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Enalapril is a pro-drug, which hydrolyses to form enalaprilat and inhibits ACE (angiotensin-converting enzyme). Renin is a chemical synthesised by kidney and released in circulation where it acts on a plasma precursor to produce angiotensin I. angiotensin-converting enzyme ACE is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to a vasoconstrictor angiotensin II. Angiotnsin II is a potent vasoconstrictor which also causes release of aldosterone from the adrenals; these two actions cause increase in blood pressure. The main functional effects of enalapril are blocking conversion of angiotensin I to angiotensin II, decreasing blood pressure, decreasing aldosterone secretion, slightly increasing serum potassium level and causing sodium and fluid loss; increased prostaglandin synthesis. The use full effects of enalapril in heart failure and hypertension are mainly as a result of suppression of the renin-angiotensin-aldosterone system. The decrease in conversion of angiotensin II will affect negative feedback of renin secretion leads to increase in plasma renin activity.
The main beneficial effect of ACE inhibitor is vasodilatation; however the survival rate with ACE inhibitor is greater compare to other vasodilators which means other mechanisms also play their part other then vasodilatation.
One of the possible mechanisms is effect on balance of water and electrolyte in body. As all other vasodilators increases salt and water retention, ACE inhibitors increase salt and water excretion by complex effects on kidney. These effects include the attenuation of secondary hyperaldosteronism with a reduction in mineral ocorticoid-stimulated sodium reabsorption. ACE inhibitors also inhibit angiotensin-mediated thirst by an action on the hypothalamus. The attenuation of aldosterone effects reduces any tendency to hypokalaemia, and this may contribute to the antiarrhythmic effect of ACE inhibitors.
Other possible beneficial effects of ACE inhibitors are effects on the adverse neurohumoral profile which accompanies heart failure. Other then activation of the renin-angiotensin-aldosterone system, heart failure activate many other neurohumoral systems. The sudden increase in secretion of adrenal catecholamines and increased sympathetic nerve activity contribute to the high incidence of malignant ventricular arrhythmias and sudden death in heart failure. The main use full effects of ACE inhibitors are major reductions in sympathetic nerve activity and plasma levels of catecholamines.
Heart failure is a progressive process under which the heart goes through major changes. I-e the patient with asymptomatic left ventricular dysfunction early post-infarction would only have minor chamber enlargement. But when the patient would reach to the stage of clinical heart failure the chamber of heart would have enlarged substantially. The process of heart enlargement is called 'remodelling'. ACE inhibitors reduce the development of heart failure by preventing the process of remodeling.
The main action of ACE inhibitor on heart is often assumed as reduction in angiotensin formation. Howeven small amount of Angeotensin continues to be formed at lower doses. ACE is quite 'promiscuous', cleaving dipeptides from a variety of other substrates e.g. the vasodilator peptide bradykinin. ACE inhibitors increases the level of bradykinin and this contribute to their vasodilator action and other effects which includes cough and inhibition of cardiac hypertrophy.
ACE inhibitors are important in treatment of heart failure and improve survival rate when added to conventional treatment. They are most beneficial in patients with severe heart failure. Comperativly less benefits are seen with patients with moderate heart failure. Although ACE inhibitors improved survival, the prognosis of moderate-to -severe heart failure remains poor. Therefore most cardiologists believe that ACE inhibitors should be added to diuretic therapy in all patients with overt heart failure, even if the heart failure is only mild.
The benefits of treatment are not just due to survival rate but ACE inhibitor in diuretic therapy improves the control of heart failure, an important symptomatic benefit. This improves the quality of life for patient and also reduces the cost of hospitalisation. There also economic benefits for health care system.
The patients with asymptomatic left ventricular dysfunction also derive benefits from ACE inhibitors. This is described as the presence of a left ventricular ejection fraction of <40-45%, when there is no symptom or sign of heart failure. These patients are most commonly identified as following acute myocardial infarction. These patients are considered to have pre-clinical heart failure. Most patients have reduced effort tolerance on formal stress testing, and most of them will progress to overt heart failure with time. ACE inhibitors started within 1-2 weeks of the infarction improve survival, reduce the chance of developing overt heart failure and reduce the need for hospitalisation.
GENERIC NAME: bisoprolol
BRAND NAME: Zebeta
The following TWO drugs are used in the treatment of heart failure.
Please describe their mechanism of action and the rationale for their
Use in this indication stating the clinical benefits anticipated.
DRUG CLASS AND MECHANISM:
Bisoprolol is an antagonist and work by blocking beta-adrenergic receptor and is mainly used in treatment of hypertension, Angina (heart pain) and heart failure. On molecular level bisoprolol is used to prevent neurotransmitters norepinephrine and adrenaline, from binding to beta receptors on nerves. The main functional role of bisoprolol involves blocking norepinephrine and adrenaline reaching the nerve terminals at heart and blood vessels. The heart rate and force with which the heart contracts reduces and this cause reduction in blood pressure and dilation of blood vessels also take part in reduction of blood pressure. This may constrict air passages by stimulating the muscles that surround the air passages. Bisoprolol cause reduction in heart rate and force with which heart muscle contracts, therefore reduces the work of the heart and the demand of the heart for oxygen.
Mechanism of action
All the useful effects of beta blockers are mostly depend on blockade of beta-1 receptor. In order to treat heart failure the use of beta blockers was a major breakthrough in treatment and analysis of this set of symptoms. Earlier heart failure was considered as a hemodynamic disorder and actvation of sympathetic activity was thought as a useful effect increasing myocardial contractility and cardiac output. However later studies have showed that the independent analytical role of sympathetic activation in Heart failure as well its long-term adverse effects on myocardial function and outcome. An increase in sympathetic activity was considered as related with increased myocardial energy expenditure and possibly ischemia of the failing heart. Whereas increase in beta-1 adrenergic receptors stimulation is a powerful mechanism which increase rate of cell death through apoptosis and cause major changes in the qualitative characteristics of myocardial cells with reduced contractility and abnormal intracellular calcium handling by the sarcoplasmic reticulum. The sympathetic stimulation in all these changes in myocardial characteristics was indirectly shown by their reversal with beta-blocker treatment.
Fibrillation with rapid ventricular response is a main factor in some patients which worsens the severity of their heart failure. If only ventricular response is controlled it will produce major improvement in heart failure. In this situation beta blockers are effective in slowing the ventricular rate and rarely worsen the situation providing ventricular systolic function is reasonably well preserved.
Diastolic heart failure
Almost one in three patients with heart failure has normal ventricular systolic function. In these patients the abnormality of ventricular filling is the primary cardiac abnormality leading to heart failure. Beta blockers will cause improvement with little risk of the patient deteriorating. By slowing the heart rate, allow a longer period for diastolic filling, particularly if atrial fibrillation is also present. Beta blockers can also facilitate diastolic filling by improving abnormal myocardial relaxation, for example in patients with diastolic failure due to severe left ventricular hypertrophy. This is generally in patients with severe, long-standing, poorly-controlled hypertension.