Dr. Anant Patil writes on the clinical use of ACE inhibitors, commonly used for hypertension. He elaborates on the benefits, adverse events, precautions, and contraindications of the drug.

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Hypertension is a growing concern worldwide including in India. In our country, the overall prevalence of hypertension is 29.8% with some differences in the urban versus rural population. Among people living in urban areas, the prevalence is comparatively more than in the rural population (33.8% vs 27.6%). [1]

Uncontrolled hypertension increases the risk of several complications including renal disease, cardiovascular disease, and cerebrovascular disease i.e. stroke. Because of increasing prevalence and associated significant morbidity and mortality, hypertension is one of the important health concerns despite the availability of several options for its treatment.

Important pharmacological options for the treatment of hypertension include diuretics, beta-blockers, drugs acting on Renin-Angiotensin System (RAS), calcium channel blockers, vasodilators and centrally acting alpha 2 agonists. These agents are either used alone or in combination.

Angiotensin-converting enzyme (ACE) inhibitors, a subclass of drugs from the category of agents acting on RAS are commonly used for the treatment of hypertension [2] used as initial therapy. Examples of ACE inhibitors include captopril, lisinopril, ramipril, enalapril, fosinopril, perindopril, and quinapril. [3]

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Mechanism of action

Angiotensin II is an octapeptide having potent vasoconstrictive action and potentially harmful effects on the heart. It also helps in the release of aldosterone. [3] ACE is an enzyme that performs two important functions.

1. First, it converts angiotensin I to angiotensin II in circulation as well as in the tissues.
2. Secondly, the enzyme also converts bradykinin into inactive components.

Inhibition of this enzyme, therefore, results in a reduction in the levels of angiotensin II and an increase in the levels of bradykinin. [3] ACE inhibitors inhibit the angiotensin-converting enzyme which converts angiotensin I to angiotensin II resulting in enhanced natriuresis and reduction in blood pressure. They also prevent the remodeling of cardiac myocytes. [4]

Although the mechanism is similar, some pharmacologic and pharmacokinetic differences exist among different ACE inhibitors. Lisinopril and captopril are ACE inhibitors that do not require activation in the body. Other ACE inhibitors are prodrugs and hence require activation in the body for showing their effect. [4]

Many ACE inhibitors are given once daily. Enalapril provides a more consistent effect when administered twice a day. Captopril has a short duration of action and hence needs to be administered two or three times a day for providing effective control of blood pressure over 24 hours. [2,3]

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Use of ACE inhibitors in hypertension

ACE inhibitors can be used as monotherapy or along with other antihypertensives for the treatment of hypertension. They can be combined with thiazide or thiazide-like diuretics and calcium channel blockers to improve the antihypertensive effect. [3] In patients who need combination therapy, a single pill containing two drugs instead of separate pills can help to improve compliance. ACE inhibitor/angiotensin receptor blocker plus a calcium channel blocker is a preferred combination.

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Benefits of ACE inhibitors

Concomitant diabetes and hypertension increase the risk of cardiovascular morbidity and mortality. [6] In patients with hypertension and concomitant type 2 diabetes, treatment with ACE inhibitors is associated with a reduced rate of cardiovascular events as compared to calcium channel blockers.

1. In a prospective long-term study in hypertensive patients with type 2 diabetes, the use of enalapril was associated with a greater decrease in albuminuria as compared to nifedipine. [7]
2. Ramipril has been shown to provide benefits for cardiovascular events and overt nephropathy in diabetic patients. Vasculoprotective and renoprotective effects make ACE inhibitors an attractive choice for the management of hypertension in patients with diabetes. [8] These agents may reduce the progression of nephropathy and risks of cardiovascular events in hypertensive patients with diabetes mellitus. [2]
3. ACE inhibitors decrease blood pressure and proteinuria in patients with renal disease and considered as first-line therapy for hypertension in patients with diabetes mellitus. [4]
4. They are useful drugs in hypertensive patients with a history of cardiovascular disease or chronic kidney disease. They can also be useful adjunctive therapy in systolic heart failure. [2]
5. They help in the improvement of heart failure by reducing afterload and reduce cardiac myocyte hypertrophy. [4]
6. ACE inhibitors are also useful in patients with coronary artery disease and hypertension and patients with ST-elevation myocardial infarction. [2]

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Important adverse events associated with ACE inhibitors

Generally, ACE inhibitors are well tolerated. However, in some patients, these drugs can be associated with the following adverse events:

1. Dry cough, one of the common class adverse events with ACE inhibitors is seen in about 15% of patients taking it. This occurs because of the accumulation of bradykinin. [3] Dry and irritant cough associated with the use of ACE inhibitors can resolve after stopping the therapy. In such patients, angiotensin receptor blocker (ARB) can be started as an alternate therapy. If cough persists, then antihypertensive drugs from a different class should be started. [2]
2. Angioedema, a rare but potentially serious adverse effect is known to occur with ACE inhibitors. [3]
3. Hyperkalemia is another possible adverse effect of these drugs because of potassium retention due to reduced aldosterone. [2,3]
4. Other rare adverse events include urticaria, skin rash, and disturbance in taste. [3]
5. Captopril can cause confusion and lethargy. [2]

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Precautions for use of ACE inhibitors

1. In order to avoid a significant initial fall in blood pressure or reduction in renal function, ACE inhibitors are generally initiated with low doses in elderly patients, patients with impaired renal function, or those with heart failure. [3]
2. In patients with dehydration, the use of ACE inhibitors may result in postural hypotension and acute renal injury. [3]
3. Renal function may be impaired in patients with bilateral renal stenosis. [3]
4. Use of potassium-sparing diuretics or potassium salt with ACE inhibitors can increase the risk of hyperkalemia especially in patients with impaired renal functions. [3]
5. Non-steroidal anti-inflammatory drugs (NSAIDs) should also be used cautiously in patients receiving ACE inhibitors. [3]

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Monitoring in patients using ACE inhibitors

Considering the risk of adverse effects mentioned before, serum potassium, BUN, serum creatinine should be measured before initiating ACE inhibitors and it should also be checked after the initiation of therapy. [3]

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Contraindications for use of ACE inhibitors

1. Because of its teratogenic effects, ACE inhibitors are avoided in pregnancy.
2. Other contraindications for their use include the history of hypersensitivity to ACE inhibitor or any other component of the medicine, history of angioedema with an ACE inhibitor, or idiopathic or hereditary angioedema. [2]
3. ACE inhibitors are also avoided in patients receiving aliskiren, a direct renin inhibitor. [2,4]

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Disclaimer: This is for educational purpose only. Physicians are requested to refer the updated prescribing information of the products for further information.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Anant Patil is an Assistant Professor of Pharmacology.