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indicationFor the treatment of essential or renovascular hypertension and symptomatic congestive heart failure. It may be used alone or in combination with thiazide diuretics.
pharmacologyEnalapril is a prodrug that is rapidly metabolized by liver esterases to enalaprilat following oral administration. Enalapril itself has little pharmacologic activity. Enalaprilat lowers blood pressure by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of enalaprilat by causing increased vasodilation and decreased blood pressure.
mechanism of actionThere are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Enalaprilat, the principle active metabolite of enalapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Enalapril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Enalaprilat's affinity for ACE is approximately 200,000 times greater than that of ATI and 300-1000 times greater than that enalapril.
toxicityOverdosage may result in marked hypotension and stupor. Most common adverse effects include hypotension, headache, dizziness and fatigue.
biotransformation~ 60% of absorbed dose is extensively hydrolyzed to enalaprilat, primarily by liver esterases
absorption55-75%, absorption is unaffected by food; enalaprilat (clinically administered IV) is poorly absorbed, 3-12%, due to its high polarity.
half life< 2 hours for unchanged enalapril in health individuals, may be increased in those with congestive heart failure (3.4 and 5.8 hours for single 5- and 10-mg doses, respectively). The average terminal half life of enalaprilat is 35-38 hours. The effective half life following multiple doses is 11-14 hours.
route of eliminationExcretion of enalapril is primarily renal.
drug interactionsAmiloride: Increased risk of hyperkalemia
Drospirenone: Increased risk of hyperkalemia
Lithium: The ACE inhibitor increases serum levels of lithium
Potassium: Increased risk of hyperkalemia
Rifampin: Rifampin, a strong CYP3A4 inducer, may increase the metabolism of enalapril. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of enalapril if rifampin is initiated, discontinued or dose changed.
Spironolactone: Increased risk of hyperkalemia
Tizanidine: Tizanidine increases the risk of hypotension with the ACE inhibitor
Tobramycin: Increased risk of nephrotoxicity
Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Triamterene: Increased risk of hyperkalemia