What is the drug group and mechanism of action (MOA) of orlistat?

Orlistat: Drug Group and Mechanism of Action

Orlistat belongs to the lipase inhibitor drug group and works by inhibiting gastrointestinal and pancreatic lipases, thereby preventing the absorption of dietary fat by approximately 30%. 1

Drug Classification and Chemical Properties

• Drug Group: Lipase inhibitor
• Chemical Name: Tetrahydrolipstatin
• Molecular Weight: 495.73 g/l 1
• Formulation: Available as oral capsules (120 mg prescription, 60 mg over-the-counter) 1

Mechanism of Action (MOA)

Orlistat functions through a specific and targeted mechanism:

1. Primary Action: Forms a covalent bond with the active serine site of gastric and pancreatic lipases 1
2. Enzymatic Inhibition:
   • Effectively inhibits gastric lipase at an inhibitor to enzyme molar ratio of 1:2,000
   • Inhibits pancreatic lipase at a molar ratio of 1:10,000 (though this effect is reversible) 1
3. Fat Malabsorption: Prevents the hydrolysis of dietary triglycerides into absorbable free fatty acids 1
4. Caloric Impact: Reduces dietary fat absorption by approximately 30%, which translates to approximately 200 fewer calories absorbed per day 2

Pharmacodynamics

• Optimal Dosing: Research has established that 120 mg three times daily (with each main meal) provides optimal lipase inhibition 3
• Concentration Requirements:
  • 1 mM concentration is typically needed to inhibit gastric lipase
  • 5 mM concentration is typically needed to inhibit intestinal lipase 1
• Non-Systemic Action: Unlike many weight loss medications, orlistat works locally in the gastrointestinal tract and is minimally absorbed systemically 4

Clinical Applications

Orlistat is FDA-approved for:

• Treatment of obesity in adults with BMI ≥30 kg/m²
• Treatment of overweight adults (BMI ≥27 kg/m²) with weight-related comorbidities 1

Important Considerations

• Vitamin Supplementation: Due to its mechanism of reducing fat absorption, orlistat can decrease absorption of fat-soluble vitamins (A, D, E, K). Patients should take a multivitamin at bedtime, at least 2 hours apart from orlistat doses 5
• Diet Requirements: Must be used in conjunction with a reduced-calorie, low-fat diet (approximately 30% of calories from fat) to minimize gastrointestinal side effects 5
• Contraindications: Should not be used in patients with chronic malabsorption syndrome, cholestasis, or organ transplant recipients taking immunosuppressants like cyclosporine 5

Distinguishing Features

• Unlike centrally-acting weight loss medications, orlistat has no effects on the central nervous system 4
• It is the first FDA-approved weight loss medication that works by interfering with dietary fat absorption rather than by suppressing appetite 2
• Available both as prescription strength (Xenical, 120 mg) and over-the-counter (Alli, 60 mg) 1

This unique mechanism of action makes orlistat particularly useful for patients with obesity and constipation or those with concomitant hypercholesterolemia, as it can improve lipid profiles by reducing total cholesterol and LDL cholesterol levels 1, 3.