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Heart failure is a clinical syndrome with many causes that may involve one or both ventricles. Heart failure is present when the heart cannot provide all organs with the blood supply they need (low cardiac output) to function properly. This means that the oxygen needed by the body's organs to function properly is not been provided but of the low cardiac output. Fatigue, shortness of breath and fluid congestion are symptoms and signs of heart failure. The fluid congestion is as a result of the heart's inability to fill or empty properly, leading to inadequate perfusion of tissues and to the retention of fluids.¹
Cardiac output (CO) = HR x SV: where HR is the rate of contraction of the heart. SV, the volume, is the amount of blood that is ejected when the heart beats. Stroke Volume is regulated by three factors, preload, after load and contractility. Preload is the load on the heart when the volume of blood is injected by the left atrium into the left ventricle at the end of ventricular diastole. This volume of blood must be ejected by each contraction.
After load refers to the total peripheral resistance. It is the load on the contracting ventricles created by the resistance to the blood pumped by the ventricles into the atria system. Contractility is the capacity of the myocardium to generate enough force necessary to respond to preload and to overcome overload.² An unresolved impairment of the heart that hinders its ability to work as a pump causes heart failure. For example, cut off of blood supply, increase in workload due to high blood pressure, poor dietary intake, genetic factors and lifestyle choices can also cause heart failure.
Two important causes of heart failure are coronary artery disease (CAD) and hypertension. Coronary artery disease is a medical condition where proliferation of cells and fatty deposit build up in the coronary arteries. The arteries become narrow as a result of the buildup of fatty materials and other substances. The narrowing of the coronary arteries causes blood flow to the heart to decrease considerably or even stop, depriving the heart from getting enough oxygen.³ Coronary artery disease causes contractility.
Hypertension is a medical condition whereby the blood pressure is highly elevated abnormally. At this level of high blood pressure, normally the benefit of investigation and treatment outweighs the risk. Individuals who are not hypertensive and with a systolic blood pressure (SBP) 130-139mmhg or diastolic blood pressure (DBP) of 85-89mmhg are classed as having "high" normal blood pressure. Figures above this level may be classified as hypertensive.
Left ventricle remodeling is the major alteration in heart failure. This is the process whereby the structure of the left ventricle is altered by the dilation of the chamber and the walls growing thicker to become more spherical. Recent studies show that the activation of the endogenous neurohormonal systems of the body, like the rennin- angiotensin-aldosterone-system may play a crucial role in the cardiac remodeling and thereby in the progression of heart failure.4
According to the British Society for Heart Failure, 1-2% of the population of the United Kingdom are affected by heart failure, and it is one of the most common reasons for emergency medical admission, re-admission and occupancy of hospital beds. It is very prevalent in patients over 70 years of age.5
The New York Heart Association (NYHA) classifies heart failure according to four classes.
Patients with cardiac disease in the class1category have no limitation on the physical activities and ordinary physical activity does not cause undue dyspnea, fatigue or palpitations.
Patients categorized in class II have slight limitations on the amount of physical activity. They are comfortable at rest, but ordinary amount of physical activity results in shortness of breath or fatigue.
Class III patients have a considerable limitation of physical activity. Symptoms are not present at rest, but a little amount of physical activity results in palpitation, fatigue or shortness of breath.
Class IV patients are considered to have severe heart failure. They are not able to carry out any physical activity without being discomfort and their symptoms are present at rest.
Heart failure may be clinically categorized into Acute or Chronic heart failure. Acute heart failure may occur with or without previous cardiac disease and it results in a quick onset of symptoms and signs secondary to abnormal cardiac function.
In chronic heart failure, the symptoms develop over time. Chronic heart failure may be caused by ischaemic heart disease, hypertension and degenerative valve disease.
Heart failure may also be classified as congestive heart failure. This is usually the combined left and right heart failure and it results in the production of both pulmonary congestion and peripheral oedema. Heart failure could be indicated as low or high output heart failure. It could also be categorized as systolic or diastolic heart failure.6
Treatment of heart failure is very complex and it is aimed at removing the underlying causes, for example, medical treatment of hypertension and surgical correction of valvular lesions. Removal of precipitating underlying causes like pulmonary embolism and arrhythmias are also objectives for the treatment of heart failure. Treatment of heart failure may also be aimed at improving the survival and relief of symptoms of patients.
Heart failure is usually managed by drug therapies like, diuretics, angiotensin converting enzyme inhibitors, digoxin, aldosterone receptor antagonists, beta-blockers and other drugs. Non pharmacological therapies like correction of obesity, healthy lifestyle and dietary restriction of sodium chloride may be used to manage heart failure.7
The mechanism of actions and clinical benefits of Lisinopril and Eplerenone, two very important drugs in the treatment of heart failure will be explored.
Lisinopril is an Angiotensin converting enzyme inhibitor. It is used in the treatment of heart failure caused by reduced left ventricular ejection fraction. It is also indicated in symptomatic heart failure, hypertension, and short-term treatment following myocardial infarction in haemodynamically stable patients and renal complications of diabetes mellitus.
Chemical Name: (S)-1-[N2-[(S-1- Carboxy-3-phenylpropyl]-l-lysyl-l-proline dihydrate11
MODE OF ACTION
Lisinopril exerts its therapeutic effects by inhibiting the actions of the angiotensin converting enzyme, (ACE). It therefore blocks the formation of angiotensin II. Angiotensin II is a vasoconstrictor which is formed by the proteolytic action of renin, which acts on angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by the angiotensin converting enzyme, (ACE). Lisinopril produces arteriolar and venous vasodilation by inhibiting the formation of angiotensin II. The therapeutic action of Lisinopril reduces the systemic vascular resistance, thereby reducing the force exerted on the heart.8 Angiotensin converting enzyme metabolizes bradykinin, a vasodilator substance. Therefore, inhibiting ACE and blocking the breakdown of bradykinin, increases bradykinin levels which contribute to the vasodilation action of Lisinopril.
The vasodilation therapeutic effect of Lisinopril reduces preload, afterload, and, arterial pressure on the failing heart. Reduced afterload enhances the ventricular stroke volume and improves the ejection fraction. Preload reduction decreases pulmonary and systemic congestion.
Lisinopril promotes renal excretion of sodium and water by inhibiting the synthesis of angiotensin II in the kidney and blocking its stimulation of the secretion of aldosterone.9 This reduces venous pressure, blood volume and arterial pressure. Lisinopril decreases sympathetic adrenergic activity by blocking the effects of angiotensin II on sympathetic nerve release and norepinephrine reuptake. It also prevents angiotensin II from triggering cardiac remodeling.
The recommended dose of Lisinopril for heart failure is 2.5mg once a day, initially under close medical supervision. The dose is increased in steps no greater than 10mg at intervals of at least two weeks up to a maximum, 35mg once a day if tolerated.10
Lisinopril, though generally tolerated, can sometimes cause severe and progressive renal failure in patients with bilateral renal artery stenosis. It can cause a rapid fall in blood pressure in volume depleted patients, dry cough, angioedema, pancreatitis, nausea, dyspepsia, diarrhoea, among others.
Eplerenone is a selective aldosterone receptor blocker, on the distal convoluted tubule of the kidney's nephron. It is indicated to be used with other drugs on stable patients with left ventricular dysfunction with evidence of heart failure, after a myocardial infarction.12
Chemical Name: 9,11Î±-Epoxy-17-hydroxy-3-oxo-17Î±-pregn-4-ene-7Î±,21-dicarboxylic acid, Î³-lactone, methyl ester13
MODE OF ACTION
Eplerenone selectively blocks the mineralocorticoid receptor by binding to it. This inhibits the binding of aldosterone, which is a component of the renin-angiotensin-aldosterone-system, (RAAS). It is synthesized in the adrenal gland. Aldosterone binds to the mineralocorticoid receptors and leads to increase in blood volume by it inducement of sodium reabsorption. By blocking the binding of aldosterone to its receptors, eplerenone is able to prevent the reabsorption of sodium and water, thereby reducing blood volume and hence reduces blood pressure. This reduces the strain on the failing heart. Eplerenone is a potassium-sparing diuretic. It does not promote the secretion of potassium.14
The recommended dose for eplerenone is an initial dose of 25mg, once a day, increasing within four weeks to 50mg once every day.
Some of the reported side effects of eplerenone are diarrhoea, nausea, hypotension, hyperkalemia, dizziness among others.
Lisinopril is well tolerated in patients with heart failure. It reduces the mortality rate as well as incidence of morbidity associated with heart failure. This is backed by evidence from large clinical trials, including ATLAS, SAVE SOLVD, AIRE, CONSENSUS and TRACE. The cardio-protective effects of Lisinopril are based on the drug's ability to change the course of the left ventricular remodeling that leads to heart failure.15
Eplerenone, administered in conjunction with an ACE inhibitor, like lisinopril, reduces the rate of death due to progressive heart failure. Eplerenone also reduces sudden death from cardiac causes as well as the rate of hospitalization for patients diagnosed with severe heart failure due to left ventricular dysfunction. Eplerenone does not have the antiandrogenic effects associated with spironolactone, since it is a selective aldosterone inhibitor.15