What is the half-life, metabolism, and clearance of Immodium (loperamide)?

Half-Life, Metabolism, and Clearance of Loperamide (Immodium)

Loperamide has an elimination half-life of approximately 10.8 hours (range 9.1-14.4 hours), is primarily metabolized by CYP2C8 and CYP3A4 enzymes in the liver, and is mainly excreted through the feces with minimal renal elimination. 1

Pharmacokinetics

Absorption and Distribution

• Loperamide has low oral absorption, with plasma concentrations of unchanged drug remaining below 2 ng/mL after intake of a 2 mg capsule 1
• Peak plasma concentrations occur approximately 5 hours after capsule administration and 2.5 hours after liquid formulation 1
• Loperamide is highly protein-bound (approximately 95%) in plasma and is a P-glycoprotein substrate 1
• Due to its low oral absorption and inability to cross the blood-brain barrier, loperamide has minimal central nervous system effects 2

Metabolism

• Loperamide undergoes oxidative N-demethylation primarily via cytochrome P450 enzymes 1
• The main metabolizing enzymes are:
  • CYP2C8 (inhibition reduces metabolism by approximately 40%)
  • CYP3A4 (inhibition reduces metabolism by approximately 90%)
  • CYP2B6 and CYP2D6 play minor roles in loperamide N-demethylation 1
• Concomitant use with CYP3A4 inhibitors (e.g., itraconazole), CYP2C8 inhibitors (e.g., gemfibrozil), or P-glycoprotein inhibitors (e.g., quinidine, ritonavir) can increase loperamide exposure 1

Elimination

• The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 hours 1
• Excretion of unchanged loperamide and its metabolites occurs mainly through the feces 1
• Unlike many other medications, loperamide has minimal renal elimination, making it safer for use in patients with renal impairment compared to drugs that require significant dose adjustments 1, 3

Clinical Implications

Dosing Considerations

• The standard dosage for acute diarrhea in adults is up to 8 mg daily (over-the-counter use) 4
• For chemotherapy-induced diarrhea, higher doses (up to 24 mg daily) may be used under medical supervision 5
• Due to its long half-life and accumulation with repeated dosing, patients should be cautioned against exceeding recommended doses 1

Safety Profile

• At therapeutic doses, loperamide has a favorable safety profile with minimal systemic effects 2
• Common adverse reactions include abdominal cramps and nausea 2
• In overdose situations (typically far exceeding therapeutic doses), serious cardiac events including QT prolongation, torsades de pointes, and cardiac arrest have been reported 5
• These cardiac events are primarily associated with extremely high doses (64-1600 mg daily) taken for extended periods 5

Special Populations

• Loperamide is generally safe in patients with renal impairment due to its minimal renal elimination 1
• In pediatric populations, careful dosing is essential as accidental overdoses have occurred, though most cases (63%) remain asymptomatic 6
• The most common symptoms in pediatric overdose cases are drowsiness (15.7%), vomiting (4.2%), and abdominal pain (3.7%) 6

Mechanism of Action

• Loperamide acts by binding to μ-opioid receptors in the gut wall 1
• This binding inhibits the release of acetylcholine and prostaglandins, reducing propulsive peristalsis and increasing intestinal transit time 1
• It also increases the tone of the anal sphincter, reducing incontinence and urgency 1
• Unlike other opioids, loperamide's peripheral action and poor blood-brain barrier penetration minimize central nervous system effects 2

Loperamide's pharmacokinetic profile makes it an effective antidiarrheal agent with minimal systemic effects when used at recommended doses, though caution should be exercised to avoid exceeding these doses due to potential cardiac risks with extreme overdose.