captopril

MECHANISM: Captopril inhibits angiotensin-converting enzyme (ACE, kininase II), so less angiotensin II is formed from angiotensin I. Results: (1) decreased vasoconstriction, so lower afterload; (2) decreased aldosterone, so less Na+/water retention and K+ excretion (hyperkalemia); (3) dilation of the efferent arteriole, so lower intraglomerular pressure (renoprotective in diabetic nephropathy, but GFR falls); (4) increased bradykinin (ACE normally degrades it), so cough and angioedema. Renin levels RISE (loss of negative feedback); angiotensin I rises; angiotensin II falls.

PHARMACOLOGY: The first ACE inhibitor developed (modeled on a peptide from Brazilian pit viper venom, Bothrops jararaca). It is the only common ACE inhibitor that is NOT a prodrug (all others, e.g., enalapril, lisinopril [also active], are different: enalapril is a prodrug, while lisinopril and captopril are active drugs). It contains a sulfhydryl (thiol) group, which is linked to some unique adverse effects (taste disturbance/dysgeusia, rash, neutropenia/proteinuria at high doses) and has free radical-scavenging properties. Short half-life, so it is dosed 2-3 times daily. Food reduces absorption. Renally cleared, so doses need adjustment in renal impairment.

INDICATIONS: Hypertension; heart failure with reduced EF (mortality benefit); post-MI (prevents ventricular remodeling, SAVE trial); diabetic nephropathy (slows progression, especially with proteinuria).

ADVERSE EFFECTS (mnemonic "CAPTOPRIL"): Cough, Angioedema, Proteinuria/Pregnancy contraindication (fetal renal malformations, oligohydramnios, pulmonary hypoplasia, skull hypoplasia), Taste changes, Hypotension (first dose, especially in volume-depleted patients), Orphan/Other (Rash), Potassium excess (hyperkalemia), Renal failure in bilateral renal artery stenosis (or stenosis in a solitary kidney), Leukopenia/neutropenia (rare), Increased creatinine.

CONTRAINDICATIONS/CAUTIONS: Pregnancy; history of ACE inhibitor-associated angioedema; bilateral renal artery stenosis; hereditary angioedema (C1 esterase inhibitor deficiency); concurrent aliskiren in diabetics; caution with K+-sparing diuretics, K+ supplements, NSAIDs, and in hyperkalemia.

BOARD PEARLS: - Cough and angioedema are bradykinin-mediated. Switching to an ARB (e.g., losartan) avoids both, because ARBs do not affect bradykinin. ARBs still carry the hyperkalemia, renal, and teratogenicity risks. - Angioedema is NOT IgE-mediated and does not respond well to antihistamines/steroids; treatment is airway protection and stopping the drug. Higher risk in Black patients. - Captopril has been used for the captopril renal scan: a rise in plasma renin activity after captopril (or a drop in GFR on renography) supports renovascular hypertension. - Hypertension from renal artery stenosis: ACE inhibitors can precipitate acute kidney injury because efferent tone is needed to maintain GFR when afferent pressure is low. - Effect on labs: increased renin, decreased angiotensin II, decreased aldosterone, increased K+, increased bradykinin. - Do not confuse with ARBs (-sartans), direct renin inhibitor (aliskiren), or neprilysin inhibitor (sacubitril, combined with valsartan; contraindicated with ACE inhibitors due to angioedema risk, needs 36-hour washout).