Captopril is an angiotensin converting enzyme inhibitor which is used in the treatment of hypertension and heart failure.
The mechanism of action of captopril has not yet been fully elucidated. It appears to lower blood pressure and be an adjunct in the therapy of congestive heart failure primarily through suppression of the renin-angiotensin-aldosterone system; however, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.
Captopril prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase.
ACE is identical to “bradykininase”, and captopril may also interfere with the degradation of the vasopressor peptide, bradykinin. However, the effectiveness of captopril in therapeutic doses appears to be unrelated to potentiation of the actions of bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril, especially in low-renin hypertension.
Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss.
The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood.
Administration of captopril results in a reduction of peripheral arterial resistance in hypertensive patients with either no change, or an increase, in cardiac output. There is an increase in renal blood flow following administration of captopril and glomerular filtration rate is usually unchanged. In instances of rapid reduction of long-standing or severely elevated blood pressure, the glomerular filtration rate may decrease transiently.
Peak reductions of blood pressure usually occur within 60 to 90 minutes after oral administration of a single dose of captopril. The duration of effect appears to be dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of captopril and thiazide-type diuretics appear to be additive. In contrast, captopril and beta-blockers have a less than additive effect.
Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients. Abrupt withdrawal of captopril has not been associated with a rapid increase in blood pressure.
The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in non-blacks.
In patients with heart failure, captopril significantly decreased systemic vascular resistance (afterload), reduced pulmonary capillary wedge pressure (preload) and pulmonary vascular resistance, increased cardiac output (stroke index), and increased exercise tolerance time (ETT). Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal.
Captopril has been studied in patients with diabetic nephropathy, most of whom had hypertension, with type I insulin-dependent diabetes mellitus, retinopathy and proteinuria ≥500 mg/day, in a multicenter, double-blind, placebo controlled trial. In this study, captopril has shown to decrease the rate of progression of renal insufficiency and to reduce associated clinical sequelae for the combined end-point of end-stage renal disease (dialysis or renal transplantation) or death (from all causes). The effect on reduction of all-cause mortality alone was not statistically significant. No dosage adjustment was made according to creatinine clearance. Patients who had already progressed to severe renal failure were not included in the clinical trial.
Studies in rats and cats indicate that captopril does not cross the blood-brain barrier to any significant extent.
