Ezetimibe

1. Drug Name

• Generic Name: Ezetimibe

• Brand Names: Zetia, Ezetrol

2. Drug Classification

• Class: Antilipemic agent

• Subclass: Cholesterol absorption inhibitor

3. Mechanism of Action

• Inhibition of Intestinal Cholesterol Absorption: Ezetimibe acts at the brush border of the small intestine to inhibit the Niemann-Pick C1-like 1 (NPC1L1) protein, a transporter responsible for absorbing cholesterol and phytosterols from the intestinal lumen.

• Impact on Hepatic LDL Processing: By reducing intestinal cholesterol absorption, less cholesterol is delivered to the liver, stimulating the liver to increase the expression of LDL receptors, enhancing LDL cholesterol clearance from the bloodstream.

• Effect on Lipid Profile: This inhibition results in a significant reduction in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and a slight increase in high-density lipoprotein (HDL) cholesterol.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Approximately 60%, unaffected by food.

  • Time to Peak: Plasma concentrations peak within 1-2 hours.

• Distribution:

  • Protein Binding: Ezetimibe and its active metabolite are highly protein-bound (~90%).

  • Volume of Distribution (Vd): Ezetimibe distributes widely in the body.

• Metabolism:

  • Primary Site: Metabolized in the liver and intestines.

  • Metabolites: Ezetimibe is converted to an active glucuronide metabolite (ezetimibe-glucuronide).

  • Enzymatic Involvement: Metabolism does not involve CYP450 enzymes, thus avoiding many common drug interactions.

• Excretion:

  • Half-Life: Approximately 22 hours.

  • Elimination Routes: Primarily fecal (~80%), with minimal urinary excretion.

• Special Populations:

  • Hepatic Impairment: Use with caution in severe hepatic impairment.

  • Renal Impairment: No dose adjustments necessary for mild to moderate impairment.

5. Indications

• Primary Indications:

  • Primary Hypercholesterolemia: Used alone or in combination with statins to reduce elevated LDL cholesterol.

  • Mixed Dyslipidemia: Useful in patients with combined hyperlipidemia, affecting LDL and triglycerides.

  • Homozygous Familial Hypercholesterolemia (HoFH): As an adjunct therapy to diet and other lipid-lowering treatments.

• Off-Label Uses:

  • Cardiovascular Disease Prevention: Occasionally used in high-risk individuals with statin intolerance.

6. Dosage and Administration

• Adults: 10 mg once daily, either as monotherapy or combined with a statin.

• Pediatrics (HoFH): Use under supervision for specific cases in children above age 10.

• Administration: Can be taken with or without food.

• Renal and Hepatic Adjustments: No adjustments for renal impairment; avoid in severe hepatic disease.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to ezetimibe or any formulation components.

  • Active liver disease in combination with a statin.

• Relative Contraindications:

  • Pregnancy and Lactation: Use only if benefits justify potential fetal or neonatal risks.

  • Severe Renal Disease: Caution, though no specific dosage adjustments are required.

8. Warnings and Precautions

• Hepatotoxicity: Monitor liver function, particularly when combined with statins, due to a possible increase in hepatic enzyme levels.

• Muscle Toxicity: Combined use with statins increases the risk of myopathy, including rhabdomyolysis; monitor for muscle pain or weakness.

• Special Populations: In severe hepatic impairment, alternative therapies are preferred.

9. Adverse Effects

• Common:

  • GI Symptoms: Diarrhea, abdominal pain.

  • Neurological: Headache.

• Less Common but Significant:

  • Liver Enzyme Elevations: Most common in combination therapy.

  • Muscle-Related Symptoms: Myalgia, potential myopathy.

• Serious Adverse Effects:

  • Rhabdomyolysis (in combination therapy).

  • Angioedema: Rare cases reported.

10. Drug Interactions

• Statins: Enhanced risk of myopathy; routine monitoring recommended.

• Cyclosporine: Increases serum ezetimibe concentrations.

• Bile Acid Sequestrants: May reduce ezetimibe absorption; administer ezetimibe either 2 hours before or 4 hours after bile acid sequestrants.

11. Clinical Pharmacology

• Pharmacodynamics: Ezetimibe’s lipid-lowering effects are primarily mediated through inhibition of the NPC1L1 cholesterol transporter, resulting in decreased LDL and minimal HDL increase.

• Additive Effect with Statins: Provides additional LDL reduction without increasing adverse effects when co-administered with a statin.

12. Special Populations

• Pregnancy: Category C; avoid unless necessary.

• Lactation: Not recommended due to lack of data.

• Geriatrics: No specific adjustments.

• Pediatrics: Limited use in specific hypercholesterolemia cases.

• Renal and Hepatic Impairment: Exercise caution in severe hepatic disease.

13. Therapeutic Uses

• Primary Hypercholesterolemia: Effective as monotherapy or adjunct to statins.

• Familial Hypercholesterolemia: Beneficial in reducing LDL levels in HoFH.

• Mixed Dyslipidemia: Used in patients needing comprehensive lipid management.

14. Monitoring and Follow-Up

• Liver Function Tests: Recommended periodically when used with statins.

• Cholesterol Panel: Regular LDL, total cholesterol, HDL, and triglyceride assessment.

• Muscle Symptoms: Monitor for myalgia, especially with combined statin therapy.

15. Overdose Management

• Symptoms: Generally mild, including nausea and GI upset.

• Treatment: Supportive care; activated charcoal if recent ingestion.

16. Patient Counseling Information

• Administration: Taken once daily, with or without food.

• Adverse Effects: Report muscle pain or unusual fatigue, especially if taking statins.

• Regular Monitoring: Importance of periodic liver and cholesterol testing.