losartan

**Class/Mechanism:** Angiotensin II receptor blocker (ARB; "-sartan"). Competitively blocks the AT1 receptor, which blocks angiotensin II-mediated vasoconstriction, aldosterone release, sympathetic activation, and efferent arteriole constriction. Losartan is a prodrug-like agent: it is converted by hepatic CYP2C9 and CYP3A4 to the more potent, longer-acting active metabolite EXP3174. Unlike ACE inhibitors, ARBs do not block ACE, so bradykinin is not increased.

**Hemodynamic/lab effects:** - Decreased BP via vasodilation and decreased aldosterone (less Na+/water retention) - Dilation of the efferent arteriole: decreased GFR and decreased intraglomerular pressure (renoprotective in diabetic nephropathy, but can cause AKI in bilateral renal artery stenosis) - Increased renin, increased angiotensin I and II (loss of negative feedback) - Hyperkalemia (decreased aldosterone) - Creatinine may rise modestly after initiation

**Clinical uses:** - Hypertension - Diabetic nephropathy (decreases proteinuria and slows progression; e.g., RENAAL trial) - Heart failure with reduced EF (when ACE inhibitors are not tolerated; ARNI sacubitril-valsartan preferred in HFrEF) - Post-MI with LV dysfunction (valsartan is the one studied) - Stroke risk reduction in hypertensive patients with LVH (LIFE trial) - Marfan syndrome (investigational/adjunct; decreases TGF-β signaling, slowing aortic root dilation)

**Unique feature:** Losartan has a uricosuric effect (blocks URAT1 in the proximal tubule), so it can lower serum uric acid. It is a useful antihypertensive in patients with gout. This is a classic high-yield distinction among ARBs.

**Adverse effects ("CHAMP"-style recall for RAAS inhibitors):** - Hyperkalemia - AKI/decreased GFR (especially with bilateral renal artery stenosis, volume depletion, or NSAIDs) - Hypotension - Fetotoxicity: contraindicated in pregnancy (oligohydramnios, pulmonary hypoplasia, renal failure/dysgenesis, skull hypoplasia, Potter-like sequence) - Angioedema: rare (much less common than with ACE inhibitors, but possible) - NO dry cough (the key advantage over ACE inhibitors)

**Interactions:** Avoid combining with ACE inhibitors or aliskiren (increased risk of hyperkalemia, AKI, and hypotension without added benefit), K+-sparing diuretics, K+ supplements, or NSAIDs (blunted effect and AKI). Fluconazole (CYP2C9 inhibitor) can decrease conversion to active metabolite.

**Board pearls:** - ACE inhibitor cough or angioedema → switch to an ARB - Both ACE inhibitors and ARBs: avoid in pregnancy and bilateral renal artery stenosis - ACE inhibitors raise bradykinin and renin; ARBs raise renin but NOT bradykinin - Compare: ACE inhibitor ends in "-pril" (captopril, lisinopril); ARB ends in "-sartan" (losartan, valsartan, candesartan) - Candesartan and valsartan have been studied in heart failure (CHARM, Val-HeFT)