Angiotensin Converting Enzyme Inhibitors

ANGIOTENSIN CONVERTING ENZYME INHIBITORS

Teprotide was the first ACE inhibitor to be synthesized taking a lead from the bradykinin potentiating factor (BPF) found in pit viper venom and the finding that the kininase was also ACE. Teprotide, a nonapeptide inhibited generation of AII from AI and lowered BP. However, it had limitations of parenteral administration and brief duration of action.

Captopril, an orally active dipeptide analogue was introduced in 1977 and quickly gained wide usage. A multitude of ACE inhibitors have since been added, of which—captopril, enalapril, lisinopril, benazepril, ramipril, fosinopril, trandolapril, imidapril and perindopril are available in India. Some others like quinapril, cilazapril zofenopril, etc. are marketed in other countries. The pharmacology of captopril is described as prototype, since most of its effects are class effects common to all ACE inhibitors.

Captopril

It is a sulfhydryl containing dipeptide surrogate of proline which abolishes the pressor action of AI but not that of AII: does not block AII receptors.

Captopril can also increase plasma kinin levels and potentiate the hypotensive action of exogenously administered bradykinin. Pretreatment with B2 kinin receptor antagonist has shown that kinins do contribute to the acute vasodepressor action of ACE inhibitors, but they appear to have little role in the long-term hypotensive effect, probably because kinins play only a minor role, if at all, in BP regulation, and another enzyme ‘Kininase I’ (which also degrades bradykinin) is not inhibited. Nevertheless, elevated kinins (and PGs whose synthesis is enhanced by kinins) may be responsible for cough and angioedema induced by ACE inhibitors in susceptible individuals. ACE inhibitors interfere with degradation of substance P also.

Captopril lowers BP, but in the short-term, magnitude of response is dependent on Na⁺ status and the level of renin-angiotensin activity. In normotensive Na⁺ replete individuals, the fall in BP attending initial few doses of ACE inhibitors is modest. This is more marked when Na⁺ has been depleted by dietary restriction or diuretics. A greater fall in BP occurs in renovascular, accelerated and malignant hypertension. In essential hypertension it has been found that RAS is overactive in 20%, normal in 60% and hypoactive in the rest. Thus, it contributes to maintenance of vascular tone in over 80% cases and its inhibition results in lowering of BP. However, in the long-term no correlation has been observed between plasma renin activity (PRA) and magnitude of fall in BP due to captopril.

Captopril induced hypotension is a result of 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 vasodilatation. They can be safely used in patients with ischaemic heart disease. The renal blood flow is not compromized even when BP falls substantially. This is due to greater dilatation of renal vessels (AII markedly constricts them). Cerebral and coronary blood flow are also not compromized.

Reflex (postural) changes in plasma aldosterone are abolished and basal levels are decreased as a consequence of loss of its regulation by AII. However, physiologically sufficient mineralocorticoid is still secreted under the influence of ACTH and plasma K⁺ . Levels of plasma renin and AI are increased as a compensatory measure, but the physiological significance of this appears to be minor (most actions are exerted through generation of AII).

Pharmacokinetics

About 70% of orally administered captopril is absorbed. Presence of food in stomach reduces its bioavailability. Penetration in brain is poor. It is partly metabolized and partly excreted unchanged in urine. The plasma t½ is ~2 hours, but actions last for 6–12 hours.

Adverse Effects

The adverse effect 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.

Hyperkalaemia: more likely in patients with impaired renal function and in those taking K⁺ sparing diuretics, NSAIDs or β 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: occur in 1–4% recipients; does 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; treat with Adr, antihistaminics, corticosteroids according to need.

Dysgeusia: reversible loss or alteration of taste sensation due to captopril has an incidence of 0.5–3%; 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 2.7fold higher malformation rate in foetuses exposed to ACE inhibitors in the first trimester. ACE inhibitors must be stopped when the woman 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.

Interactions

Indomethacin (and other NSAIDs) attenuate the hypotensive action. 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 reduce bioavailability of captopril, while ACE inhibitors reduce Li⁺ clearance and predispose to its toxicity.

Dose 25 mg BD, increased gradually upto 50 mg TDS according to response. In patients on diuretics and in CHF patients it is wise to start with 6.25 mg BD to avoid marked fall in BP initially. Tablets should be taken 1 hr before or 2 hr after a meal. It has become less popular due to need for twice/thrice daily dosing and possibly higher incidence of side effects compared to other ACE inhibitors. ANGIOPRIL 25 mg tab, ACETEN, CAPOTRIL 12.5, 25 mg tab.

Other ACE Inhibitors

Differences among ACE inhibitors are primarily pharmacokinetic reflected in time course of their action; no single drug is superior to others.

Enalapril

This is the second ACE inhibitor to be introduced. It is a prodrug—converted in the body to enalaprilat (a tripeptide analogue), which is not used as such orally because of poor absorption, but is marketed as injectable preparation in some countries. Enalapril has the same pharmacological, therapeutic and adverse effect profile as captopril, but may offer certain advantages:

·      More potent, effective dose 5–20 mg OD or BD.

·      Its absorption is not affected by food.

·      Onset of action is slower (due to need for conversion to active metabolite), less liable to cause abrupt first dose hypotension.

·      Has a longer duration of action: most hypertensives can be treated with single daily dose.

·      Rashes and loss of taste are probably less frequent.

ENAPRIL, ENVAS, ENAM 2.5, 5, 10, 20 mg tab.

Lisinopril

It is the lysine derivative of enalaprilat: does not require hydrolysis to become active ACE inhibitor. Its oral absorption is slow (making first dose hypotension less likely) and incomplete, but unaffected by food. The duration of action is considerably longer, permitting single daily dose and ensuring uniform hypotensive action round the clock. A reduction in venous return, cardiac contractility and cardiac output has been noted after few weeks of lisinopril use.

LINVAS, LISTRIL, LIPRIL 2.5, 5, 10 mg tab, LISORIL 2.5, 5, 10, 20 mg tab.

Perindopril

Another long-acting ACE inhibitor with a slow onset of action: less chance of first dose hypotension. Though 66–95% of orally administered perindopril is absorbed, only about 20% is converted to the active metabolite perindoprilat. Extensive metabolism to other inactive products occurs. Efficacy and tolerance of perindopril are similar to other ACE inhibitors.

COVERSYL 2, 4 mg tab.

Fosinopril

This ACE inhibitor is unique in being a phosphinate compound that is glucuronide conjugated and eliminated both by liver and kidney. The t½ is not altered by renal impairment; dose remains the same. However, like most others, it is a prodrug suitable for once daily administration. First dose hypotension is more likely.

Dose: Initially 10 mg (elderly 5 mg) OD; maximum 40 mg/day.

FOSINACE, FOVAS 10, 20 mg tabs.

Trandolapril

It is a carboxyl prodrug that is 40–60% bioavailable in the active form. Absorption is delayed but not decreased by food. The peak effect occurs at 4–6 hours. It is partly metabolized and eliminated both in urine and faeces. The plasma t½ of active metabolite is 16– 24 hours, suitable for once daily dosing.

Dose: 2–4 mg (max 8 mg) OD; ZETPRIL 1, 2 mg tabs.

Ramipril

The distinctive feature of this long-acting ACE inhibitor is its extensive tissue distribution. It may thus inhibit local RAS to a greater extent. Whether this confirs any therapeutic advantage is not known. The plasma t½ of its active metabolite ramiprilat is 8–18 hours, but terminel t½ is longer due to slow release of tissue bound drug.

CARDACE, RAMIRIL, CORPRIL, R.PRIL 1.25, 2.5, 5 mg caps.

Imidapril

The oral bioavailability of this long-acting prodrug ACE inhibitor is 40%, that is reduced by taking with meals. The peak effect occurs at 6–8 hours and plasma t½ is >24 hours.

Dose: Initially 5 mg OD taken 1 hour before food; usual maintenance dose 10 mg OD.

TANATRIL 5, 10 mg tabs.

Benazepril

Another non-sulfhydryl prodrug ACE inhibitor; has a bioavailability of 37% and is excreted by kidney with a t½ of 10–12 hr.

Dose: 10 mg initially, max 20–40 mg/day;

BENACE 5, 10, 20 mg tab.

Uses

Hypertension

The ACE inhibitors are now first line drugs in all grades of hypertension. About 50% patients of essential hypertension respond to monotherapy with ACE inhibitors and majority of the rest to their combination with diuretics or β blockers. The hypotensive effect of lower doses develops gradually over 2–3 weeks. They offer the following advantages:

• Lack of postural hypotension, electrolyte disturbances, feeling of weakness and CNS effects.

• Safety in asthmatics, diabetics and peripheral vascular disease patients.

• Recent evidence indicates that long-term ACE inhibitor therapy has the potential to reduce incidence of type 2 diabetes in high risk subjects.

• Prevention of secondary hyperaldosteronism and K⁺ loss due to diuretics.

•  Renal blood flow is well maintained.

•  They reverse left ventricular hypertrophy and the increased walltolumen ratio of blood vessels that occurs in hypertensive patients.

• No hyperuricaemia, no deleterious effect on plasma lipid profile.

•  No rebound hypertension on withdrawal.

•  Minimum  worsening  of  quality  of  life parameters like general wellbeing, work performance, sleep, sexual performance, etc.

Large multicentric trials have confirmed that ACE inhibitors reduce cardiovascular morbidity and increase life expectancy of hypertensive patients. It appears that by their specific effect on myocardial and vascular cell growth/remodeling, they have greater protective potential than other classes of antihypertensive drugs.

ACE inhibitors are highly effective and first choice drugs in renovascular and resistant hypertension. They are particularly suitable for diabetic hypertensives in whom they reduce cardiovascular complications more than other antihypertensive drugs, probably by improving endothelial function.

CHF

ACE inhibitors cause both arteriolar and venodilatation in CHF patients: reduce afterload as well as preload. Haemodynamic measurements in severe CHF patients have shown reduction in right atrial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, systemic vascular resistance, systolic wall stress and systemic BP. Though they have no direct myocardial action, stroke volume and cardiac output are increased, while heart rate is reduced. Accumulated salt and water are lost due to improved renal perfusion and abolition of mineralocorticoid mediated Na⁺ retention. Cardiac work as measured by heart rate × pressure product is reduced; thereby, exercise capacity of CHF patients is enhanced. Beneficial effects are well sustained with chronic therapy and the NYHA functional class of most patients is improved.

Robust multicentric trials have shown that ACE inhibitors retard the progression of left ventricular systolic dysfunction and prolong survival of CHF patients of all grades (I to IV). Unless contraindicated, ACE inhibitors are now advocated by several professional bodies, including American Heart Association and American College of Cardiology, as first line drugs in all patients with symptomatic as well as asymptomatic left ventricular inadequacy. A diuretic, β blocker with or without digitalis may be added according to need. ACE inhibitors reduce episodes of decompensation, myocardial infarction and sudden death. In addition to improved haemodynamics, long-term benefits of ACE inhibitors accrue from withdrawal of AII mediated ventricular hypertrophy, remodeling, accelerated myocyte apoptosis and fibrosis. Indirect benefits occur due to reduction in sympathetic activation and aldosterone levels.

The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial on 3164 heart failure patients (NYHA class II to IV) has shown that high dose lisinopril (32.5–35 mg/ day) given for 39–58 months was more effective in reducing all cause mortality, hospitalization for heart failure and risk of MI than lower dose (2.5–5 mg/day). To afford maximum protection against progression of heart failure, the dose of ACE inhibitors needs to be titrated to nearly the upper limit of recommended dose range, as shown in other mega trials like GISSI3, SOLVD, AIRE, etc. as well. ACE inhibitors are effective in reducing development of ventricular dysfunction, heart failure and related mortality in post-MI patients also (SAVE, TRACE, AIRE trials).

Myocardial Infarction (MI)

Several megatrials have established that oral ACE inhibitors administered while MI is evolving (within 24 hr of an attack) and continued for 6 weeks reduce early as well as long-term mortality, irrespective of presence or absence of systolic dysfunction, provided hypotension is avoided. In high risk patients and those with latent or overt ventricular dysfunction (CHF) extension of therapy continues to afford survival benefit over years. In unstable angina/non-ST segment elevation MI, long-term ACE inhibitor therapy reduces recurrent MI and need for coronary angioplasty (SAVE and SOLVD trials), though no benefit was apparent in the shortterm (ISIS4 study). Current evidence shows that if there are no contraindications, all MI patients stand to gain from ACE inhibitor therapy, though magnitude of benefit is greatest in those having associated hypertension and/or diabetes.

Prophylaxis In High Cardiovascular Risk Subjects

The results of Heart Outcomes Prevention Evaluation (HOPE) study in 9297 post-MI and other high risk subjects, but having no left ventricular dysfunction or heart failure have shown that ramipril reduced cardiac death and MI or stroke by 22% over a period of 4.5 years. Risk of developing heart failure or diabetes was also reduced. These results have been confirmed by the EUROPA trial and appear to hold true even for patients who have undergone coronary revascularization (APRES trial). Thus, ACE inhibitors are protective in high cardiovascular risk subjects even when there is no associated hypertension or left ventricular dysfunction. Protective effect is exerted both on myocardium as well as vasculature, may involve improved endothelial function, and is independent of hypotensive action.

Diabetic Nephropathy

Prolonged ACE inhibitor therapy has been found to prevent or delay endstage renal disease in type I as well as type II diabetics. Albuminuria (an index of glomerulopathy) remains stable in those treated with ACE inhibitor, but aggravates in untreated diabetics. Treated patients have higher creatinine clearance, require less dialysis and have longer life expectancy. Benefits appear to be due to haemodynamic (systemic and intrarenal) as well as abnormal mesangial cell growth attenuating effects of ACE inhibitors. They reduce intraglomerular pressure and hyperfiltration. ACE inhibitors arrest/partly reverse any degree of albuminuria, but benefits are restricted after macroalbuminuria in type 2 diabetes has set in. The RAS seems to accentuate micro and macrovascular complications in diabetics, and ACE inhibitors have specific organ protective effect by attenuating the same. Deterioration of retinopathy in diabetics also appears to be retarded by ACE inhibitors. All patients with diabetic nephropathy, whether hypertensive or normotensive, deserve ACE inhibitor therapy.

Non-diabetic Nephropathy 

There is evidence now that chronic renal failure due to nondiabetic causes may also be improved by ACE inhibitors. They reduce proteinuria by decreasing pressure gradient across glomerular capillaries as well as by altering membrane permeability. This retards disease progression. Among hypertensive nephropathy patients the incidence of doubling of serum creatinine or end stage renal failure is significantly lower in those treated with ACE inhibitors than those treated with other antihypertensives.

Scleroderma Crisis

The marked rise in BP and deterioration of renal function in scleroderma crisis is mediated by AII. ACE inhibitors produce dramatic improvement and are life saving in this condition.

Captopril Test 

This test has been devised to obviate the need for renal angiography for diagnosis of renovascular hypertension. The basis of the test is—acute blockade of AII formation by captopril results in a reactive increase in PRA which is much higher in renovascular compared to essential hypertension. However, this test is only of adjunctive value.