Combination Therapy in Heart Failure

The ability of the midpoint to warmness blood Is impaired and It can no longer meet the bodys metabolic requirements Table 1 . New York Heart Association Classiflcation of Heart Failure. Remme W, Swedberg K. Guidelines for the diagnosing and treatment of chronic heart failure. European Heart Journal. Online 2001 22(17) 1527-1 560. during the rest or exercisel. By treating HF we try to relieve patients symptoms, Improve their quality of life, preclude hospitalization and most importantly prolong their life. The treatment Includes Improved feed (reduced salt intake), physical activity and pharmacological treatment.There be many angiotensin-receptor blockers (ARBs), vasodilators, angiotensin-converting enzyme (ACE) inhibitors Ramipril) and beta-blockers (Carvedilol). We willing control a look at the last two classes. They select been PATHOPHYSIOLOGY The previous hemodynamic model was not adequate and was therefore replaced by neurohormonal model, which involves Reninangiotens in-aldosterone-system likable nervous system 1 , (RAAS) 3 is summarized in Figure 1. The energizing of RAAS leads to vasoconstriction, oedema and myocardial fibrosis, which are induced by Angiotensin autistic . roven to be very efficient in HF by numerous clinical studies2-4. SYMPTOMS AND SIGNS HF involves many symptoms such as dyspnoea fatigue, and mortise-and-tenon joint oedema. l The signs of HF are achycardia (100 beats per minute), tachyarrhythmia, tachypnoea, distended Jugular murmur and S3 and S4 heart sounds. The Figure 1 . pathophysiology of heart failure and contrastive levels of therapeutic intervention. interpreted from Perrenoud J. Heart failure (Part 1). European Geriatric Medicine. Online 2011 2(3) 159-171. ccurrence of these symptoms and signs depends on One of the early neurohormonal changes in HF is the severity of heart failure and whether it is cause sympathetic energizing and it has a primary role in vein, peripheral oedema, hepatomegaly, heart by systolic dysfunction or diastolic dysfunction . isease progression. Left ventricular remodeling, cell death and changes in gene expression are believed to be the main mechanisms that induce ejection fraction8-11. Because it is very potent, small myocardial doses of the yellow journalism should be taken at the start of damage nervous input 10. treatment (3. 125mg) twice daily.The dose is Heart failure can be categorized in predominantly gradually increased up to utmost of 50mg twice systolic dysfunction where the emptying of the left daily8. ventricle is not optimal and predominantly diastolic dysfunction where the filling of the left ventricle is molecular(a) targets ot optimall -6. As mentioned above, its major molecular targets are membrane receptors (?l, ?2 and 01). It acts on ion TREATMENT channels (Ca2+ and K+) as well. Carvedilol inhibits As mentioned above, the unhealthiness can be treated cardiac voltage-dependent potassium IKr channels utilise several different drug classes4. Multidrug with extravagantly potency, voltage-dependent calcium therapy is widely used in patients with heart failure. channels as well as Ca2+-permeable momentary receptor potential (TRP) family channels in Failure Zealand cardiomyocytes and in vascular smooth brawniness Carvedilol Trial) have been conducted to test the ells. Furthermore, a study conducted by (Kikuta et benefits of different combinations of drugs. It was al. , 2006) suggests that the drug blocks ATP- proven that these therapies significantly reduce the sensitive (KATP) and G-protein-activated (KG) adventure of mortality and improve the symptoms. otassium However, hyperinsulinemia and hypoglycemia. It is believed implementing multi drug therapy. ACE inhibitors that the KG channel is loose by G protein in can cause hypotension, cough, and worsen the nephritic response to stimulation of G-protein-coupled function. Cough can cause patient noncompliance, uscarinic acetylcholine receptors in atria and sino- which i n turn may result in the need of different drug therapy. Beta-blockers can cause bradycardia, channel would result in anti-cholinergic set up in hypotension, fatigue and fluid retention.Also, in the heartl 2. Study patients there with Australian-New are risks diabetes, associated beta-blockers channels. This results in could Pharmacodynamics Carvedilol is a racemic mixture of R and S Carvedilol enantiomorphs. Both enantiomers fancy al receptor Carvedilol is a non-selective beta-blocker (?l and prohibition era. However, only S enantiomer inhibits ? ?2) has drenoreceptors. It competitively blocks both ?l and vasodilatation and antioxidant effects. Previously it ?2 receptors. The drug reduces high blood pressure be mainly due to the al and ? blockage.The inhibition contraindicated in HF as it has cast out ionotropic of al receptor lowers thorough peripheral vascular effect. However, studies have shown that carvedilol resistance. Hence, it reduces afterload and balances in combinat ion with ACE inhibitors improves the negative ionotropic effect the ? inhibition. As a function of the heart, especially left ventricular result, the stroke volume and cardiac output are al-blocker. elieved that Furthermore, carvedilol it should maintained or even increased. The systemic arterial The effects of carvedilol are summarized in practice pressure is lowered without reducing the renal 3. lood flow13-14. The antioxidant effects carvedilol and some of its metabolites are due to the presence of carbazole moiety (shown in Figure 2). In myocardial cell membrane carvedilol inhibits lipid peroxidation. Moreover, endothelial, vascular and neuronal smooth muscle cells from re prompt oxygen species. Metabolite SB209995 is much more potent antioxidant than carvedilol itself. Animal studies have shown (Feuerstein et l. , 1998) heart failure imbalances the production of reactive oxygen species and the oxidant self-denial mechanism. The consequence is an excess of free radicals.This m ay result in cytotoxic effects as well as cardiovascular remodelingl 3. Figure 3. Molecular targets, pharmacodynamics and clinical implications of carvedilol. Cheng J, Kamiya K, Kodama l. Carvedilol Molecular and Cellular Basis for its multilateral Therapeutic Potential. cardiovascular Drug Revvtevs. coniine 2006 19(2) 152-71. Therapeutic efficacy Many different controlled clinical studies were do in order to determine the efficacy of carvedilol. The most known are COPERNICUS, CAPRICORN and USCHFS. They have all shown significant reduction in morbidity and mortality in comparison placebol 5-16.COMET investigating the difference between carvedilol and metoprolol efficacy. The study showed that the allcause mortality was lower with carvedilol (34%) Figure 2. Chemical structure of carvedilol (with postulated active sites) and its active metabolites. * denotes the point of assymetry. Taken from Cheng J, Kamiya K, Kodama l. Carvedilol Molecular and Cellular Basis for its Multifaceted Therapeutic Potential. cardiovascular Drug Rewtevs. coniine 2006 19(2) 152-71. Carvedilol aids lipid metabolism as it prevents the oxidation of low-density lipoproteins (LDL).It is known that LDL has destructive effects endothelial cells. Carvedilol also inhibits the Renin-angiotensin system (RAS). Hence, the production of Angiotensin II is lowered. Furthermore, studies on cardiac rat myocytes showed that carvedilol enhances the production of nitrite. It is therefore believed that it can increase the NO deductive reasoning through some adrenoreceptor independent mechanism. However, the role of excessive amounts of NO in the diseased heart remains unclear 13-14. than with metoprolol (40%) as shown in figure 417. Figure 4.All-cause Mortality between Carvedilol and Metoprolol. Poole-Wilson PA, Swedberg K, Cleland JGF et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET) randomiz ed controlled tnal.