Pyrazinamide

Usage

• Pyrazinamide is an antituberculosis drug used in combination with other antituberculosis agents for the initial treatment of active tuberculosis (TB) caused by Mycobacterium tuberculosis. It is crucial for shortening the duration of TB treatment and preventing relapse. It is not effective against atypical mycobacteria.
• Pharmacological classification: Antituberculosis agent, Antimycobacterial agent.
• Mechanism of Action: The precise mechanism is not fully understood but Pyrazinamide is thought to exert its bactericidal activity specifically against semi-dormant M. tuberculosis residing within the acidic environment of lysosomes inside macrophages. Pyrazinamide is a prodrug that is converted to the active form pyrazinoic acid by the bacterial enzyme pyrazinamidase. Pyrazinoic acid disrupts mycobacterial cell membrane transport and energy production. It’s particularly effective against bacterial populations that are less susceptible to other anti-TB drugs.

Alternate Names

• Pyrazinoic acid amide
• Brand Names: Tebrazid, Zinamide

How It Works

• Pharmacodynamics: Pyrazinamide is bactericidal against M. tuberculosis, particularly in the acidic intracellular environment of macrophages. Pyrazinamide primarily targets intracellular organisms that are metabolically less active and less susceptible to other antituberculosis agents.
• Pharmacokinetics:
  • Absorption: Well-absorbed orally, reaching peak plasma concentrations within 1-2 hours.
  • Distribution: Widely distributed throughout the body, including the cerebrospinal fluid (CSF), achieving therapeutic concentrations.
  • Metabolism: Pyrazinamide is a prodrug hydrolyzed in the liver to its active metabolite, pyrazinoic acid, by the enzyme pyrazinamidase. Pyrazinoic acid is further metabolized by the liver to 5-hydroxypyrazinoic acid.
  • Excretion: Primarily eliminated by the kidneys. Dose adjustment is needed for renal impairment.
• Mode of Action: Pyrazinamide’s precise antibacterial mechanism is not fully understood. Its active form, pyrazinoic acid, appears to target the mycobacterial membrane potential, disrupting energy production and interfering with membrane transport processes. It also inhibits fatty acid synthase I (FAS I), which is crucial for mycobacterial cell wall synthesis.
• Receptor binding, enzyme inhibition or neurotransmitter modulation: The mechanism of action does not involve receptor binding or neurotransmitter modulation. It acts via inhibiting the enzyme fatty acid synthase (FAS I) in M. tuberculosis and disrupting membrane potential.
• Elimination Pathways: Pyrazinamide and its metabolites are primarily excreted by renal excretion.

Dosage

Standard Dosage

Adults:

• Daily: 15-30 mg/kg (up to 2 g/day) orally once a day.
• Intermittent (twice weekly): 50-70 mg/kg (up to 3g twice weekly for intermittent regimens) orally, depending on the regimen and patient characteristics.
• Maximum daily dose: 3 g. The CDC recommends not exceeding 2g/day for daily regimens.
• Duration: Usually given for the first two months of a multi-drug regimen (typically 6 months total).

Children:

• Daily: 15-40 mg/kg orally once a day (based on child’s weight, up to 2g/day).
• Intermittent (twice weekly): Adjustments may be required. Consult pediatric TB treatment guidelines for specific recommendations.
• Pediatric Safety Considerations: Monitor closely for hepatotoxicity.

Special Cases:

• Elderly Patients: Close monitoring for adverse effects is essential, especially hepatotoxicity. Dosage adjustments may be needed based on renal and hepatic function.
• Patients with Renal Impairment: Dose reduction and/or less frequent administration is necessary. See specific guidelines for recommendations based on creatinine clearance.
• Patients with Hepatic Dysfunction: Use with caution due to risk of hepatotoxicity. Closely monitor liver function tests. Consider dosage adjustment or alternative agent.
• Patients with Comorbid Conditions: For those with gout, monitor uric acid levels and consider using uricosuric agents. Closely monitor diabetic patients for glucose control.

Clinical Use Cases

Pyrazinamide is not typically adjusted for specific clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It’s part of a standard TB treatment regimen, continuing in these situations unless contraindicated by liver dysfunction.

Dosage Adjustments

Dose adjustments are based on renal or hepatic dysfunction, body weight, drug resistance pattern of the TB strain, and patient tolerance.

Side Effects

Common Side Effects

• Nausea, vomiting, anorexia
• Arthralgia, myalgia
• Hyperuricemia (usually asymptomatic)

Rare but Serious Side Effects

• Hepatotoxicity (ranging from mild transaminitis to hepatic failure). This is the most significant side effect.
• Gout (acute attacks)
• Fever, malaise
• Rash, pruritus, photosensitivity.

Long-Term Effects

Long-term effects are uncommon if pyrazinamide is used for the standard two-month duration. Chronic hepatotoxicity is possible with extended use.

Adverse Drug Reactions (ADR)

Hepatotoxicity, including jaundice, hepatitis, liver failure, requires immediate discontinuation. Acute gout attacks necessitate discontinuation and treatment.

Contraindications

• Acute gout or severe hyperuricemia
• Severe hepatic impairment (acute or chronic)
• Hypersensitivity to pyrazinamide

Drug Interactions

• Allopurinol: Pyrazinamide can decrease the effectiveness of allopurinol. Monitor uric acid and adjust allopurinol dose as necessary.
• Probenecid, Sulfinpyrazone: These uricosuric agents may increase the risk of pyrazinamide-induced hyperuricemia and gout.
• Rifampin: May increase the risk of hepatotoxicity. Monitor liver function tests.
• Isoniazid: Combination increases risk of hepatotoxicity. Close monitoring required.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Category C (Animal studies have shown adverse effects, but there are no adequate and well-controlled studies in humans, or studies in humans and animals are not available. ) In the United States, pyrazinamide is generally avoided during pregnancy for drug-susceptible TB due to a lack of adequate safety data. If the TB strain is drug-resistant and susceptible to pyrazinamide, its use may be considered if the potential benefit outweighs the potential risk to the fetus.
• Fetal risks: While there’s no definitive evidence of teratogenicity, potential risks cannot be ruled out.
• Breastfeeding: Pyrazinamide is present in breast milk. In the United States, due to limited safety data, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Drug Profile Summary

• Mechanism of Action: Converted to pyrazinoic acid, which disrupts mycobacterial cell wall synthesis, energy production, and membrane transport.
• Side Effects: Nausea, vomiting, anorexia, hyperuricemia, hepatotoxicity, gout.
• Contraindications: Severe hepatic impairment, acute gout, hypersensitivity.
• Drug Interactions: Rifampin, isoniazid, allopurinol, probenecid.
• Pregnancy & Breastfeeding: Use with caution; weigh risk-benefit ratio.
• Dosage: Adults: 15-30 mg/kg/day (up to 2g/day) or 50-70 mg/kg twice weekly (up to 3g twice weekly); Children: 15-40 mg/kg/day; adjustments for renal/hepatic dysfunction.
• Monitoring Parameters: Liver function tests (ALT, AST, bilirubin), uric acid, signs of gout/hepatitis, renal function.

Popular Combinations

Pyrazinamide is almost always used as part of a multi-drug regimen for tuberculosis, commonly with isoniazid, rifampin, and ethambutol (or streptomycin). This combination is essential for optimal efficacy and preventing the development of drug resistance.

Precautions

• General Precautions: Obtain baseline liver function tests and uric acid levels. Monitor for signs of hepatotoxicity and gout throughout therapy.
• Specific Populations: Pregnant Women: Avoid if possible unless drug-resistant TB necessitates use; Breastfeeding Mothers: Exercise caution; weigh risk-benefit ratio; Children & Elderly: Monitor liver function and adverse effects closely.
• Lifestyle Considerations: Alcohol should be avoided during pyrazinamide treatment due to the increased risk of hepatotoxicity.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Pyrazinamide?

A: Adults: 15-30 mg/kg (up to 2 g/day) daily or 50-70 mg/kg twice weekly (up to 3 g/dose); Children: 15-40 mg/kg/day. Adjust for renal or hepatic impairment.

Q2: What is the most serious side effect of Pyrazinamide?

A: Hepatotoxicity, which can be potentially fatal.

Q3: Can Pyrazinamide be used in pregnant women?

A: It’s generally avoided unless the TB is drug-resistant and the benefit outweighs the potential risk to the fetus.

Q4: How does renal impairment affect Pyrazinamide dosing?

A: Dose reduction and/or less frequent administration is required in patients with renal impairment.

Q5: Does Pyrazinamide interact with other medications?

A: Yes, it interacts with medications like rifampin, isoniazid, allopurinol, and probenecid.

Q6: What should be monitored in patients taking Pyrazinamide?

A: Liver function tests (ALT, AST, bilirubin) and uric acid levels. Monitor for signs of hepatotoxicity and gout.

Q7: Why is Pyrazinamide used in combination with other anti-TB drugs?

A: To maximize efficacy, shorten treatment duration, and prevent drug resistance.

Q8: Can Pyrazinamide be used in patients with gout?

A: It is contraindicated in patients with acute gout. In patients with a history of gout or hyperuricemia, careful monitoring of uric acid is necessary, and prophylaxis with a uricosuric agent may be considered.

Q9: What is the duration of Pyrazinamide treatment?

A: It’s usually given for the first two months of a standard six-month multi-drug regimen for TB.