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Heart failure, also known as congestive cardiac failure, is a clinical condition where the hearts ability to pump blood around the blood is affected. Typical symptoms of heart failure are dyspnoea (shortness of breath), fatigue (extreme tiredness) and oedema (swelling in legs and ankles). Common causes of heart failure include myocardial infarction, hypertension (high blood pressure), ischaemic heart disease and cardiomyopathy.
For this essay, we are going to look at drug treatments for heart failure that is associated with left ventricular systolic dysfunction. There are number of treatments available to relieve symptoms and reduce mortality when it comes to heart failure, such as Angiotensin-converting enzyme inhibitor, beta blockers, diuretics, angiotensin receptor blockers, digoxin and aldosterone antagonists. We will look at Lisinopril and Eplerenone, which are an ACE (angiotensin-converting enzyme) inhibitor and an aldosterone antagonist respectively.
In order to understand how ACE inhibitor and aldosterone antagonist work, we need to understand how the 'RAAS' (Renin angiotensin aldosterone system) system works. Initially, RAAS becomes activated as a compensatory mechanism, however, as heart failure develops, it becomes responsible for the increase in preload and afterload, which are the typical symptoms of heart failure. Heart failure drugs work by modulating this system to either enhance or inhibit its effect to minimise symptoms and mortality.
RAAS is a system that controls the blood pressure and fluid balance of your body. When renal blood pressure is too low (low perfusion pressure of arteries), kidneys release a chemical called renin from juxtaglomerular cells directly into the blood stream. The main purpose of renin is to cleave the polypeptide angiotensin I from angiotensinogen, which is released from the liver. Ang I is a substrate for angiotensin-converting enzyme, and it gets converted into ang II by ACE. Ang II is the resulting effector of this process,
Angiotensin II is a potent vasoconstrictor and it increases blood pressure through several mechanisms. Firstly, angiotensin II constricts arteries directly to increase blood pressure. Secondly, it stimulates adrenal cortex to release aldosterone, which goes to the collecting duct of nephron to facilitate reabsorption of sodium and water by increasing the number of sodium channels present on the duct membrane, this increases the retention of water and sodium, which eventually contributes to an increase in blood pressure. Thirdly, angiotensin II also stimulates the posterior pituitary gland to secrete vasopressin, which inserts water channels called aquaporin into the collecting duct to further increase water reuptake. Apart from what's mentioned above, angiotensin II also induces thirst response by stimulating hypothalamic neurons, to retain more fluid, thus indirectly increasing blood pressure as a result.
The ACE inhibitor lisinopril is an orally-active competitive antagonist to RAAS. It competitively inhibits angiotensin-converting enzyme, to reduce the formation of angiotensin II from angiotensin I, and because angiotensin II promotes the release of aldosterone, lisinopril indirectly reduces fluid volume retention and causes vasodilation to lower blood pressure. ACE inhibitor also inhibits the inactivation of bradykinin by angiotensin II. As a result, bradykinin induces the release of vasodilator nitric oxide from the endothelium, and this further relaxes arteries and thus lowers blood pressure.
Aldosterone antagonist is another treatment used for treating hypertension and heart failure, it is usually used in conjunction with ACE inhibitor or Beta blockers. For this essay we shall look at Eplerenone.
Eplerenone is an aldosterone antagonist which means it binds to the mineralocorticoid receptor on collecting duct in nephron and thereby competitively inhibits the effect of aldosterone binding. As previously mentioned, the main effect of aldosterone is to increase water and sodium retention by the nephron. The synthesis of aldosterone is carried out by adrenal cortex, and this can be triggered by factors such as angiotensin II. It binds to mineralocorticoid receptors in collecting duct and posterior pituitary gland to induce an increase in reabsorption of water and sodium, thus raising blood pressure as a result.
The clinical benefits of lisinopril include lowering of blood pressure and increased supply of blood and oxygen to the heart. It is also used in some patients after a heart attack, as some of the heart muscle is damaged, which will significantly reduce heart's efficiency to pump blood around the body effectively to meet the demand, so lisinopril treatment would be implemented after the attack, to lower the patient's blood pressure to avoid further damage.
Lisinopril lowers the blood pressure to avoid excess workload on the heart and arteries. Excess pressure can damage blood vessels in the brain and heart, which could lead to a stroke or heart failure. So by taking lisinopril, the risk of strokes and heart attacks are reduced significantly.
Eplerenone is a potassium-sparing diuretic, its main clinical benefits are to help body get rid of water, so to lower blood pressure, decreases chances of cardiac failure and reducing mortality rate in the long run.
Eplerenone may also have a lower incidence of sexual side effects such as feminization, impotence, low sex drive and reduction of size of male genitalia, but this is not known for certain.
In conclusion, we have established that lisinopril has proven to be clinically beneficial, it's versatility in treating hypertension through various mechanisms such as inhibiting the conversion of ang I to ang II and the indirect inhibition of aldosterone production, results in a drastic reduction in the risk of heart failure occurring, hence significantly reduces mortality rate. however, not all aldosterone release is triggered by ang II, therefore by combining eplerenone treatment with lisinopril, eplerenone inhibits the remaining aldosterone activity to further lower blood pressure by 'getting rid of' excess fluid in the body. Therefore it's safe to say that the clinical benefits of using these two drugs, far outweighs the potential side-effects and the risk of not using them, and the combination of ACE inhibitor and aldosterone antagonist treatments is ideal to reduce the risk of cardiac failure, hypertension and studies have proven that these treatments reduce the rate of mortality by a significant amount each year.