Usage
This combination drug is primarily prescribed for the treatment of active tuberculosis (TB). It is classified as an antimycobacterial agent, specifically a first-line treatment for drug-susceptible TB. The combination targets different aspects of Mycobacterium tuberculosis metabolism, thereby enhancing efficacy and minimizing the development of drug resistance. It attacks replicating and semi-dormant M. tuberculosis bacilli.
Alternate Names
This combination is often referred to as “RHZ” (Rifampicin, Isoniazid, Pyrazinamide). It is part of a standard four-drug regimen, which also includes Ethambutol. A common brand name is Rifater®.
How It Works
Isoniazid: Inhibits mycolic acid synthesis, a crucial component of the mycobacterial cell wall. It is bactericidal against actively growing bacilli. It is metabolized primarily by acetylation in the liver and eliminated through the kidneys. Genetic variations in acetylator status influence individual pharmacokinetics and dosage requirements.
Pyrazinamide: Mechanism not fully understood, but likely involves disrupting mycobacterial membrane transport and energy production. It is active against intracellular bacilli, particularly in the acidic environment of infected macrophages. It is metabolized in the liver, with its major metabolite, pyrazinoic acid, excreted renally.
Rifampicin: Inhibits bacterial DNA-dependent RNA polymerase, preventing RNA synthesis and thus protein synthesis. It is bactericidal against both actively growing and semi-dormant bacilli. Rifampicin undergoes hepatic metabolism through deacetylation and is primarily eliminated in bile and feces.
Dosage
Standard Dosage
Adults:
The standard adult dose is based on weight, typically:
- Isoniazid: 5 mg/kg (up to 300 mg maximum) daily.
- Rifampicin: 10 mg/kg (up to 600 mg maximum) daily.
- Pyrazinamide: 15-30 mg/kg (up to 2 g maximum) daily or 50-70 mg/kg two to three times per week in directly observed therapy.
All three drugs are usually given orally once daily for the initial two months of treatment.
Children:
Pediatric dosages are also weight-based:
- Isoniazid: 10-15 mg/kg (up to 300 mg maximum) daily.
- Rifampicin: 10-20 mg/kg (up to 600 mg maximum) daily.
- Pyrazinamide: 30-40 mg/kg daily.
Special Cases:
- Elderly Patients: Dosage adjustments based on renal and hepatic function are important in older adults.
- Patients with Renal Impairment: Dosage adjustments, especially for Isoniazid and Pyrazinamide, are necessary.
- Patients with Hepatic Dysfunction: Close monitoring of liver function is crucial. Dose reduction or discontinuation may be necessary.
- Patients with Comorbid Conditions: Co-existing medical conditions, like diabetes or HIV, may require specific considerations.
Clinical Use Cases
Isoniazid, Pyrazinamide, and Rifampicin are not typically used in isolation for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose adjustments are based on individual patient factors, including renal and hepatic function, drug interactions, and potential adverse effects. Therapeutic drug monitoring may be helpful in certain cases.
Side Effects
Common Side Effects
Nausea, vomiting, loss of appetite, abdominal discomfort, mild liver enzyme elevations (especially with Isoniazid), peripheral neuropathy (Isoniazid), orange discoloration of body fluids (Rifampicin), arthralgia (Pyrazinamide), and rash.
Rare but Serious Side Effects
Hepatotoxicity (especially with Isoniazid and Pyrazinamide), severe cutaneous adverse reactions, thrombocytopenia, acute kidney injury, seizures (Isoniazid).
Long-Term Effects
Peripheral neuropathy, hepatitis, gout (Pyrazinamide).
Adverse Drug Reactions (ADR)
Severe hepatotoxicity, drug-induced lupus (Isoniazid), optic neuritis (Ethambutol, often used in conjunction with RHZ).
Contraindications
Acute liver disease, severe hypersensitivity reactions to any of the drugs, porphyria (Pyrazinamide).
Drug Interactions
Rifampicin is a potent inducer of CYP450 enzymes and can reduce the efficacy of numerous medications, including anticoagulants, oral contraceptives, and some antiretrovirals. Isoniazid can interact with certain anticonvulsants, increasing the risk of toxicity. Alcohol should be avoided during treatment with these drugs, especially with Isoniazid and Pyrazinamide, due to increased risk of hepatotoxicity.
Pregnancy and Breastfeeding
The combination is generally considered safe during pregnancy, but benefits must outweigh potential risks. All three drugs are excreted in breast milk, but breastfeeding is considered safe with careful monitoring for potential adverse effects in the infant.
Drug Profile Summary
- Mechanism of Action: Isoniazid inhibits mycolic acid synthesis; Rifampicin inhibits RNA polymerase; Pyrazinamide disrupts energy production.
- Side Effects: Hepatotoxicity, peripheral neuropathy, nausea, vomiting, rash.
- Contraindications: Acute liver disease, hypersensitivity.
- Drug Interactions: Rifampicin induces CYP450, numerous drug interactions.
- Pregnancy & Breastfeeding: Generally safe with monitoring.
- Dosage: Weight-based, adjusted for renal/hepatic function.
- Monitoring Parameters: Liver function tests, signs of hepatotoxicity, peripheral neuropathy, complete blood count, renal function.
Popular Combinations
The most common combination is RHZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol), which forms the standard four-drug regimen for the initial phase of TB treatment.
Precautions
Baseline liver and renal function tests should be performed before initiating therapy. Patients should be monitored for signs of hepatotoxicity, such as jaundice, dark urine, and abdominal pain. Patients should be counseled about the potential for drug interactions and the importance of adherence to the prescribed regimen. Alcohol consumption should be avoided.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Isoniazid + Pyrazinamide + Rifampicin?
A: Dosage is weight-based and varies for adults and children. Adults: Isoniazid 5 mg/kg (max 300mg), Rifampicin 10 mg/kg (max 600mg), Pyrazinamide 15-30 mg/kg daily. Children: Isoniazid 10-15 mg/kg, Rifampicin 10-20 mg/kg, Pyrazinamide 30-40 mg/kg daily.
Q2: What are the most common side effects?
A: Nausea, vomiting, abdominal discomfort, and liver enzyme elevations are common. Peripheral neuropathy may occur with Isoniazid, and orange discoloration of body fluids with Rifampicin.
Q3: What are the serious side effects to watch for?
A: Hepatotoxicity is the most serious adverse effect. Monitor for jaundice, dark urine, and abdominal pain.
Q4: What are the contraindications to this drug combination?
A: Acute liver disease, hypersensitivity to any of the components, and porphyria are contraindications.
Q5: What drug interactions are important to consider?
A: Rifampicin is a potent CYP450 inducer and interacts with numerous medications. Alcohol should be avoided due to increased risk of hepatotoxicity.
Q6: Can this drug be used in pregnancy and breastfeeding?
A: It is generally considered safe during pregnancy and breastfeeding, but careful monitoring is required.
Q7: How should liver function be monitored during treatment?
A: Regular liver function tests (LFTs) are essential, along with clinical monitoring for signs of hepatotoxicity.
Q8: What patient education is crucial for successful treatment?
A: Emphasize the importance of adherence to the medication regimen, avoidance of alcohol, reporting any signs or symptoms of adverse effects, and potential drug interactions.
Q9: Why is this combination used instead of the individual drugs alone?
A: Combining these drugs prevents the development of drug resistance, a major challenge in TB treatment. Each drug targets a different mechanism of M. tuberculosis, maximizing efficacy.
Q10: How long is the typical treatment duration?
A: The intensive phase with this combination typically lasts for two months, followed by a continuation phase with other antitubercular drugs for several more months, depending on the type of TB.
