Medicinal Chemistry and Pharmaceutical Properties of Enalapril Including Physiology and Molecular Mechanisms of Hypertension

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Abstract
Enalapril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension, cardiac failure, diabetic nephropathy and progressive renal insufficiency. This essay evaluates the medicinal chemistry and pharmaceutical properties of the drug enalapril including the physiology of hypertension, pharmacodynamics, chemical structure, pharmacokinetics, toxic effects and molecular mechanisms of its therapeutic properties. Since the introduction of captopril, ACE inhibition has been an integral part in the therapy of primary and second hypertension (Bajaj, 1988). The toxicity profile of captopril related to the sulfhydryl group lead to the development of enalapril. The therapeutic effects of enalapril have been extremely effective in treating hypertension. However, while the safety and efficacy of enalapril has been well documented, there is also evidence of various side effects associated with its administration. But the benefits clearly outweigh the toxic side effects and ACE inhibitors are continually improving to minimise these side effects. In view of the efficacy and limited toxicity of enalapril, it should be strongly considered as the first line converting enzyme inhibitor.

Introduction
Enalapril is an example of an angiotensin converting enzyme (ACE) inhibitor, clinically used to treat hypertension as well as cardiac failure, diabetic nephropathy and progressive renal insufficiency (Rang et al. 2007). ACE inhibitors are developed to mainly treat hypertension by modifying the renin-angiotensin-aldosterone system (RAAS). Potency, efficacy and adverse effects of ACE inhibitors vary due to its chemical structures. Moreover, the chemical structure influences the metabolism of the drug which determines its absorption, onset of action, duration, distribution and elimination. Enalapril is the first member of the group of ACE inhibitors known as the dicarboxylate-containing ACE inhibitors.

Disease state - Hypertension
Hypertension, more commonly high blood pressure is the most common form of blood pressure anomaly. It occurs when the blood pressure reaches above 140/90 mmHg (Sherwood, 2007). There are two types of hypertension, primary (or essential) and secondary. Patients with secondary hypertension generally have an underlying adrenal or renal disease, which causes a raise in blood pressure. Primary hypertension accounts for 90% of all hypertension cases, however, is due to a number of factors, including obesity, stress, smoking, excessive salt intake and defective salt management by the kidneys (Sherwood, 2007). Other contributing factors may include insulin resistance, the renin-angiotensin system, the sympathetic nervous system, genetics, endothelial dysfunction, low birth weight, intrauterine nutrition, and neurovascular abnormalities (Beevers et al. 2001). Normal blood pressure is maintained by achieving a balance between cardiac output and peripheral vascular resistance; patients with primary hypertension generally have an increased peripheral resistance in the smaller arterioles, the arterioles that contain smooth muscle cells within the walls (Beevers et al. 2001). Ongoing smooth muscle constrictions cause arteriolar vessel walls to thicken; this structural change is mediated by angiotensin, resulting in an irreversible rise in peripheral resistance (Beevers et al. 2001). Conversely, once the underlying defect causing hypertension initiates, hypertension self-perpetuates because continuous exposure to elevated blood pressure predisposes vessel walls to developing atherosclerosis, a chronic inflammatory response in the arteriole walls resulting in deposition of lipoproteins and consequently a hardening of the arteries, resulting from the formation of multiple plaques (Sherwood, 2007). Atherosclerosis then leads to a further raise in blood pressure.

Figure 1: The Renin-Angiotensin System and its effects on blood pressure and aldosterone release (Beevers et al., 2001) RAAS...
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