CAPTOPRIL is a sulfhydryl containing dipeptide surrogate of proline which abolishes the pressor action of Angiotensin – I but not that of Angiotensin – II: does not block AT1 or AT2 receptors.
Angiotensin Converting Enzyme (ACE) is a relatively nonspecific enzyme; splits off a dipeptidyl segment from several peptides including bradykinin, substance P, a natural stem cell regulating peptide, etc. In additional to Angiotensin-I.As such, captopril increases plasma kinin levels and potentiates the hypotensive action of exogenously administered bradykinin.
Pretreatment with B2 kinin receptor antagonists has shown that kinins do contribute to the acute vasodepressor action of Angiotensin Converting Enzyme (ACE) inhibitors, but they appear to have little role in the long-term hypotensive effects, probably because, firstly kinins play only a minor role, if at all, in BP regulation, and, secondly another enzyme ‘Kininase I’ (which also degrades bradykinin) is not inhibited by captopril.
Nevertheless, elevated kinins (and Prostaglandins (PGs) whose synthesis is enhanced by kinins) may be responsible for cough and angioedema induced by Angiotensin Converting Enzyme inhibitors in susceptible individuals.
Angiotensin Converting Enzymes (ACE) inhibitors interfere with degradation of substance P also. Rise in the level of stem cell regulator peptide caused by Angiotensin Converting Enzyme (ACE) inhibitors could, in part, be responsible for their cardioprotective effect in Congestive Heart Failure (CHF).
Captopril induced hypotension is a result f decrease in total peripheral resistance. The arterioles dilate and compliance of larger arteries is increased. Both systolic and diastolic BP fall. It has no effect on cardiac output. Cardiovascular reflexes are not interfered with and there is little dilatation of capacitance vessels. As such, postural hypotension is not a problem. Reflex sympathetic stimulation does not occur despite vasodilation, and ACE inhibitors can be safely used in patients with ischemic heart disease. The renal blood flow is not compromised even when BP falls substantially. This is due to greater dilation of renal vessels (Angiotensin-II markedly constrict them). Cerebral and coronary blood flow are also not compromised.
The adverse effects profile of all ACE inhibitors is similar. Captopril is well tolerated by most patients, especially if daily dose is kept below 150 mg.
- Hypotension: an initial sharp fall in BP occurs especially in diuretic treated and CHF patients; persistent hypotension may be troublesome in MI patients.
- Hyperkaliemia: more likely in patients with impaired renal function and in those taking K+ sparing diuretics, NSAIDs or Beta blockers. In others significant rise in plasma K+ is rare.
- Cough: a persistent brassy cough occurs in 4-16% patients within 1-8 weeks, often requires discontinuation of the drug-subsides 4-6 days thereafter. It is not dose related and appears to be caused by inhibition of bradykinin/substance P breakdown in the lungs of susceptible individuals.
- Rashes, urticaria: occurs in 1-4% recipients; but do not usually warrant drug discontinuation.
- Angioedema: resulting in swelling of lips; mouth, nose, larynx may develop within hours to few days in 0.06-0.5% patients; may cause airway obstruction. This can be treated with adrenaline, antihistaminic and corticosteroids according to need.
- Dysgeusia: reversible loss or alteration of taste sensation due to captopril occurs in few patients. A still lower incidence with other ACE inhibitors has been noted.
- Foetopathic: foetal growth retardation, hypoplasia of organs and foetal death may occur if ACE inhibitors are given during later half of pregnancy. A recent report indicates 2.7-fold higher malformation rate in fetuses exposed to ACE inhibitors must be stopped when the women conceives.
- Headache, dizziness, nausea and bowel upset: each reported in 1-4% patients.
- Granulocytopenia and proteinuria: are rare, but warrant withdrawal. Renal disease predisposes to these adverse effects. However, ACE inhibitors retard diabetic nephropathy, reduce attendant proteinuria, and are renoprotective.
- Acute renal failure: is precipitated by ACE inhibitors in patients with bilateral renal artery stenosis due to dilatation of efferent arterioles and fall in glomerular filtration pressure. ACE inhibitors are contraindicated in such patients.
- Diuretics synergize with the hypotensive action of ACE inhibitors by depleting Na+ and raising renin levels. In diuretic treated patients, the starting dose of ACE inhibitors should be low.
- Indomethacin (and other NSAIDs) attenuate the hypotensive action by retaining salt and water. Incidents of renal failure have been reported when a NSAID was given to patients (especially elderly) receiving ACE inhibitor + diuretic.
- Hyperkalaemia can occur if K+ supplements/K+ sparing diuretics are given with captopril.
- Antacids reduces bioavailability of captopril.
- ACE inhibitors reduce Li+ clearance and predispose to its toxicity.