How does olmesartan (an angiotensin II receptor blocker) work, what are its common and serious side effects, and what are the consequences of abrupt withdrawal?

Olmesartan: Mechanism, Side Effects, and Withdrawal

How Olmesartan Works

Olmesartan is an angiotensin II receptor blocker (ARB) that selectively and insurmountably binds to the AT₁ receptor, preventing angiotensin II from causing vasoconstriction, aldosterone release, and sympathetic nervous system activation, thereby lowering blood pressure. 1

Mechanism of Action Details

• Olmesartan blocks angiotensin II at the AT₁ receptor with very high selectivity and minimal affinity for AT₂ or AT₄ receptor subtypes 2
• The drug prevents angiotensin II from promoting vascular smooth muscle cell hypertrophy, growth factor expression (platelet-derived growth factor, fibroblast growth factor), inflammatory cytokine production (monocyte chemoattractant protein-1), and oxidative stress through NAD(P)H oxidase activation 3
• By blocking AT₁ receptors, olmesartan reduces aldosterone secretion, which decreases sodium retention and potassium excretion 4
• Olmesartan may also increase cardiac ACE2 expression, leading to conversion of angiotensin II to angiotensin 1-7, which has vasodilatory and cardioprotective effects beyond simple receptor blockade 5
• Peak blood concentration occurs approximately 2 hours after oral administration, with a half-life of 13 hours allowing once-daily dosing 2

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Side Effects of Olmesartan

Common Side Effects

• Dizziness and lightheadedness occur due to blood pressure reduction, particularly during initial therapy or dose escalation 6
• Hyperkalemia is a class effect caused by reduced aldosterone secretion and diminished renal potassium excretion 4
• The tolerability profile of olmesartan is comparable to placebo in clinical trials, with adverse event rates similar to other ARBs 1, 6

Serious Side Effects Requiring Immediate Action

• Angioedema occurs in <1% of ARB-treated patients (higher in individuals of African ancestry) and requires permanent discontinuation of olmesartan and avoidance of all ARBs 4
• Acute renal dysfunction manifesting as creatinine increase >100% above baseline (or >310 µmol/L / 3.5 mg/dL) with eGFR <20 mL/min/1.73 m², requiring immediate drug cessation and specialist consultation 4
• Severe hyperkalemia (potassium >5.5 mmol/L) necessitates stopping olmesartan and addressing contributing factors 4
• Fatal cardiovascular events were observed at higher rates in a diabetes trial comparing olmesartan to placebo in patients with pre-existing cardiovascular disease, though this finding requires further investigation 4
• Fetal toxicity including renal dysfunction, oligohydramnios, skull hypoplasia, and fetal death occurs during second and third trimester exposure; olmesartan is absolutely contraindicated in pregnancy 4

Risk Factors for Hyperkalemia

The following patients face increased hyperkalemia risk and require closer monitoring 4:

• Diabetes mellitus
• Chronic kidney disease (eGFR <60 mL/min/1.73 m²)
• Baseline potassium >4.5 mmol/L
• Concurrent use of mineralocorticoid receptor antagonists, potassium supplements, or potassium-sparing diuretics
• Never combine olmesartan with ACE inhibitors or direct renin inhibitors (triple RAAS blockade), as this markedly increases severe hyperkalemia risk without additional benefit 4

Monitoring Requirements

• Check serum potassium and renal function (creatinine/eGFR) at 1–2 weeks after starting olmesartan and after any dose increase 4
• Acceptable laboratory changes: creatinine rise ≤50% above baseline (or ≤266 µmol/L / 3 mg/dL) with eGFR ≥25 mL/min/1.73 m²; potassium ≤5.5 mmol/L 4
• If creatinine rises approximately 30% or potassium exceeds 5.5 mmol/L, consider dose reduction or temporary discontinuation before full cessation 4
• Before discontinuing for hyperkalemia or renal dysfunction, first withdraw NSAIDs, potassium supplements, and potassium-sparing diuretics; if no congestion, reduce loop diuretic dose; if needed, halve olmesartan dose and recheck labs in 1–2 weeks 4

Special Populations

• Renal impairment: ARBs including olmesartan should be used with caution, close supervision, and specialist advice when significant renal impairment exists 3
• Peripheral vascular disease: Use caution due to association with renovascular disease 3
• Renovascular disease: Olmesartan is sometimes used under specialist supervision despite being a relative contraindication 3
• Hemodialysis patients: Olmesartan showed no cardiovascular benefit (hazard ratio 1.00) compared with no RAAS blocker therapy 4

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Withdrawal and Discontinuation

Olmesartan can be stopped abruptly without causing a physiological withdrawal syndrome; however, loss of blood pressure control and end-organ protection will occur, necessitating clinical monitoring. 4

Key Points About Stopping Olmesartan

• No taper is required—there is no rebound hypertension or withdrawal syndrome from abrupt ARB cessation 4
• Blood pressure will rise back toward pre-treatment levels over days to weeks after discontinuation, so alternative antihypertensive therapy should be initiated if hypertension treatment remains indicated 4
• Loss of renoprotective and cardioprotective effects occurs immediately upon stopping, particularly important in patients with proteinuria, heart failure, or diabetic nephropathy 3

Switching Between Medications

• Switching from olmesartan to an ACE inhibitor requires no wash-out period—start the ACE inhibitor the day after stopping olmesartan 4
• Switching from an ACE inhibitor to olmesartan also requires no wash-out period, unlike the 36-hour interval needed when transitioning to an ARNI (angiotensin receptor-neprilysin inhibitor) 4
• Never switch patients with prior ACE inhibitor-induced angioedema to olmesartan or any ARB, as cross-reactivity occurs in 2–17% of cases 4

Clinical Indications for Olmesartan Use

Understanding when olmesartan is indicated helps contextualize the consequences of withdrawal 3:

Compelling indications:

• ACE inhibitor intolerance (particularly cough)
• Type 2 diabetic nephropathy
• Heart failure in ACE inhibitor-intolerant patients
• Post-myocardial infarction left ventricular dysfunction (when ACE inhibitors cannot be used)

Possible indications:

• Left ventricular dysfunction after myocardial infarction
• Intolerance of other antihypertensive drugs
• Hypertension with left ventricular hypertrophy
• Proteinuric renal disease or chronic kidney disease
• Heart failure

Absolute contraindications:

• Pregnancy (second and third trimesters)
• History of angioedema with any ARB

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Comparative Efficacy

• Olmesartan 20 mg once daily demonstrated superior blood pressure reduction compared to losartan 50 mg, valsartan 80 mg, and irbesartan 150 mg at their recommended maintenance doses, with significant differences evident as early as week 2 7
• Olmesartan 20 mg was more effective than candesartan 8 mg in lowering 24-hour ambulatory blood pressure, with treatment effects evident after 1–2 weeks 7
• The superior efficacy profile combined with once-daily dosing and placebo-level tolerability supports olmesartan as a first-line treatment option for mild to severe essential hypertension 1