinal tract: anorexia, nausea, vomiting, and diarrhea Central nervous system: chemoreceptor trigger zoon stimulation; disorientation; hallucination, visual disturbances including aberrations of color perception：xanthopsia，chloropsia

ADR OF DIGITALIS Cardiac: Supra -/-Ventricular arrhythmia , Atrial Ventricular Block , ventricular premature beat Therapy: Drug withdrawal K+ supplement Phenytoin sodium/lidocaine Digoxin antibody

Treatment of toxicity caused by cardiac glycoside 强心苷中毒的治疗 停药 竞争 A C Phenytoin sodium Drug withdrawal 8字诀 B 补钾 强抢 D Digoxin antibody K+ supplement

Non-cardiac glycosides positive inotropic drugs PDEI (milrinone, amrinone, vesnarinone) cyclic adenosine monophosphate Adenosine Triphosphate PDEI ATP cAMP 5’AMP Increase cardiac output Increase mortality adenyl cyclase Ca++ influx

The renin–angiotensin–aldosterone system juxtaglomerular (J-g) cells The renin–angiotensin–aldosterone system

Ang Ⅱ & hypertrophy c-fos c-myc gene Ang Ⅱ + AT1, AT2 + PLC-IP3(DAG-PKC ) Ca PTK nuclear transcription factor +MAPK nuclear protein phosphorylation proto-oncogene:c-fos、c-jun、c-myc Cell growth and proliferation c-fos c-myc + + cellular cycle gene

ADR of RAASI hyperpotassemia hypotension Dry cough (ACEI+ ; ARB-)

β-adrenoceptor blockers Attenuation of the adverse effects of high concentrations of catecholamines Up-regulation of receptors to increase the sensitivity to catecholamines Decrease oxygen consumption

Therapeutic considerations Indication: Ⅱ-Ⅲ Low dosage as possible Combination therapy with positive inotropic drug sufficiently long-term application

Others Diuretics CCB Vasodilators: sodium nitroprusside、nitroglycerin prazosin、hydrolazine Nesiritide(Brain natriuretic peptide) Bosentan(Endothelin R Blocker)