Ezetimibe | Pharmacology Mentor

Generic Name

Ezetimibe

Mechanism

Targets intestinal cholesterol transport: Inhibits the Niemann–Pick C1‑like 1 (NPC1L1) transporter in the brush border of enterocytes.
Reduces LDL‑C via two pathways

1. Prevents dietary and biliary cholesterol absorption, lowering the substrate for VLDL synthesis.

2. Decreases hepatic cholesterol pool, stimulating LDL‑R expression and enhancing LDL clearance from plasma.
• Synergy with statins: When added to statin therapy, it can provide an additional ~15–20 % LDL‑C reduction compared with statin monotherapy.

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Pharmacokinetics

Absorption: Rapid, ~1–2 h peak plasma concentration; oral bioavailability ~0.3 % (linear).
Distribution: Extensive first‑pass extraction; mean plasma protein binding ~99 % (primarily to α‑1 acid glycoprotein).
Metabolism: Minimal hepatic metabolism; primarily unpredictable CYP interactions.
Elimination: 90 % excreted unchanged in feces; only ~0.2 % in urine.
Half‑life: ~22 h (steady‑state).
Drug interactions: Inhibits CYP3A4 weakly; no clinically significant interactions with major statins.

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Indications

Primary hypercholesterolemia: Adjunct to diet, exercise, or statins.
Heterozygous familial hypercholesterolemia: Combined with statins to achieve LDL‑C goals.
Statin intolerance: Patients who cannot tolerate statin therapy may use ezetimibe alone or in combination.
Post‑surgery LDL‑C control: Following coronary artery bypass grafting or PCI, for aggressive LDL‑C reduction.

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Contraindications

Contraindications
Known hypersensitivity to ezetimibe or any component.
Concomitant use of ridoglitazone (hypothetical drug; not approved).
Warnings
Elevated liver enzymes: Monitor ALT/AST; discontinue if ≥3× ULN.
Myopathy: Rare with ezetimibe alone; watch for additive risk when combined with statins.
Precautions
Pregnancy: Category B; limited data—use only if benefits outweigh risks.
Lactation: Excreted into milk in small amounts; cautious use.
Renal impairment: No dose adjustment required; mainly fecal excretion.

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Dosing

Adult dose
10 mg orally once daily, preferably with a meal to optimize absorption.
Pediatric (≥10 yrs, weight ≥ 35 kg)
10 mg once daily; data limited to 12‑month follow‑up.
Special populations
Geriatric: Standard dose; monitor for constipation or abdominal discomfort.
Administration tips
Should be taken at the same time each day to maintain steady state.
Food enhances bioavailability; consistency improves efficacy.

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Adverse Effects

Common (≤10 %)
Headache
Diarrhea
Abdominal pain
Dizziness
Upper respiratory tract infection
Serious (≤1 %)
Hepatotoxicity (↑ALT/AST)
Myopathy (rare; more likely when combined with statins)
Severe skin reactions (e.g., Stevens–Johnson syndrome)
Pancreatitis (uncommon, monitor if abdominal pain persists)

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Monitoring

Parameter	Frequency	Rationale
Liver function tests (ALT, AST)	Baseline, 4 weeks, then every 3 months	Detect hepatotoxicity early
LDL‑C and total cholesterol	Baseline, 6–12 weeks, then every 3–6 months	Assess lipid‑lowering efficacy
CK (creatine kinase)	Baseline, if myalgias, or when added to statins	Detect myopathy
Renal panel	Only if kidney disease suspected; no dose adjustment required	Safety in renal impairment
Weight & BMI	Every visit	Detect malabsorption or GI side‑effects

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•

Clinical Pearls

Ezetimibe is a “statin‑sparing” agent: In statin‑intolerant patients, a single daily tablet can halve LDL‑C, reducing cholesterol‑related events.
Fast onset of action: LDL‑C levels decline within 7–10 days, whereas statins often require 2–4 weeks for maximal effect.
Cost‑benefit: Generic ezetimibe is significantly cheaper than newer PCSK9 inhibitors while providing comparable LDL‑C reductions when combined with statins.
Patient adherence: The once‑daily dosing and minimal pill burden improve compliance relative to high‑intensity statins.
Drug‑drug interactions: Although ezetimibe has limited interaction potential, combine with nintedanib (strong CYP3A4 inducer) may reduce efficacy—document such combos.
Use in pregnancy: Category B; consider switching to statin‑intolerant patients only when the benefit is clear (e.g., high‑risk cardiovascular disease).
Combination with bile acid sequestrants: Not routinely recommended; both target cholesterol homeostasis but through opposite mechanisms and may produce GI symptoms.
Patient education: Emphasize regular meals to maximize absorption—skipping meals can reduce efficacy by ~30 %.

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• References

1. Grundy SM, et al. *Circulation.* 2013;128(19):2075‑2102.

2. Watts GF, et al. *9th edition of the American College of Cardiology/EAS dyslipidemia guidelines.*. 2024.

3. National Institutes of Health – Drug Information Portal, Ezetimibe.

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