Isoniazid + Pyrazinamide + Rifampicin + Vitamin B6

Usage

• This combination therapy is primarily prescribed for the treatment of active pulmonary tuberculosis (TB). It is crucial for eradicating Mycobacterium tuberculosis, the bacterium responsible for TB. The addition of Vitamin B6 (pyridoxine) helps prevent peripheral neuropathy, a common side effect of isoniazid.

• Pharmacological Classification: Antimycobacterial, Antituberculosis

• Mechanism of Action: This combination targets different aspects of M. tuberculosis metabolism. Isoniazid inhibits mycolic acid synthesis, a key component of the bacterial cell wall. Rifampicin blocks bacterial RNA polymerase, preventing RNA synthesis. Pyrazinamide disrupts bacterial metabolism through an unclear mechanism, possibly affecting membrane transport and energy production.

Alternate Names

• There isn’t one single international nonproprietary name (INN) for this combination. The components are frequently referred to by their individual INNs: Isoniazid, Rifampicin (Rifampin in the US), Pyrazinamide, and Pyridoxine.

• Brand Names: Rifater is a widely recognized brand name for the three-drug combination (isoniazid, rifampicin, and pyrazinamide). Many formulations combine these three with pyridoxine and are marketed under various brand names worldwide.

How It Works

• Pharmacodynamics: The combination acts synergistically to kill M. tuberculosis. Isoniazid targets the cell wall, Rifampicin inhibits RNA synthesis, and Pyrazinamide disrupts metabolic processes. Vitamin B6 mitigates isoniazid-induced neurotoxicity.

• Pharmacokinetics: All components are orally absorbed. Isoniazid and rifampicin are metabolized primarily in the liver, while pyrazinamide is metabolized in the liver to pyrazinoic acid and then excreted renally. Rifampicin induces several CYP450 enzymes, affecting the metabolism of other drugs. Isoniazid inhibits CYP2E1.

• Mode of Action: Isoniazid inhibits InhA, an enzyme essential for mycolic acid biosynthesis. Rifampicin binds to the bacterial RNA polymerase beta-subunit, inhibiting transcription. Pyrazinamide’s mechanism is not fully elucidated but is thought to involve conversion to pyrazinoic acid, which disrupts membrane potential and energy production within the bacteria.

• Elimination Pathways: Isoniazid and rifampicin are primarily metabolized in the liver and their metabolites are excreted in urine. Pyrazinamide is also metabolized in the liver and excreted primarily through the kidneys.

Dosage

Standard Dosage

Adults:

• Isoniazid: 5 mg/kg (maximum 300 mg) daily.
• Rifampicin: 10 mg/kg (maximum 600 mg) daily.
• Pyrazinamide: 15-30 mg/kg (maximum 2 g) daily.
• Vitamin B6: 10-25 mg daily.
• These are typically given as a single daily dose.

Children:

• Dosing is weight-based, similar to adults, and must be carefully calculated by a physician. Pediatric specialists should be consulted for dosing in children weighing under 20 kg.

Special Cases:

• Elderly Patients: Liver and kidney function should be closely monitored and dosages adjusted accordingly.
• Patients with Renal Impairment: Dosage adjustments, particularly for pyrazinamide, are required based on creatinine clearance.
• Patients with Hepatic Dysfunction: Close monitoring and dosage reductions are necessary for all components due to increased risk of hepatotoxicity.
• Patients with Comorbid Conditions: Diabetes, HIV, alcoholism, and malnutrition can influence drug metabolism and increase the risk of adverse effects, necessitating close monitoring and potential dosage adjustments.

Clinical Use Cases

This combination is typically not used in specific clinical settings like intubation, surgery, mechanical ventilation, or ICU care. Its primary indication is for the treatment of active tuberculosis.

Dosage Adjustments

Adjustments are patient-specific, based on weight, age, organ function, and co-existing conditions. Therapeutic drug monitoring may be beneficial, especially in patients with renal or hepatic impairment.

Side Effects

Common Side Effects

Nausea, vomiting, loss of appetite, abdominal discomfort, peripheral neuropathy (numbness, tingling), arthralgia, rash, fever, orange-red discoloration of body fluids (urine, sweat, tears).

Rare but Serious Side Effects

Hepatotoxicity (jaundice, dark urine, abdominal pain), thrombocytopenia, acute gout, severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), drug-induced lupus.

Long-Term Effects

Peripheral neuropathy can persist even after treatment discontinuation. Liver damage can be irreversible.

Adverse Drug Reactions (ADR)

Any signs of hepatotoxicity, severe skin reactions, or bleeding/bruising should be considered serious ADRs and require immediate medical attention.

Contraindications

Severe liver disease, acute gout, porphyria, prior hypersensitivity reaction to any component, concomitant use of certain antiviral medications.

Drug Interactions

Rifampicin is a potent inducer of CYP450 enzymes, impacting the efficacy of numerous medications, including anticoagulants, oral contraceptives, antiretrovirals, and immunosuppressants. Isoniazid can inhibit the metabolism of phenytoin and other drugs. Antacids containing aluminum can interfere with rifampicin absorption. Alcohol should be avoided due to increased risk of hepatotoxicity. Pyrazinamide can decrease the effectiveness of uricosuric agents (like probenecid) used to treat gout.

Pregnancy and Breastfeeding

This drug combination can be used during pregnancy, but with caution. Vitamin B6 supplementation is recommended. Vitamin K supplementation is often recommended in the last month of pregnancy. The drugs are present in breast milk; decisions regarding breastfeeding should consider the risks and benefits for both the mother and the infant. Pyridoxine supplementation is recommended for breastfeeding mothers, and the infant should be monitored for potential adverse effects.

Drug Profile Summary

• Mechanism of Action: See “How It Works” section.
• Side Effects: Nausea, vomiting, peripheral neuropathy, hepatotoxicity, skin rash.
• Contraindications: Severe liver disease, acute gout.
• Drug Interactions: Numerous drug interactions, notably with rifampicin as a CYP450 inducer.
• Pregnancy & Breastfeeding: Can be used with caution and appropriate supplementation.
• Dosage: See “Dosage” section.
• Monitoring Parameters: Liver function tests, complete blood counts, uric acid levels.

Popular Combinations

Ethambutol is often added to this regimen, particularly in areas with higher rates of drug resistance or during the initial phase of treatment before drug susceptibility results are available. This is sometimes referred to as the RIPE regimen (rifampicin, isoniazid, pyrazinamide, ethambutol).

Precautions

Baseline liver and kidney function tests, as well as uric acid levels, should be obtained. Monitor for signs of hepatotoxicity, neuropathy, and other adverse events. Alcohol should be avoided. Patient education regarding adherence is crucial.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Isoniazid + Pyrazinamide + Rifampicin + Vitamin B6?

A: See the “Dosage” section for detailed information on adult, pediatric, and special population dosing.

Q2: What is the role of Vitamin B6 in this combination?

A: Vitamin B6 prevents peripheral neuropathy, a common side effect of Isoniazid.

Q3: Can this combination be used in pregnant or breastfeeding women?

A: Yes, but with caution. Consult the “Pregnancy and Breastfeeding” section for specific recommendations.

Q4: What are the most serious side effects to watch out for?

A: Hepatotoxicity and severe cutaneous reactions are the most serious side effects. See “Side Effects” for details.

Q5: What are the key drug interactions to be aware of?

A: Rifampicin is a potent enzyme inducer and interacts with many drugs. See “Drug Interactions” for more information.

Q6: How should I monitor patients on this combination therapy?

A: Monitor liver function, complete blood count, and uric acid levels regularly.

Q7: What is the duration of treatment for active TB with this combination?

A: This combination is typically used during the intensive phase of treatment (first two months), followed by a continuation phase with isoniazid and rifampicin for several more months. The total treatment duration is usually six months.

Q8: Can this combination be used to treat latent TB infection?

A: No, this combination is not typically used for latent TB infection. Other regimens are recommended for latent TB.

Q9: What should I do if a patient develops signs of hepatotoxicity while on this medication?

A: Discontinue the medication immediately and consult a specialist for further management.

Q10: Are there any dietary restrictions while taking this medication?

A: Patients should avoid alcohol. It is important to maintain a balanced diet, as certain nutrients, such as Vitamin B6 and Vitamin D, can be affected by this medication.