ACE inhibitors (angiotensin-converting-enzyme inhibitors) are a class of drugs used in the treatment hypertension, heart disease, and chronic kidney failure. They lower blood pressure by several means – not least through competitive inhibition of plasma ACE. Lower plasma ACE levels mean less circulating angiotensin II and a further, consequent reduction in the release of aldosterone. Quite a few ACE inhibitors are administered as prodrugs because their active forms are invariably polar and poorly taken in by the gut. Unwanted effects include persistent dry cough, postural hypotension, taste disturbance, nausea, dyspepsia and angioedema (frequently in those of Afro-Caribbean origin). First, though, let’s take a closer look at the pharmacology of ACE inhibitors.
Pharmacology of ACE Inhibitors
One of the primary aims of ACE inhibitors is to lower blood pressure. The pharmacology by which they achieve this is actually quite simple. Let’s begin in reverse, with a molecule known as aldosterone. This molecule, produced by the zona glomerulosa of the adrenal cortex, is responsible for acting on the distal tubules and collecting ducts of the kidney. There, it increases water retention, conserves sodium ions and promotes potassium secretion. These effects increase blood pressure.
ACE inhibitors indirectly inhibit aldosterone release by halting conversion of angiotensin I into angiotensin II. This latter molecule, angiotensin II, acts at AT1 receptors on the adrenal cortex to release aldosterone. Not only this, but reduced tissue concentrations of angiotensin II lead directly to arterial and, to a lesser extent, venous dilation. Angiotensin II is also implicated in exacerbating left ventricular hypertrophy, meaning that ACE inhibitors are also well equipped to regress this cardiac condition.
Quite a few ACE inhibitors are formulated as prodrugs, because their active forms are sufficiently polar to result in poor gut absorption. These prodrugs are converted into their active forms via hepatic means. Ramipril is, for example, converted into its active form, ramiprilat, in the liver. This contrasts with other ACE inhibitors – such as captopril and lisinopril – which are administered as active molecules. Enalapril is, similarly, converted into its active form – enalaprilat – in the liver.
Half-lives vary with ACE inhibitors. Some members – such as captopril and ramipril – have quite low half-lives, oscillating around the 2 hr mark. This contrasts with enalapril and perindopril, which have half-lives up to ten times this value. ACE inhibitors should be avoided, if possible, in pregnant women – as it’s associated with birth defects, particularly if taken during the second and third trimester. Caution should be taken if taken with K+-sparing diuretics, NSAIDs, anticoagulants, and DDP-4 inhibitors.
There are many adverse effects associated with ACE inhibitor use. Chief among these is a persistent dry cough. This is caused – returning to pharmacology – by the conversion of kininogens to bradykinin, and from bradykinin into further breakdown products. Production of these breakdown products increases with ACE inhibitor use, and it’s these breakdown products which cause persistent dry cough. Patients finding such a cough intolerable may take angiotensin II receptor antagonists instead.
Other adverse effects associated with ACE inhibitors include:
- Postural hypotension, particularly if taken with diuretics
- Renal impairment, in those with severe bilateral renal artery stenosis
- Taste disturbance, which – for some – is often permanent
- Angioedema, more frequent in Afro-Caribbean populations
- Nausea, vomiting, dyspepsia, hyperkalemia, dizziness, and fatigue
Test your knowledge of the pharmacology of ACE inhibitors today with our handy quiz – featuring ten relevant and topical questions on some of the most widely prescribed drugs in cardiovascular medicine.