ARBs
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"angiotensin receptor blockers" AND hypertension
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Here is a thorough overview of ARBs (Angiotensin Receptor Blockers) based on authoritative textbook sources:
Angiotensin Receptor Blockers (ARBs)
Mechanism of Action
ARBs selectively block the angiotensin type 1 (AT1) receptor, the receptor subtype responsible for virtually all the adverse biological effects of angiotensin II relevant to cardiovascular and renal pathology. By blocking this receptor, ARBs prevent:
- Vasoconstriction
- Sodium and water retention
- Myocardial hypertrophy and cardiac remodeling
- Aldosterone secretion
- Sympathetic activation
Unlike ACE inhibitors (which block conversion of angiotensin I to angiotensin II), ARBs act downstream at the receptor level. This means angiotensin II levels actually rise (stimulating the unopposed AT2 receptor, which may be vasodilatory/cardioprotective), but AT1-mediated effects are blocked. Crucially, ARBs do not inhibit bradykinin breakdown - hence no cough.
- Braunwald's Heart Disease, p. 1575 | Brenner and Rector's The Kidney, p. 2595
Available Agents ("sartans")
| Drug | Brand Name |
|---|---|
| Losartan | Cozaar |
| Valsartan | Diovan |
| Candesartan | Atacand |
| Irbesartan | Avapro |
| Olmesartan | Benicar |
| Telmisartan | Micardis |
| Azilsartan | Edarbi |
| Eprosartan | Teveten |
- Katzung's Basic and Clinical Pharmacology, 16e, p. 297
Clinical Indications
1. Hypertension
ARBs are first-line antihypertensives alongside ACE inhibitors, thiazide diuretics, and calcium channel blockers. A 2024 network meta-analysis (PMID: 38861046) compared six ARBs and found broadly equivalent efficacy in blood pressure lowering, with some individual differences in tolerability.
2. Heart Failure with Reduced EF (HFrEF)
ARBs are indicated (Class I) when patients are ACE inhibitor-intolerant (due to cough, rash, or angioedema - but NOT due to hyperkalemia or renal insufficiency). Key trial evidence:
- CHARM-Alternative: Candesartan (titrated to 32 mg/day) significantly reduced all-cause mortality, cardiovascular death, and HF hospitalizations vs. placebo in ACE inhibitor-intolerant patients.
- Val-HeFT subset: Valsartan (160 mg twice daily) reduced all-cause mortality and combined mortality/morbidity vs. placebo in ACE inhibitor-intolerant patients (17.3% vs. 27.1%, P=0.017).
- ELITE-II: Losartan was not superior to captopril in survival, but was significantly better tolerated.
- HEAAL: High-dose losartan (150 mg/day) was superior to low-dose (50 mg/day) for death or HF admission (HR 0.90, P=0.027).
ACE inhibitors remain first-line (Class I); ARBs are Class IIa in ACE inhibitor-intolerant patients, and Class IIb as an add-on in persistently symptomatic patients already on ACE inhibitor + beta-blocker when an aldosterone antagonist is not tolerated.
- Braunwald's Heart Disease, p. 1575-1583 | Textbook of Family Medicine 9e, p. 692
3. Post-MI Left Ventricular Dysfunction
VALIANT trial: Valsartan was non-inferior to captopril for all-cause mortality post-MI with LV dysfunction. Combination of valsartan + captopril did not improve survival but increased adverse events.
4. Diabetic Nephropathy (Type 2 DM)
ARBs have proven renoprotective effects beyond their blood pressure-lowering action:
-
RENAAL trial (losartan): 25% reduction in creatinine doubling, 28% reduction in ESKD risk vs. placebo.
-
IDNT trial (irbesartan): 33% lower risk of creatinine doubling vs. placebo, 37% lower vs. amlodipine.
-
Irbesartan microalbuminuria trial: Dose-dependent reduction in progression to overt nephropathy (HR 0.30 at 300 mg vs. placebo). Up-titration to maximum dose is recommended.
-
Meta-analysis confirms: ARBs reduce ESKD risk (RR 0.78) and creatinine doubling (RR 0.79).
-
Brenner and Rector's The Kidney, p. 2595-1017
Adverse Effects
| Effect | Notes |
|---|---|
| Hyperkalemia | Due to reduced aldosterone; monitor K+ and renal function 1-2 weeks after initiation/dose change |
| Hypotension | Especially with first dose or volume depletion |
| Azotemia/Acute kidney injury | Risk in bilateral renal artery stenosis, volume depletion |
| Angioedema | Less frequent than with ACE inhibitors, but still reported |
| No cough | Key advantage over ACE inhibitors (bradykinin not affected) |
| Fetal toxicity | Contraindicated in 2nd and 3rd trimester - causes hypocalvaria, renal tubular dysplasia, IUGR |
- Braunwald's Heart Disease, p. 1588 | Brenner and Rector's The Kidney, p. 2641
Contraindications
-
Pregnancy (2nd and 3rd trimester - absolute)
-
Bilateral renal artery stenosis
-
Concurrent ACE inhibitor use - combination increases risk of renal injury, hyperkalemia, and hypotension with no additional benefit (avoid dual RAAS blockade)
-
Concurrent aliskiren (direct renin inhibitor) in patients with diabetes, renal insufficiency, or as a combination - contraindicated
-
History of angioedema from ARBs
-
Goldman-Cecil Medicine, Clinical Use; Washington Manual
ARBs vs. ACE Inhibitors
| Feature | ARB | ACE Inhibitor |
|---|---|---|
| Site of action | AT1 receptor | ACE enzyme |
| Cough | No | Yes (bradykinin accumulation) |
| Angioedema | Rare | Less rare |
| Efficacy in HF | Non-inferior (in trials) | First-line (guidelines) |
| Post-MI | Non-inferior (VALIANT) | Preferred |
| Diabetic nephropathy | Strong evidence | Strong evidence |
Special Combination: ARNI (Sacubitril/Valsartan - Entresto)
A newer class combines an ARB (valsartan) with a neprilysin inhibitor (sacubitril). This enhances natriuretic peptide signaling while blocking AT1. In PARADIGM-HF, sacubitril/valsartan was superior to enalapril for reducing all-cause mortality, CV mortality, and HF hospitalizations in HFrEF (LVEF ≤35%). It is now preferred over ACE inhibitors or ARBs alone in eligible HFrEF patients. ARNIs are contraindicated with ACE inhibitors (angioedema risk) and with other ARBs.
- Braunwald's Heart Disease, p. 1591 | Lippincott Pharmacology
Key takeaway: ARBs are versatile RAAS blockers with the same hemodynamic profile as ACE inhibitors, but without cough. They are the drug of choice for ACE inhibitor-intolerant patients and have strong evidence in hypertension, HFrEF, post-MI LV dysfunction, and diabetic nephropathy. Monitor renal function, potassium, and blood pressure at initiation and dose changes. Avoid in pregnancy and bilateral renal artery stenosis.
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