Terizidone

Usage

• Terizidone is a second-line antituberculosis drug prescribed for the treatment of multidrug-resistant tuberculosis (MDR-TB) caused by Mycobacterium tuberculosis. It is used in combination with other anti-TB medications when first-line drugs are ineffective due to resistance or intolerance.
• Pharmacological classification: Antituberculosis drug, specifically a structural analog of cycloserine.
• Mechanism of action: Terizidone is a prodrug of cycloserine. It is hydrolyzed to cycloserine and para-phthalate in the body. Cycloserine inhibits bacterial cell wall synthesis by interfering with the formation of D-alanine and its incorporation into the peptidoglycan layer. It acts by inhibiting two enzymes, alanine racemase and D-alanyl-D-alanine synthetase, essential for peptidoglycan synthesis.

Alternate Names

• Terizidon
• Cycloserine dimer
• No widely recognized international variations.
• Brand names (examples): Terizidon, Terizidone Macleods

How It Works

• Pharmacodynamics: Terizidone exerts its antibacterial effect by inhibiting cell wall synthesis, specifically peptidoglycan synthesis, leading to bacterial cell death.

• Pharmacokinetics:

  • Absorption: Terizidone is administered orally. High-fat meals can delay and reduce the drug’s absorption.
  • Metabolism: Terizidone is a prodrug that is hydrolyzed to its active metabolite cycloserine.
  • Elimination: Cycloserine is primarily eliminated through renal excretion. Dose adjustments are necessary in patients with renal impairment.

• Mode of action: Terizidone is hydrolyzed to cycloserine, which then inhibits two key enzymes, alanine racemase, and D-alanyl-D-alanine synthetase involved in peptidoglycan biosynthesis in bacterial cell walls.

• Receptor binding/enzyme inhibition: Cycloserine inhibits alanine racemase and D-alanyl-D-alanine synthetase.

• Elimination pathways: Primarily renal excretion.

Dosage

Standard Dosage

Adults:

• 750-1000 mg/day, administered in 3 or 4 divided doses, with or without food.
• Maximum daily dose: 1000 mg.

Children:

• 10-20 mg/kg/day, administered in two divided doses every 12 hours or once daily if tolerated.
• Maximum daily dose: 1000 mg.
• For children unable to swallow capsules, the contents can be dissolved in 10 ml of water.
• Pediatric safety considerations: Monitor closely for central nervous system toxicity.

Special Cases:

• Elderly Patients: Caution is advised; dose adjustments may be necessary due to age-related decline in renal function.
• Patients with Renal Impairment: Dose reduction is required for patients with creatinine clearance <30 ml/min (250 mg once daily or 500 mg three times a week, administered after dialysis).
• Patients with Hepatic Dysfunction: No specific dose adjustments are necessary, but monitor closely for signs of toxicity.
• Patients with Comorbid Conditions: Use with caution in patients with pre-existing neurological or psychiatric conditions.

Clinical Use Cases

The dosage recommendations for terizidone are consistent across various clinical settings in which it might be used as part of a multidrug regimen for MDR-TB. There are no specific dosage modifications for Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit (ICU) Use, or Emergency Situations.

Dosage Adjustments

• Dose adjustments based on creatinine clearance are essential.
• Therapeutic drug monitoring is recommended to maintain peak serum cycloserine concentrations below 35 µg/ml.

Side Effects

Common Side Effects

• Headache, dizziness, drowsiness, insomnia, tremor, nervousness, irritability, difficulty speaking, numbness or tingling in extremities.

Rare but Serious Side Effects

• Seizures, psychosis, depression, suicidal ideation, allergic dermatitis, hypersensitivity reactions, peripheral neuropathy.

Long-Term Effects

• Chronic neurological or psychiatric complications are possible with prolonged use.

Adverse Drug Reactions (ADR)

• Neurotoxicity (seizures, psychosis, depression) and hypersensitivity reactions require immediate intervention.

Contraindications

• Hypersensitivity to terizidone or cycloserine.
• Epilepsy, severe depression, psychosis, severe anxiety, chronic alcoholism, severe renal impairment.

Drug Interactions

• Alcohol, isoniazid, ethionamide: Increased risk of neurotoxicity.
• Medications affecting the central nervous system (antidepressants, antipsychotics, anticonvulsants): Exacerbation of neurological side effects.
• High-fat meals: Decreased terizidone absorption.

Pregnancy and Breastfeeding

• Limited human data available.
• Use only if potential benefits outweigh the risks to the fetus.
• Terizidone is excreted in breast milk. Supplementation with pyridoxine is recommended for both mother and infant.

Drug Profile Summary

• Mechanism of Action: Inhibits bacterial cell wall synthesis.
• Side Effects: Headache, dizziness, drowsiness, seizures, psychosis, depression.
• Contraindications: Epilepsy, psychosis, severe renal impairment, alcoholism.
• Drug Interactions: Alcohol, isoniazid, ethionamide, CNS-active drugs.
• Pregnancy & Breastfeeding: Use with caution if benefits outweigh risks; monitor infant.
• Dosage: Adults: 750-1000 mg/day; Children: 10-20 mg/kg/day.
• Monitoring Parameters: Cycloserine serum concentrations, renal function, neurological and psychiatric status.

Popular Combinations

Terizidone is typically used in combination with other second-line anti-TB drugs based on susceptibility testing.

Precautions

• Pre-screening for renal function, neurological/psychiatric conditions, and alcohol abuse is essential.
• Co-administration of pyridoxine (vitamin B6) is recommended to prevent neurological side effects (50 mg of pyridoxine for every 250 mg of terizidone).

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Terizidone?

A: Adults: 750-1000 mg/day in divided doses. Children: 10-20 mg/kg/day in divided doses.

Q2: What are the common side effects of Terizidone?

A: Headache, dizziness, drowsiness, tremor, and peripheral neuropathy.

Q3: What are the serious side effects of Terizidone?

A: Seizures, psychosis, depression, and suicidal ideation.

Q4: What are the contraindications for Terizidone?

A: Epilepsy, severe depression, psychosis, severe renal impairment, and chronic alcoholism.

Q5: How does Terizidone interact with other drugs?

A: Increased neurotoxicity with alcohol, isoniazid, and ethionamide. Exacerbated neurological side effects with CNS-active drugs.

Q6: Can Terizidone be used during pregnancy and breastfeeding?

A: Use with caution if benefits outweigh risks. Monitor infant if breastfeeding. Supplement with pyridoxine.

Q7: What is the mechanism of action of Terizidone?

A: Inhibits bacterial cell wall synthesis by inhibiting alanine racemase and D-alanyl-D-alanine synthetase.

Q8: What are the key monitoring parameters for patients on Terizidone?

A: Cycloserine serum concentrations, renal function, and neurological/psychiatric status.

Q9: Why is pyridoxine co-administered with Terizidone?

A: To mitigate the risk of neurological side effects.

Q10: What kind of diet should be recommended during Terizidone usage?

A: Avoid high-fat meals, as they interfere with terizidone absorption. It is recommended to administer the drug without food or with orange juice.