How does olmesartan (angiotensin II receptor blocker) work, what are its common and serious adverse effects, and what are the considerations for discontinuation or tapering?

Olmesartan: Mechanism of Action, Side Effects, and Discontinuation

Mechanism of Action

Olmesartan works by selectively and insurmountably blocking the angiotensin II type 1 (AT1) receptor, preventing vasoconstriction and aldosterone release without affecting bradykinin metabolism. 1

• Olmesartan medoxomil is a prodrug that is rapidly converted to its active form (olmesartan) during absorption from the gastrointestinal tract 1
• It blocks angiotensin II from binding to AT1 receptors in vascular smooth muscle, preventing vasoconstriction, aldosterone synthesis, cardiac stimulation, and sodium reabsorption 1
• Unlike ACE inhibitors, olmesartan does not inhibit the breakdown of bradykinin, which explains why it does not cause the persistent dry cough seen with ACE inhibitors 1, 2
• Olmesartan has >12,500-fold greater affinity for AT1 receptors compared to AT2 receptors, making it highly selective 1
• Peak plasma concentration occurs 1-2 hours after oral administration, with a half-life of approximately 13 hours, allowing once-daily dosing 1, 3

Common Side Effects

The most frequently reported adverse effect is dizziness (occurring in approximately 3% of patients), with olmesartan demonstrating a tolerability profile comparable to placebo. 4

Cardiovascular Effects

• Hypotension, particularly in volume- or salt-depleted patients (e.g., those on high-dose diuretics) 1
• Dizziness (the most common adverse effect occurring significantly more than placebo) 4

Metabolic Effects

• Hyperkalemia through reduced aldosterone secretion and decreased renal potassium excretion—this is a class effect of all ARBs, not specific to olmesartan 5, 1
• Risk factors amplifying hyperkalemia include diabetes mellitus, chronic kidney disease (eGFR <60 mL/min), baseline potassium >4.5 mEq/L, and concurrent use of mineralocorticoid receptor antagonists 5

Renal Effects

• Worsening renal function, particularly in patients whose renal perfusion depends on angiotensin II (e.g., bilateral renal artery stenosis, severe heart failure) 1
• Oliguria, progressive azotemia, and rarely acute renal failure 1

Serious Adverse Effects

Sprue-like Enteropathy (Unique to Olmesartan)

• Severe, chronic diarrhea with substantial weight loss occurring months to years after initiation—this is a unique and serious adverse effect specific to olmesartan 1
• Intestinal biopsies often show villous atrophy 1
• If this develops, exclude other etiologies and consider switching to an alternative ARB 1

Angioedema

• Occurs in fewer than 1% of patients taking ARBs, but is more frequent in Black patients 6
• Unlike ACE inhibitors, ARBs have a significantly lower incidence of angioedema, though cross-reactivity can occur in 2-17% of patients with prior ACE inhibitor-induced angioedema 6, 7
• If angioedema occurs, olmesartan should be permanently discontinued and all ARBs should be avoided 6

Fetal Toxicity

• Olmesartan causes fetal harm when used during the second and third trimesters of pregnancy, including fetal renal dysfunction, oligohydramnios, skull hypoplasia, and death 1
• Discontinue immediately when pregnancy is detected 1

Monitoring Requirements

Monitor serum potassium and renal function within 1-2 weeks after initiation and after each dose increase. 6, 5

Acceptable Changes

• Creatinine increase up to 50% above baseline or up to 266 μmol/L (3 mg/dL) / eGFR ≥25 mL/min/1.73 m² 6
• Potassium increase to ≤5.5 mmol/L 6

Concerning Changes Requiring Action

• If potassium rises to >5.5 mmol/L or creatinine increases by >100% or to >310 μmol/L (3.5 mg/dL) / eGFR <20 mL/min/1.73 m², stop olmesartan and seek specialist advice 6
• If creatinine rises 30% or potassium exceeds 5.5 mEq/L, consider dose reduction or discontinuation 6

Discontinuation and Withdrawal Considerations

There is no physiologic withdrawal syndrome from olmesartan—it can be stopped abruptly without tapering, but clinical deterioration from loss of blood pressure control and end-organ protection is likely. 6

When to Discontinue

• Development of sprue-like enteropathy with chronic diarrhea and weight loss 1
• Angioedema (permanent contraindication to all ARBs) 6
• Pregnancy detection 1
• Persistent hyperkalemia >5.5 mmol/L despite medication adjustments 6
• Severe worsening of renal function (creatinine increase >100% or eGFR <20 mL/min/1.73 m²) 6

Management Before Discontinuation

• Before stopping olmesartan for hyperkalemia or renal dysfunction, first discontinue nephrotoxic drugs (NSAIDs), potassium supplements, and potassium-sparing diuretics 6
• If no signs of congestion, reduce loop diuretic dose 6
• If these measures fail, halve the olmesartan dose and recheck labs in 1-2 weeks 6
• It is very rarely necessary to stop an ARB, and specialist advice should be sought before treatment discontinuation 6

Switching to Alternative Agents

• When switching from olmesartan to an ACE inhibitor, no washout period is required 6, 8
• When switching from an ACE inhibitor to olmesartan, no washout period is required (unlike switching to an ARNI, which requires 36 hours) 6, 8
• If switching due to sprue-like enteropathy, consider a different ARB or an ACE inhibitor 1
• If switching due to angioedema, avoid all ARBs and ACE inhibitors permanently 6

Important Clinical Caveats

• Olmesartan showed an unexpected higher rate of fatal cardiovascular events compared to placebo in patients with pre-existing cardiovascular disease in one diabetes trial, though this finding requires further investigation 6
• Avoid triple RAAS blockade (ACE inhibitor + ARB + mineralocorticoid receptor antagonist) due to excessive hyperkalemia risk 5
• In hemodialysis patients, olmesartan showed no cardiovascular benefit (HR 1.00) compared to no ACE inhibitor/ARB use 6
• Olmesartan is not recommended in children <1 year of age due to effects on immature kidney development 1