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Drugs for Treatment of Congestive Heart Failure

Drugs for Treatment of Congestive Heart Failure. Contents. Overview ACE inhibitors (ACEI) AT1 receptor blockers(ARB) mineralocorticoid receptor blockers(MRB) Diuretics  receptor blockers Cardiac glycoside Others. A. Overview.

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Drugs for Treatment of Congestive Heart Failure

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  1. Drugs for Treatment of Congestive Heart Failure

  2. Contents • Overview • ACE inhibitors (ACEI) • AT1 receptor blockers(ARB) • mineralocorticoid receptor blockers(MRB) • Diuretics •  receptor blockers • Cardiac glycoside • Others

  3. A. Overview 1.Pathophysiological changes of congestive heart failure (CHF) (1) Function and structure changes (2) Neuroendocrine changes (3) Changes of  receptor signal transduction

  4. Cardiac failure Cardiac output Blood supply Venous pressure Renal blood flow Renin - angiotension Ⅱ Venous hyperemia Aldosterone Pulmonary circulation: cough, emptysis, dyspnea Systemic circulationhyperemia: jugular vein distension, edema Sodium and water retention Changes of hemodynamics in CHF

  5. A. Overview Changes of -adrenergic receptors • 1-receptor down-regulation • uncoupling of 1-adrenergic receptors • increased activity of the inhibitory G-protein(Gi) • increased activity of G-protein receptor kinase

  6. A. Overview 2. Grades of CHF Ⅰ(A): no symptoms Ⅱ(B): physical activities were limited and symptoms could be induced by general activity Ⅲ(C): physical activities were markedly limited Ⅳ(D): symptoms appear even at rest

  7. A. Overview  Cardiac remodeling Decrease overload 3. Therapeutic strategies in CHF (1) Increasing contractility of the cardiac muscles (2) Inhibiting RAAS (3) Decrease sympathetic activity (4) Dilating vessels (5) Diuresis

  8. B.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers(ARB) ACEI: captopril 卡托普利 enalapril 依那普利 ARB: losartan 氯沙坦 irbesartan 厄贝沙坦

  9. B.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists ACEI 1. Pharmacological effects • Inhibiting the production of Ang II • vasoconstriction ; sodium retention ; • cardiac remodeling (myocardial hypertrophy)  • Inhibiting the degradation of bradykinin • vasodilatation  • Increasing ANP and scavenge free radicals

  10. PGI2 NO Actions of ACEI Inactive peptide Angiotensin II brandykinin Angiotensin I ACEI (—) B2 receptor ACEI ACE Circulation and local tissues (—) ACE Circulation and local tissues Vasodilatation Anti-proliferation, anti-hypertrophy

  11. Box Actions of angiotensin II • Constricting vessels, increase peripheral resistance and returned blood volume. • Increasing sympathetic tension, promote release of sympathetic transmitter. • Stimulating release of aldosterone. • Inducing expression of c-fos、c-myc、c-jun rapidly. • Activating MAPK and PTK pathway

  12. AngII AngII

  13. B.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists • Cardiovascular effects • Decrease resistance of peripheral vessels • Dilate coronary artery, increase blood supply of heart and kidney, improve cardiac and renal function • Reverse myocardial hypertrophy and ventricular remodeling

  14. B.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists 2. Clinical uses (1) CHF increase motor tolerance decrease mortality (2) Hypertension

  15. B.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists 3. Adverse effects Hypotension • Cough and angioedema • Hyperpotassemia • Contraindications: pregnancy and stenosis of renal artery

  16. B.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists AT1 receptor blockers(ARB) Compared with ACEI: • Blocking actions of angiotensin II directly • Not influencing bradykinin metabolism • Protecting renal function • Used for CHF and hypertension

  17. CV Risk: reduction in future cardiovascular events; DN: diabetic nephropathy; H: hypertension; HF: heart failure; Post MI: reduction in heart failure or other cardiac events following myocardial infarction.

  18. C.mineralocorticoid receptor blockers(MRB)or aldosterone blocker • Spironolactone (螺内酯) • a nonselective aldosterone blocker • Eplerenone (依普利酮) • a selective aldosterone blocker • either alone or in combination with other agents, and for the first-line treatment of heart failure secondary to myocardial infarction • Aldosterone action • MR (in nonepithelial tissues such as the brain and heart )activates transcription of target genes upon aldosterone binding • Formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling

  19. Fig1. The renin-angiotensin-aldosterone (RAA) system and aldosterone blockade and renin-angiotensin inhibitors (ACE inhibitors and ARBs). * RALES, the Randomized Aldactone Evaluation Study; EPHESUS, the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study.

  20. Fig. 2. mineralocorticoid receptor signal transduction. MR, mineralocorticoid receptor; HRE, hormone responsive element.

  21. C.mineralocorticoid receptor blockers(MRB)or aldosterone blocker Eplerenone(依普利酮)Pharmacology/ pharmacokinetics • Eplerenone selectively binds to the mineralocorticoid receptor, thereby blocking the binding of aldosterone and thus inhibiting sodium reabsorption and other deleterious aldosterone-mediated mechanisms. • Eplerenone is metabolized via the cytochrome P450 (CYP) 3A4 pathway. No active metabolites are known to exist. The elimination half-life is 4 to 6 hours. Steady state is achieved within 2 days. Blood levels are potentiated and increased with concomitant use of inhibitors of the CYP3 A4 pathway (e.g., ketoconazole, saquinavir, erythromycin). The pharmacokinetics of eplerenone did not differ between men and women or between whites and blacks. Steady-state area under the curve and maximum concentration are increased with renal and hepatic insufficiency. Hemodialysis does not remove eplerenone.

  22. C.mineralocorticoid receptor blockers(MRB)or aldosterone blocker • Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis. • In humans, eplerenone appears to be effective for the treatment of hypertension.

  23. Adverse events reported most frequently with eplerenone Adverse event Rate (%) of adverse eventHyperkalemia (K+ >5.5 mEq/L) 33% (eplerenone alone)  38% (eplerenone and enalapril) Hypertriglyceridemia 15% Hyponatremia 2.3% Mastodynia 0.8% (men) Abnormal vaginal bleeding 0.6% (women) Gynecomastia 0.5% (men) Proc (Bayl Univ Med Cent). 2004 April; 17(2): 217–22

  24. D.Diuretics 1. Pharmacological effects • Reduce plasma volume • Reduce Na+-Ca2+ exchange in vessel smooth muscle cells 2. Clinical uses • CHF: grand I – IV (mainly used in II –III), alone or combined with other drugs • Edema, hypertension, etc. 3. Adverse effects plasma level of renin  hypokalemia hyperuricemia hyperglycemia hyperlipidemia

  25. D.Diuretics

  26. Therapeutic effects of diuretics in CHF

  27. D.Diuretics • Thiazides &analogue: • Hydrochlorothiazide(氢氯噻嗪) • Chlorthalidone(氯肽酮) • Indapamide(吲达帕胺) • metolazone (美托拉宗) • Aldosterone antagonists： • Spironolactone (螺内酯) • Amiloride(阿米洛利) • Loop agents: • furosemide(呋塞米) • Bumetanide(布美他尼) • torasemide(托拉塞米) • Piretanide(吡咯他尼) • Furosemide 40mg= Bumetanide1mg= Piretanide 6mg= torasemide 20mg

  28. E. receptor blockers Conmmonly used: Carvedilol 卡维地洛, labetalol 拉贝洛尔 1. Pharmacological effects (1) Blocking effects of catecholamines on myocardium: decreasing heart rate and cardiac oxygen demand (2) Up-regulating  receptor (3) Inhibiting RAAS and VP (vosopressin, 加压素): anti- myocardial hypertrophy and remodeling (4) Blocking -receptor and anti- free radical (5) Anti-arrhythmic and anti-hypertensive effects

  29. E. receptor blockers Inverse agonist activity:The ability of β blockers to reduce this basal β-AR activity is termed "inverse agonist activity." Thus, a β blocker does not simply "block" the receptor, but further inactivates receptor activity beyond its baseline value, depending on its degree of inverse agonist activity. Metoprolol>bisoprolol=nebivolol>carvedilol

  30. Significance of inverse agonist activity • β-AR regulation • Activated β-ARs are a substrate for receptor phosphorylation by β-AR kinase. Beta-AR phosphorylation leads to uncoupling of the receptor from the stimulatory G protein ("desensitization") or even internalization of the receptor ("down-regulation"). • Inactivation of β-ARs by inverse agonists inhibits phosphorylation of receptors and thus desensitization and down-regulation. • In chronic heart failure, where β-ARs are down-regulated due to chronic sympathetic activation, only the strong inverse agonist metoprolol, but not the weak inverse agonist carvedilol, leads to up-regulation of ventricular β-AR density.

  31. E. receptor blockers 2. Clinical uses (1) CHF: NYHA grand II - III decrease of mortality (2) Other uses: hypertension, arrhythmias, angina, etc.

  32. E. receptor blockers Therapeutic effects of β receptor antagonists on cardiac function in CHF patients

  33. E. receptor blockers Carvedilol -- antioxidative effects in vitro • Hydroxyl radicals lead to systolic and diastolic dysfunction in human myocardium. • Carvedilol, but not metoprolol, reduces hydroxyl radical-induced cardiac contractile dysfunction in human myocardium. • In patients with heart failure, treatment with carvedilol reduces oxidative stress determined in myocardial biopsies.

  34. E. receptor blockers 3. Adverse effects • Inhibition of cardiac function • Contraindications: • severe heart failure severe A-V block hypotension bronchial asthma

  35. F.Cardiac glycosides Digoxin 地高辛

  36. F.Cardiac glycosides 1. Pharmacological effects (1) Positive inotropic effects inhibiting Na+-K+-ATPase, free Ca2+  excitation-contraction coupling  cardiac output  organ blood supply  Vmax  diastolic duration   venous return   coronary blood supply  cardiac oxygen consumption 

  37. Inhibition of Na+-K+-ATPase by digitalis and potentiation of cardiac muscle contraction

  38. F.Cardiac glycosides (2) Negative chronotropic effects Reflex inhibition of sympathetic activity cardiac output   Sympathetic activity   HR  Increasing vagal activitydirectly

  39. F.Cardiac glycosides (3) Electrophysiological effects decreasing automaticity of sinoatrial node slow conduction increasing automaticity of Purkinje fibres shortening ERP of fast response cells Mechanisms: intracellular Na+, K+, Ca2+MDP , afterdepolarization

  40. F.Cardiac glycosides

  41. Overdose: Na+, K+, Ca2+   MDP   afterdepolarization Electrophysiological basis for digitalis overdose

  42. F.Cardiac glycosides (4) Other effects Nervous system autonomic nervous system: NE  central nervous system: CTZ D2 receptor Neuroendocrine system inhibiting RAAS increasing ANP（心房钠尿肽） Kidney increase blood supply of kidney diuretic effect: decrease Na+ resorption

  43. F.Digitalis 2. Clinical uses (1) CHF especially associated with atrial fibrillation and sinus tachycardia (2) Arrhythmias atrial fibrillation atrial flutter paroxysmal surpraventricular tachycardia

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