Antihypertensive Drugs

Angiotensin converting enzyme is a zinc-containing enzyme with two physiologically important substrates. First, it converts angiotensin I to angiotensin II — the potent vasoconstrictor that drives blood pressure elevation, aldosterone release, sodium retention, and cardiac and renal remodeling. Second, it is the principal enzyme that degrades bradykinin, a vasodilatory and natriuretic peptide.

Angiotensin converting enzyme inhibitors block both of these functions simultaneously. The primary antihypertensive and organ-protective mechanism is the reduction of angiotensin II. The accumulation of bradykinin provides additional vasodilation — but also underlies the two most clinically important adverse effects of this class: dry cough and angioedema. The net hemodynamic effect is reduced total peripheral resistance with no reflex tachycardia, and modest reduction in both preload and afterload that is particularly beneficial in heart failure.

Most angiotensin converting enzyme inhibitors are prodrugs requiring hepatic conversion to their active form — the exceptions are captopril and lisinopril, which are active as administered. Lisinopril is water-soluble and excreted renally unchanged, making it the preferred agent when hepatic function is impaired. Fosinopril has dual elimination through both the kidney and liver, making it the preferred angiotensin converting enzyme inhibitor in advanced chronic kidney disease where renal clearance is severely reduced. Most other agents require dose reduction as estimated glomerular filtration rate falls. Ramipril has the broadest outcome trial evidence base across multiple indications.

A compelling indication is an evidence-based outcome benefit independent of blood pressure lowering. Angiotensin converting enzyme inhibitors have compelling indications in several settings where they reduce mortality or organ damage beyond what would be expected from blood pressure reduction alone.

The two angiotensin converting enzyme inhibitor-specific adverse effects — dry cough and angioedema — both result from bradykinin accumulation and distinguish this class from angiotensin receptor blockers.

Class adverse effects shared with angiotensin receptor blockers include hyperkalemia (from reduced aldosterone production — monitor potassium one to two weeks after initiation), functional acute kidney injury (from efferent arteriolar dilation — a rise in creatinine of up to 30 percent is expected and acceptable; above 30 percent warrants dose reduction), and first-dose hypotension (more pronounced in volume-depleted or high-renin states). Teratogenicity is a black-box warning for both classes — all trimesters of pregnancy are contraindicated, as the fetal renin-angiotensin-aldosterone system is critical for normal renal development.