Studies on the inhibitors of angiotensin converting enzyme

Hodsman, George Peter (1983) Studies on the inhibitors of angiotensin converting enzyme. MD thesis, University of Glasgow.

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Several aspects of the pharmacological properties, therapeutic efficacy, side-effects and tolerability of captopril and two new converting enzyme inhibitors have been examined. CAPTOPRIL (a) Therapeutic efficacy The long-term use of captopril has been examined in 70 patients with severe hypertension resistant to previous conventional antihypertensive therapy. Good blood pressure control was achieved in nearly all patients, with essential and secondary forms of hypertension, but most required large doses of loop diuretic. Diuretic-induced tachycardia occurred in one third of patients but there were few instances of electrolyte disturbance or deterioration in renal function. (b) First dose hypotensive effect. In this study, 8% of 65 severely hypertensive patients sustained an acute reduction of mean arterial pressure in excess of 50% within two hours of receiving captopril. Six patients developed symptoms of acute hypotension, including dizziness, stupor, dysphasia and hemiparesis. Analysis of several pre-treatment variables, including renal function, serum sodium and severity of blood pressure, did not permit consistent prediction of a severe first dose effect in individual patients. (c) Side-effects In a study of 100 consecutive patients treated with captopril, a 20% incidence of toxic side-effects was encountered. Analysis shows that the serious side- effects of proteinuria and neuropathy occurred only in patients with poor renal function who received high doses of captopril. There was no evidence in this study that the minor side-effects of taste loss and skin rash were related to dose or renal function, and occurred occasionally even when captopril dosage was low. (d) Tolerability and mood change. Despite the high incidence of adverse reactions and side-effects, captopril was well accepted. Many patients commented on an enhanced sense of well-being while taking captopril when compared with their previous antihypertensive therapy. A possible euphoriant property of captopril was thus examined in a placebo-controlled trial in 8 patients with moderate hypertension. This showed no evidence of mood enhancement while taking captopril, indeed there was statistically significant lowering of mood when compared with placebo. It is likely that the well-being experienced while taking captopril reflects the absence of mood lowering side- effects of previous therapy. ENALAPRIL (MK421) AND LYSINE ANAL'OGUE (a) Pharmacological properties. The immediate and long-term effects of these new inhibitors on blood pressure, serum electrolytes, renin- angiotensin system and sodium balance have been assessed and compared in a placebo-controlled study of 12 healthy subjects. In a dose of 10 mg once daily, MK421 and MK521 were shown to be potent inhibitors with a long duration of action. Both inhibitors fully suppressed converting enzyme activity and plasma angiotensin II 6 hours after administration but the effects of MK521 were more long-lasting. In this study in which sodium intake was fixed, a significant natriuresis occurred during the administration of both drugs, although this effect had largely disappeared after 8 days. Both drugs were well- tolerated and there were no serious side-effects. (b) Therapeutic efficacy and tolerabllity. The therapeutic effects of enalapril have been assessed in a long-term study of 20 hypertensive patients with renal artery stenosis. Ten patients had previous therapy withdrawn and detailed measurements of changes in blood pressure, serum and body electrolytes, and components of the renin-angiotensin system were made. In doses of 10-40 mg once daily there was sustained suppression of plasma angiotensin II and all patients achieved good blood pressure control. Nine patients had evidence of a significant natriuresis with a fall in total exchangeable sodium. All patients had a small but significant rise in serum creatinine but none suffered marked renal impairment. Ten further patients (five with bilateral renal artery stenosis) were too ill to be studied to the above protocol. All were started on enalapril and previous therapy was then gradually removed when possible. Even in this group with many adverse features, excellent blood pressure control was achieved by all patients and only three required additional therapy. There were no cases of deterioration in renal function even in the patients with bilateral arterial disease. Enalapril was well-tolerated by all patients and there were no serious side-effects.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Ian Robertson
Keywords: Pharmacology
Date of Award: 1983
Depositing User: Enlighten Team
Unique ID: glathesis:1983-72628
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 11 Jun 2019 11:06

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