Captopril: An Update Review of its Pharmacological Properties and Therapeutic Efficacy in Congestive Heart Failure
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Synopsis: Captoprl1 is the first angiotensin-converting enzyme inhibitor for oral administration. In combination with continued digitalis and diuretic therapy it has been demonstrated to be effective in the management of severe heart failure refractory to optimal digitalis, diuretic and, in many patients, vasodilator treatment. Most studies to date have been open trials of several weeks or months duration, but a number of patients have received continued treatment, with sustained benefit, for up to 1 year or more. A placebo-controlled trial in a limited number of patients with less severe heart failure has confirmed the results of open trials. Captopril administration improves cardiac performance as a result of a reduction in systemic vascular resistance (afterload) and the various determinants of left ventricular filling pressure (preload). Improvements in exercise tolerance and functional classification, with associated reduction of clinical symptomatology, occur with simultaneous decreases in myocardial oxygen consumption.
At present, captopril is worthy of a trial in patients refractory to more traditional medical management. Whether it should be considered a ‘first-line’ agent after failure of optimal digitalis and diuretic therapy, and before instituting other vasodilator therapy, is less clear. In patients with severe or resistant heart failure, a response to captopril is usually accompanied by a general improvement in the quality of life. The effect of captopril treatment on 1- and 2-year survival rates in patients with severe heart failure appears similar to that reported for other vasodilators. Most patients tolerate captopril treatment well, but hypotension, reduced renal function, skin rash, dysgeusia, and neutropenia have been reported.
Pharmacodynamic Studies: Captopril is an orally effective inhibitor of angiotensin-converting enzyme, the enzyme responsible for conversion of inactive angiotensin I to angio tensin II. Angiotensin II is a potent vasoconstrictor and stimulator of aldosterone production and release. Captopril administration to normotensive and hypertensive animals and man, and to heart failure patients, reduces plasma angiotensin II and plasma and urinary aldosterone concentrations, and elevates plasma renin activity.
Part of captopril’s action may result from its influence on the kallikrein-kinin-prostaglandin system. However, data in this area have often been divergent, requiring additional study before definitive conclusions can be made. Although a reduction in urinary kallikrein activity follows captopril administration in animals and man, the clinical significance of this finding is not known. Some studies in man and animals reported increases in plasma and urinary bradykinin after captopril therapy, but other studies did not. No effect on plasma bradykinin was observed in 7 congestive heart failure patients treated with captopril. In vitro data suggest that captopril has a direct effect on prostacyclin production. In animal studies indomethacin has reduced captopril potentiation of bradykinin-induced bronchoconstriction and hypotension and prostaglandin release, but no antagonism of captopril’s effect on renal haemodynamics was observed. Either no change or increases in urinary prostaglandin E2 or F2α metabolites have followed captopril administration, and increases have correlated with the hypotensive response. The contribution of these effects to the action of captopril are not known.
In short term haemodynamic studies of captopril in patients with severe congestive heart failure, a number of beneficial effects have been observed. Administration of captopril (12.5 to 150mg) results in consistent increases in cardiac output (25 to 30%), cardiac index (15 to 40%) and stroke volume index (18 to 49%). The effects are accompanied by reductions in systemic vascular resistance (20 to 45%), pulmonary vascular resistance (35 to 45%), total vascular resistance (25 to 35%), pulmonary artery pressure (15 to 30%), pulmonary capillary wedge pressure (25 to 50%) and right atrial pressure (25 to 45%). A consistent fall in mean arterial pressure (7 to 25%) is generally seen but it rarely becomes symptomatic. After short term administration a slight reduction in heart rate occurs which generally returns to pre-captopril levels with long term therapy. Occasionally, a more marked reduction in heart rate may occur.
In studies involving a small number of patients with heart failure, a reduction in coronary blood flow (14%), which correlated with a fall in myocardial oxygen demand, has been observed with simultaneous increases in cardiac index and reduction in systemic vascular resistance. Preliminary data comparing captopril with hydralazine and prazosin suggest that captopril improves cardiac performance as do the other agents, but captopril has a greater effect on lowering myocardial oxygen demand.
In limited studies involving heart failure patients, divergent findings regarding the short term effect of captopril on renal blood flow, filtration fraction and glomerular filtration have been reported. Most short term studies report an increase in renal blood flow and a reduction in filtration fraction with no consistent effect on glomerular filtration rate. Transient deterioration in these parameters has also been observed, which correlates with the short term blood pressure-lowering effect. With continued therapy, these parameters return to pre-captopril levels as a result of reduced renal vascular resistance. However, long term captopril therapy has usually resulted in improved renal function in severely ill patients with heart failure. Additionally, pre-existing hyponatraemia and hypokalaemia have been normalised during long term captopril administration.
Pharmacokinetic Studies: In healthy fasting patients, 70% of an orally administered dose of captopril is absorbed. In heart failure patients a single dose of 25mg produced peak blood concentrations of about 120 ng/ml 1.4 hours after administration. Captopril is about 30% protein bound. In rats it does not enter the central nervous system, and in humans does not readily enter breast milk. Approximately 35% of a dose undergoes renal elimination as unchanged drug. Renal elimination correlates with creatinine clearance, requiring dosage adjustment in more severe stages of renal dysfunction.
Therapeutic Trials: Studies to date have primarily involved patients with severe, often resistant, heart failure. All patients received continued therapy with digitalis and diuretics during captopril administration. Many open trials involving small numbers of these patients (New York Heart Association Functional Class III or IV) have clearly demonstrated the effectiveness of captopril. Captopril administration (37.5mg to 450mg daily) for several weeks or months, or in a number of patients for 1 year or more, has resulted in sustained improvement in cardiac haemodynamics, similar to those observed after short term administration. Improved ejection fraction (22 to 120%), reductions in left ventricular diastolic dimension (7%), and increased exercise tolerance time (33 to 83%) accompanied a reduction in cardiac oxygen utilisation, and improvement in New York Heart Association Functional Class has reflected improvement in cardiac haemodynamics. These beneficial effects have been confirmed in a double-blind placebo-controlled evaluation in patients with somewhat less severe heart failure.
Side Effects: The most frequently observed side effect associated with captopril administration to heart failure patients is hypotension. Approximately 50% of patients experience an acute fall in mean arterial pressure of 20%, which is rarely symptomatic and with continued therapy usually returns to levels not significantly different from baseline values. When symptoms have occurred, they usually subsided despite continued therapy, or with a dosage reduction of either captopril or the concomitantly administered diuretic. Skin rash (7% of patients) and taste alterations (3%) have also been reported in heart failure patients. (Interestingly, their incidence is approximately 50% of that seen in the hypertensive population.) Both of these side effects are reversible with discontinuation of therapy, or in some cases with continued therapy at the same or lower doses.
The most frequent haematological reaction associated with captopril is neutropenia. Most recent evidence suggests that in patients with normal renal function the incidence of neutropenia associated with captopril is low (0.02%), but the incidence is higher in patients with renal dysfunction (0.4%), and much higher in patients with elevated serum creatinine as well as collagen-vascular diseases such as lupus or scleroderma (7.2%). Transient deterioration in renal function tests has been associated with the initial fall in mean arterial pressure. About 20% of heart failure patients experience modest deterioration in renal function tests usually with stabilisation at a new level. Occasionally, severe deterioration has occurred which responded to discontinuation of therapy. However, in a limited number of long term treated severe heart failure patients with pre-existing renal disease, improvement in indexes of renal function has resulted. Although proteinuria (1.1%) and a few cases of nephrotic syndrome have occurred in hypertensive patients on long term treatment with captopril, similar findings have not been observed to date in the heart failure population with the exception of a single patient who developed the nephrotic syndrome, reflecting either the limited long term treatment experience in this population, a different effect of the diseases on the kidney or the generally lower doses of captopril used in patients with heart failure.
Dosage and Administration: The usual initial dosage of captopril for the management of the heart failure patient refractory to optimal therapy with digitalis and diuretics and/ or vasodilators is 25mg 3 times daily. Initial doses lower than 25mg may minimise any hypotensive effect and in some patients may be therapeutically adequate. Patients have responded to doses as low as 6.25mg. Subsequent dosage should be titrated and individualised according to clinical response, with most patients requiring 25 to 50mg 3 times daily. Wherever possible, increases in dosage beyond 50mg 3 times daily should be instituted only after a minimum interval of 2 weeks to allow adequate time for the maximum response at the previous dosage level to occur. The maximum recommended dose is 450mg daily. Careful blood pressure monitoring during dosage titration is essential because of potentially abrupt blood pressure falls. Particular caution in this regard is necessary in sodium- or volume-depleted patients. Optimum digitalis and diuretic therapy should be continued during captopril administration. Since potassium retention may accompany captopril therapy, potassium-sparing diuretics and potassium supplements should be used with caution. Routine periodic assessment of urinary protein should be performed in patients with a history of renal disease, or who are receiving high doses of captopril. Periodic evaluation of haematological status, especially white cell count, is necessary for ‘high risk’ patients; i.e., those with renal impairment, connective tissue disease and/or patients receiving other drugs known to affect the white blood cells or immune response. Dosage should be adjusted according to creatinine clearance in patients with severe renal disease, using the established guidelines.
KeywordsHeart Failure Captopril Heart Failure Patient Prazosin Renal Blood Flow
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