lisinopril

**Class/Mechanism:** Angiotensin-converting enzyme (ACE) inhibitor (the "-pril" suffix). Lisinopril is the only common ACE inhibitor that is NOT a prodrug (it is the active drug; enalapril, ramipril, etc. are prodrugs). It is not hepatically metabolized and is renally excreted unchanged, so dose adjust in renal impairment. - ACE (kininase II) normally converts angiotensin I to angiotensin II and degrades bradykinin. - Inhibition leads to: decreased angiotensin II (less vasoconstriction, less aldosterone, less efferent arteriole constriction), decreased aldosterone (natriuresis, K+ retention), and increased bradykinin (vasodilation, but also cough and angioedema). Renin levels rise (loss of negative feedback), and angiotensin I rises. - Net hemodynamic effects: decreased preload and afterload, and decreased GFR via efferent arteriolar dilation (this lowers intraglomerular pressure, which is renoprotective in diabetic nephropathy).

**Indications:** - Hypertension - Heart failure with reduced EF (decreases mortality; prevents remodeling) - Post-myocardial infarction (prevents ventricular remodeling) - Diabetic nephropathy / proteinuric chronic kidney disease (slows progression by lowering intraglomerular pressure)

**Adverse effects (mnemonic "CAPTOPRIL"):** - **C**ough (dry, persistent; due to bradykinin/substance P). Switch to an ARB. - **A**ngioedema (bradykinin-mediated; contraindicated in hereditary angioedema/C1 esterase inhibitor deficiency. ARBs are generally safe alternatives but use caution). - **P**roteinuria (historical), **T**aste changes (more with captopril) - **O**rthostatic/first-dose **hypotension** - **P**regnancy: fetal toxicity (renal agenesis/oligohydramnios, pulmonary hypoplasia, hypocalvaria, fetal renal failure). Contraindicated in pregnancy. - **R**ash, **I**ncreased renin - **L**ower angiotensin II - Hyperkalemia (reduced aldosterone) and acute kidney injury/increased creatinine, especially in bilateral renal artery stenosis or a solitary kidney with stenosis (loss of efferent tone causes a drop in GFR). A small creatinine rise (<30%) is acceptable. - Neutropenia (rare)

**Contraindications/cautions:** Pregnancy, history of angioedema, bilateral renal artery stenosis, hyperkalemia. Avoid combining with ARBs or aliskiren (dual RAAS blockade increases hyperkalemia and AKI), and use caution with K+-sparing diuretics, K+ supplements, NSAIDs, and trimethoprim.

**Comparison with ARBs (e.g., losartan):** ARBs block the AT1 receptor and do not increase bradykinin, so they do not cause cough or (typically) angioedema. Renin and angiotensin II levels are increased with ARBs, but angiotensin II levels are decreased with ACE inhibitors.

**Board pearls:** - Cough after starting an ACE inhibitor: switch to an ARB. - Hyperkalemia plus a rise in creatinine after starting an ACE inhibitor in a patient with atherosclerotic disease: think bilateral renal artery stenosis. - ACE inhibitors are first-line for hypertension in diabetics with albuminuria. - Lisinopril is the only common ACE inhibitor that is not a prodrug. - Sacubitril/valsartan (neprilysin inhibitor + ARB) must not be given with an ACE inhibitor (angioedema risk); a 36-hour washout is required.