Pharmacokinetic Studies and Side effect of Captopril

Captopril is the first orally active inhibitor of angiotensin-converting enzyme, the enzyme responsible for conversion of inactive angiotensin I to the potent pressor peptide angiotensin II. Captopril is a potent, relatively specific competitive inhibitor of angiotensin-converting enzyme (kininase II), as well as an effective antihypertensive agent. Prior experience with the nonapeptide inhibitor of angiotensin-converting enzyme, teprotide, demonstrated that this parenterally administered agent was effective in the treatment of most patients with hypertension.

Figure1: Picture of Captopril

Overview

Captopril represents the first orally available inhibitor of angiotensin‑converting enzyme and has so far been primarily investigated in the context of hypertension. In mild to moderate essential hypertension, it demonstrates efficacy comparable to that of standard doses of hydrochlorothiazide or propranolol, with approximately half of such patients requiring the addition of a diuretic to achieve adequate blood‑pressure control. In severe hypertension, the combination of captopril with a diuretic—and in certain cases a β‑blocker—typically produces a more pronounced reduction in blood pressure than ‘standard triple therapy’ in patients who have responded inadequately to conventional regimens, often accompanied by an improved sense of well‑being in those previously on intensive multidrug therapy. At its current stage of development, captopril is considered most appropriate for patients who either do not respond to or cannot tolerate traditional antihypertensive medications. Although generally well tolerated, captopril has been associated with several notable or potentially serious adverse effects, including agranulocytosis, dysgeusia, and impaired renal function. While a direct causal link to captopril has not always been established, the ultimate role of this agent in hypertension management may depend on further clarification of its safety profile. Beyond hypertension, captopril has also shown promising clinical improvement in a limited number of patients with severe congestive heart failure refractory to conventional treatment. Captopril undoubtedly constitutes a valuable addition to the therapeutic arsenal. Together with future pharmacologically related compounds, it will continue to attract considerable interest as its definitive position in clinical practice becomes clearer through well‑designed studies and expanded clinical experience. [1]

Pharmacokinetic Studies

Pharmacokinetic data for Captopril in man are limited. About 70% of an oral dose is absorbed by healthy subjects. The drug is about 30% bound to plasma protein. Captopril does not appear to enter readily into the central nervous system or into breast milk. More than 30% of an oral dose is excreted unchanged in the urine, about another 30% appearing in the urine as polar metabolites. In patients with renal dysfunction the overall (Captopril plus metabolites) elimination rate correlated closely with Creatinine clearance; the dose should be appropriately reduced in patients with moderate to severe renal impairment. [1]

Hypertension Research

Although in most studies in patients with hypertension Captopril was given in 3 or 4 divided doses, there is some evidence that twice daily administration provides adequate blood pressure control throughout the day. The relationship between pretreatment plasma renin activity and blood pressure-lowering response to Captopril is somewhat unsettled, some authors reporting a close correlation and others finding none. However, when results of a multicentre study were pooled, an increased response in high renin patients was apparent, although Captopril may lower blood pressure also in normal or low renin states. In addition to studies in hypertension, a few small studies in severe treatment-resistant congestive heart failure have shown encouraging improvement in indexes of cardiac function (cardiac output, cardiac index, stroke volume, and ejection fraction increased; pulmonary resistance, and left ventricular end diastolic dimension decreased), and in exercise performance (exercise time usually increased by about 50 to 60%) and symptomatology in patients receiving Captopril 25 to 150mg 3 times daily for up to 6 months. [1]

Effect on Heavy Proteinuria

This study investigated the potential of the angiotensin‑converting‑enzyme inhibitor captopril to reduce proteinuria in patients with advanced diabetic nephropathy. Ten azotemic diabetic patients with heavy proteinuria were treated with captopril at a dosage of 37.5 mg administered in three divided doses daily. Within two weeks of treatment, urinary protein excretion decreased significantly—from 10.6 ± 2.2 g per day to 6.1 ± 1.4 g per day (mean ± SEM, P < 0.01). This reduction in proteinuria was not accompanied by a concurrent decline in systemic blood pressure or blood glucose levels. Serum creatinine and potassium levels remained stable in all but one patient. These findings suggest that captopril may lower intrarenal hypertension, thereby contributing to decreased urinary protein excretion. The clinical therapeutic significance of this intervention requires further confirmation. [2]

Therapeutic Trials

In open studies in patients with essential or renovascular hypertension, often not responding to ‘optimal conventional therapy’, Captopril (usually 200 to 400mg daily) reduced both systolic and diastolic blood pressure by about 20 to 25% in responding patients; about 50% or more of these moderately to severely hypertensive patients required the addition of a diuretic for satisfactory blood pressure control. In placebo comparisons, Captopril (usually up to 450mg daily) reduced systolic and diastolic pressures by about 15 to 25% in mild to moderate essential or renovascular hypertension, or in a few patients with hypertension related to chronic renal failure, but as in open studies ‘satisfactory’ blood pressure control often required the addition of a diuretic. In patients treated for ‘longer’ periods in such studies there was no evidence of decreased effectiveness of Captopril after periods of up to 2 years. In single-blind comparative studies with other antihypertensive drugs, Captopril, hydrochlorothiazide (up to 100mg daily) or Propranolol (up to 360mg daily) were about equally effective in patients with mild to moderate essential or renovascular hypertension. In severe resistant hypertension Captopril alone usually lowered blood pressure to about the same level as with standard ‘triple therapy’ (consisting of hydrochlorothiazide 100mg, Propranolol 320mg and hydralazine 200mg daily), but neither treatment adequately controlled blood pressure in most of these ‘resistant’ patients. However, a combination of Captopril plus a diuretic, and in some patients a βr-blocker, usually reduced blood pressure more than was achieved with standard triple therapy, although a small number of patients could not be adequately controlled on any combination used. [1]

Side effect

Reversible deterioration in renal function (accompanied by hyperkalaemia in 1 patient) occurred in a few patients with pre-existing renal disease, or renal transplants, receiving widely varying doses of Captopril (25 to 450mg daily). A clear relationship to Captopril was demonstrated by rechallenge in 1 patient. Whether such changes were due to a nephrotoxic effect of the drug or were secondary to haemodynamic changes is unclear. Proteinuria occurred in about 2% of patients treated for 8 months or more, and the nephrotic syndrome, and/or evidence of membranous glomerulopathy, have been reported in a small number of patients receiving Captopril. Tachycardia on standing has occasionally occurred, and chest pain and acute myocardial infarction have been reported in isolated individuals during treatment with Captopril. Postural hypotension has not been a common problem during Captopril treatment. [1]

Dosage and Administration

During Captopril therapy urinary protein loss and haematological status should be monitored periodically. In the presence of sodium depletion (which would include some patients receiving a diuretic) the first few doses may produce dramatic reductions in blood pressure. Since Captopril may increase serum potassium concentrations, potassium supplements or potassium-sparing diuretics should be used only if clearly required, and then with caution. In hypertension treatment may be initiated with 25mg 3 times daily taken on an empty stomach, increasing to 50mg 3 times daily after 1 to 2 weeks if required. After a further 1 to 2 weeks a diuretic may be added in gradual dosage increments if necessary. If response is inadequate when the usual maximum dosage of the diuretic is reached, the Captopril dose may be further increased in increments to a maximum of 150mg 3 times daily, with continued administration of the diuretic. If rapid blood pressure reduction is necessary the dose of Captopril may be increased at 24-hour intervals, but a maximum dose of 450mg daily should not be exceeded. [1]

Reference

[1] Romankiewicz J A, Brogden R N, Heel R C, et al. Captopril: an update review of its pharmacological properties and therapeutic efficacy in congestive heart failure[J]. Drugs, 1983, 25(1): 6-40.

[2] Taguma Y, Kitamoto Y, Futaki G, et al. Effect of captopril on heavy proteinuria in azotemic diabetics[J]. New England Journal of Medicine, 1985, 313(26): 1617-1620.

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