Usage
- Prothionamide is an antimycobacterial drug primarily used in the treatment of multi-drug resistant (MDR) tuberculosis (TB). It is typically employed when primary anti-TB drugs (like isoniazid and rifampicin) are ineffective due to bacterial resistance. It may also be used to treat Mycobacterium leprae, the bacteria that causes leprosy, in combination with other anti-leprosy drugs.
- Pharmacological Classification: Antitubercular agent, Second-line antituberculosis agent, Nicotinamide derivative.
- Mechanism of Action: Prothionamide is a prodrug activated by the mycobacterial enzyme EthA. The active metabolite inhibits mycolic acid synthesis, a crucial component of the mycobacterial cell wall, ultimately leading to bacterial death.
Alternate Names
How It Works
- Pharmacodynamics: Prothionamide disrupts the synthesis of mycolic acids, essential components of the mycobacterial cell wall. This disruption compromises the structural integrity of the cell wall, leading to bacterial death.
- Pharmacokinetics:
- Absorption: Readily absorbed from the gastrointestinal tract, with peak plasma concentrations reached in approximately 1-2 hours. Taking it with food may improve tolerability.
- Metabolism: Metabolized in the liver, primarily to its active sulfoxide metabolite.
- Elimination: Excreted mainly through the kidneys, with less than 1% eliminated unchanged in urine.
- Mode of Action: After activation by EthA, the active metabolite of prothionamide interferes with the synthesis of mycolic acids by blocking the enzyme enoyl-ACP reductase, eventually leading to bacterial cell death.
- Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
- 15-20 mg/kg body weight once daily, up to a maximum of 1g (1000mg) daily. Doses up to 25mg/kg have been suggested. Some studies suggest best efficacy at 15mg/kg, while others suggest 20mg/kg or a fixed dose of 600mg if weight based dosing is impractical. If the once daily dose is equal to or less than 750mg, it may be divided into two doses.
- Gradual dose escalation may be employed starting with 250mg daily, and increasing by 250mg every 3-5 days to improve tolerability.
- Pyridoxine (Vitamin B6) supplementation (50–100mg daily, or 50mg per 250mg of prothionamide) is recommended to prevent peripheral neuropathy.
Children:
- 15-20 mg/kg body weight once daily, up to a maximum of 1g (1000mg) daily. If the once daily dose is equal to or less than 750mg, it may be divided into two doses.
- Pediatric safety considerations are similar to adults. Monitor closely for gastrointestinal and neurological side effects.
Special Cases:
- Elderly Patients: No specific dose adjustment is recommended, but it is advised to start at the lower end of the dose range and titrate cautiously, monitoring for adverse effects.
- Patients with Renal Impairment: No dose adjustment is typically required, as it does not rely solely on renal clearance.
- Patients with Hepatic Dysfunction: Use with caution. Start with a lower dose and monitor closely for hepatotoxicity.
- Patients with Comorbid Conditions: Exercise caution in patients with diabetes (risk of hypoglycemia) or depression.
Clinical Use Cases
Prothionamide’s use is primarily confined to the treatment of MDR-TB in combination with other antitubercular agents and has no specific dosage recommendations for:
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations
Dosage Adjustments
- Dose adjustments may be necessary based on patient tolerance and adverse events.
Side Effects
Common Side Effects:
- Nausea, vomiting, diarrhea, anorexia, metallic taste, abdominal pain, stomatitis, and excessive salivation.
- Transient increases in liver function tests (LFTs).
Rare but Serious Side Effects:
- Acute hepatitis
- Peripheral neuropathy, dizziness, encephalopathy
- Optic neuritis
- Psychotic disturbances, depression
- Hypoglycemia, hypothyroidism
- Gynaecomastia
Long-Term Effects:
- Chronic liver disease (with prolonged high-dose therapy)
- Peripheral neuropathy
Adverse Drug Reactions (ADR):
- Acute hepatitis and severe neurological reactions require immediate discontinuation of the drug and appropriate management.
Contraindications
- Severe hepatic impairment
- Hypersensitivity to prothionamide or other thioamides
Drug Interactions
- Isoniazid, Cycloserine, Terizidone: Increased risk of neurotoxicity.
- Para-aminosalicylic acid (PAS): Increased risk of gastrointestinal upset and hypothyroidism.
- Alcohol: May increase risk of hepatotoxicity and neurological side effects.
- Aluminum-containing antacids: Reduced absorption of prothionamide.
Pregnancy and Breastfeeding
- Not classified under the FDA Pregnancy Category system due to lack of clinical trials. Limited data suggests potential adverse effects. Therefore, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Excretion into breast milk is unknown. Use with caution in breastfeeding mothers. Consider the potential risk to the infant.
Drug Profile Summary
- Mechanism of Action: Inhibits mycolic acid synthesis.
- Side Effects: Nausea, vomiting, hepatotoxicity, peripheral neuropathy.
- Contraindications: Severe hepatic impairment.
- Drug Interactions: Isoniazid, cycloserine, PAS.
- Pregnancy & Breastfeeding: Limited data suggests potential risk. Should be used if potential benefit outweighs risk.
- Dosage: 15-20mg/kg/day up to 1g, once or twice daily.
- Monitoring Parameters: LFTs, blood glucose, thyroid function tests.
Popular Combinations
Prothionamide is often used in combination with other second-line anti-TB drugs, such as:
- Kanamycin
- Levofloxacin
- Moxifloxacin
- Cycloserine
- Ethambutol
Precautions
- Baseline liver function tests, renal function tests, and blood glucose (in diabetics) should be assessed.
- Monitor regularly for hepatotoxicity, peripheral neuropathy, and other side effects.
- Patients should avoid alcohol consumption during treatment.
FAQs
Q1: What is the recommended dosage for Prothionamide?
A: 15-20 mg/kg daily up to 1g, administered orally once or divided into two doses.
Q2: What are the common side effects?
A: Gastrointestinal disturbances (nausea, vomiting, diarrhea) are common.
Q3: What are the serious side effects?
A: Hepatotoxicity and peripheral neuropathy are serious potential side effects.
Q4: What are the contraindications?
A: Severe hepatic impairment is a contraindication.
Q5: How does Prothionamide interact with other drugs?
A: It can interact with isoniazid, cycloserine, and PAS, increasing the risk of neurotoxicity.
Q6: Can Prothionamide be used in pregnancy?
A: Use with caution during pregnancy only if the benefits outweigh the potential risks to the fetus, due to limited safety data.
Q7: What is the mechanism of action of Prothionamide?
A: It inhibits mycolic acid synthesis, a key component of the mycobacterial cell wall.
Q8: What monitoring is required during Prothionamide therapy?
A: Monitor liver function, blood glucose, and neurological function.
Q9: How should Prothionamide be administered?
A: Orally, with food to enhance tolerability.
Q10: Is there a need for dose adjustment in renal failure?
A: No dose adjustment is generally required in renal impairment.
