Pyrazinamide

Pyrazinamide is an Antitubercular agent belonging to mycobacterial infection.

Pyrazinamide is used in the treatment of Tuberculosis.

Pyrazinamide is readily absorbed from the GI tract and widely distributed in body fluids and tissues, diffuse in the CSF and enters breast milk. Plasma protein binding: 50%. It undergoes hepatic metabolism via hydrolysis to pyrazines acid (major active metabolite) and is subsequently hydroxylated to 5-hydroxypyrazinoic acid (major excretory product) and get excreted via urine by glomerular filtration (approx 70% mainly as metabolites, approx 4% as unchanged drug). Half-life: Approx 9-10 hr.

The Tmax of pyrazinamide was achieved Within 2 hours .Cmax was about 20-50 mg/L

Pyrazinamide shows common side effects like Headache, dizziness, Diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Pyrazinamide is available in capsules and Solution Reconstituted, Intravenous

Pyrazinamide is available in India, Germany, Canada, Italy, USA

Pyrazinamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of the infection and the susceptibility of the infecting organism. Its activity appears to partly depend on the conversion of the drug to pyrazinoic acid (POA), which lowers the pH of the environment below that which is necessary for growth of Mycobacterium tuberculosis. Susceptible strains of M. tuberculosis produce pyrazinamidase, an enzyme that deaminates pyrazinamide to POA, and the in vitro susceptibility of a given strain of the organism appears to correspond to its pyrazinamidase activity.

Pyrazinamide is available in the form of tablets.

• Tablet : Do not administer with food (bioavailability is decreased).

Pyrazinamide is used in the treatment of Tuberculosis.

Pyrazinamide diffuses into active M. tuberculosis that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids.

Pyrazinamide is approved for use in the following clinical indications

Tuberculosis

Adult: As part of a multidrug regimen: For standard unsupervised 2-mth treatment: <50 kg: 1.5 g daily; ≥50 kg: 2 g daily. For intermittent supervised 2-mth treatment: <50 kg: 2 g 3 times weekly; ≥50 kg: 2.5 g 3 times weekly.

Child: As part of a multidrug regimen: For standard unsupervised 2-mth treatment: 35 mg/kg daily. For intermittent supervised 2-mth treatment: 50 mg/kg 3 times weekly.

Pyrazinamide is available in the form of tablets.

• Dosage Adjustment in Kidney Patient

● CrCl ≥30 mL/minute: No dosage adjustment necessary.

● CrCl <30 mL/minute: Dosage adjustment recommendations utilize the indication-specific usual recommended daily dose but extend the dosing interval to 3 times weekly.

● Tuberculosis, treatment (drug-susceptible): Oral:

● 40 to 55 kg: 1 g 3 times weekly.

● 56 to 75 kg: 1.5 g 3 times weekly.

● 76 to 90 kg: 2 g 3 times weekly.

● Tuberculosis, treatment (drug-resistant) (alternative agent): Oral: 25 to 40 mg/kg 3 times weekly.

● Hemodialysis, intermittent (thrice weekly): Dialyzable (~45 to 55%) : Oral: Dose as CrCl <30 mL/minute; administer 3 times weekly after hemodialysis on dialysis days. Consider therapeutic drug monitoring when available . Close monitoring of response and adverse effects (eg, hepatotoxicity) due to drug accumulation is important (expert opinion).

● Peritoneal dialysis: Dialyzable (15% of total clearance): Oral: Due to limited pharmacokinetic data in this population, dose as for CrCl <30 mL/minute; consider therapeutic drug monitoring when available; expert opinion). Close monitoring of response and adverse effects (eg, hepatotoxicity) due to drug accumulation is important (expert opinion).

● CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse effects (eg, hepatotoxicity) due to drug accumulation is important.

• Dosage Adjustment in Hepatic impairment Patient

There are no dosage adjustments provided in the manufacturer’s labeling; however, use with caution, may accumulate and additional liver damage may occur in patients with preexisting liver disease. Contraindicated in patients with acute liver disease or previous Pyrazinamide -associated hepatic injury.

For ALT or AST >3 times the ULN: discontinue or temporarily withhold treatment. Treatment with Pyrazinamide for latent tuberculosis infection should be deferred in patients with acute hepatic diseases.

● Dosage Adjustment for Pediatric Patients

● Active TB infection, treatment: Note: Always use as part of a multidrug regimen. Any regimens using less than once daily dosing should administer dosing as directly observed therapy (DOT). Treatment regimens for pulmonary Tuberculosis consist of an initial 2-month intensive phase of a 4-drug regimen, followed by a continuation phase of an additional 4 to 7 months of Pyrazinamide and rifampin. Pyrazinamide frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines for detailed information :

Once daily or 5-times-weekly (DOT):

● Infants, Children, and Adolescents weighing <40 kg: Oral: 35 mg/kg/dose once daily or 5 times weekly DOT; suggested range: 30 to 40 mg/kg/dose

● Children and Adolescents weighing ≥40 kg: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established): Oral: Weight-band dosing for whole tablets:

40 to 55 kg: 1,000 mg (18.2 to 25 mg/kg/dose) once daily or 5-times-weekly (DOT)

56 to 75 kg: 1,500 mg (20 to 28.6 mg/kg/dose) once daily or 5-times-weekly (DOT)

76 to 90 kg: 2,000 mg (22.2 to 26.3 mg/kg/dose) once daily or 5-times-weekly (DOT)

● Three-times-weekly DOT: Note: Although suggested dosing based on experience with twice-weekly regimen; experts suggest three-times-weekly regimens are more effective than twice-weekly DOT regimens; pyrazinamide-containing three-times-weekly DOT may be used as part of an intensive phase; consult guidelines for specific information.

● Infants, Children, and Adolescents weighing <40 kg: Oral: 50 mg/kg/dose three times weekly

● Children and Adolescents weighing ≥40 kg: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established) Oral: Weight-band dosing for whole tablets:

40 to 55 kg: 1,500 mg (27.3 to 37.5 mg/kg/dose) three-times-weekly

56 to 75 kg: 2,500 mg (33.3 to 44.6 mg/kg/dose) three-times-weekly

76 to 90 kg: 3,000 mg (33.3 to 39.5 mg/kg/dose) three-times-weekly

● Twice-weekly DOT: Note: Regimen not generally recommended; do not use in HIV patients or those with smear-positive and/or cavitary disease. This therapy should only be used following completion of a 2-week intensive phase once-daily (or 5-times-weekly) regimen. Missed doses result in the equivalent of once-weekly dosing which has been shown to be inferior and is associated with treatment failure, relapse, and development of drug resistance.

● Infants, Children, and Adolescents weighing <40 kg: Oral: 50 mg/kg/dose twice weekly

Children and Adolescents weighing >40 kg: Oral:

40 to 55 kg: 2,000 mg (36.4 to 50 mg/kg/dose) twice weekly

56 to 75 kg: 3,000 mg (40 to 53.6 mg/kg/dose) twice weekly

76 to 90 kg: 4,000 mg (44.4 to 52.6 mg/kg/dose) twice weekly

Do not take with food; avoid tyramine- and/or histamine-containing foods. Increase dietary intake of folate, niacin, magnesium

Hypersensitivity to Pyrazinamide or any component of the formulation, including drug-induced hepatitis; acute liver disease; previous history of hepatic injury during Pyrazinamide therapy; previous severe adverse reaction (drug fever, chills, arthritis) to Pyrazinamide

Concerns related to adverse effects:

• Hepatotoxicity: Dose-related hepatotoxicity ranging from transient ALT/AST elevations to jaundice, hepatitis and/or liver atrophy (rare) has occurred.

Disease-related concerns:

• Alcoholism: Due to concerns for preexisting hepatic dysfunction, use with caution in patients with a history of alcoholism (even if ethanol consumption is discontinued during therapy).

• Diabetes: Use with caution in patients with diabetes mellitus.

• Gout: May inhibit uric acid excretion; acute gouty attacks have been reported. Use with caution in patients with chronic gout; contraindicated with acute gout.

• Porphyria: Use with caution in patients with porphyria.

• Renal impairment: Use with caution in patients with renal failure.

Concurrent drug therapy issues:

• Hepatotoxic agents: Use with caution in patients receiving concurrent medications associated with hepatotoxicity (particularly with rifampin). The 2-month rifampin-pyrazinamide regimen for the treatment of latent tuberculosis infection (LTBI) has been associated with severe and fatal liver injuries; incidence increased with pyrazinamide doses >30 mg/kg/day. The Infectious Diseases Society of America and Centers for Disease Control and Prevention recommend that the 2-month rifampin-pyrazinamide regimen should not generally be used in patients with LTBI.

Pyrazinamide may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

• Pyrazinamide is present in breast milk.
• Breast milk concentrations are less than maternal plasma concentration.
• Breastfeeding is not a contraindication during therapy for drug-susceptible Tuberculosis in patients deemed noninfectious who are treated with first-line agents (ie, pyrazinamide). Exposure to pyrazinamide via breast milk should not be considered an effective treatment for the breastfeeding infant. Infants exposed to pyrazinamide via breast milk should be monitored for jaundice . Patients with multidrug-resistant Tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible

Pregnancy Category C

Pyrazinamide has been shown to be teratogenic in rodents. Congenital malformations, primarily spina bifida, were increased in the offspring of pregnant rats given Pyrazinamide during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons). Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons). Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given Pyrazinamide at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area comparisons).

• Administration with food significantly reduces bioavailability. Management: Avoid administration with food.

• Pyrazinamide may decrease folic acid absorption and alters pyridoxine metabolism.

Management: Increase dietary intake of folate, niacin, and magnesium.

• Tyramine-containing food: Pyrazinamide has weak monoamine oxidase inhibiting activity and may potentially inhibit tyramine metabolism. Several case reports of mild reactions (flushing, palpitations, headache, mild increase in blood pressure, diaphoresis) after ingestion of certain types of cheese or red wine, have been reported.

Management: Manufacturer’s labeling recommends avoiding tyramine-containing foods (eg, aged or matured cheese, air-dried or cured meats including sausages and salamis; fava or broad bean pods, tap/draft beers, Marmite concentrate, sauerkraut, soy sauce, and other soybean condiments). However, the clinical relevance of the tyramine reaction for the vast majority of patients receiving Pyrazinamide has been questioned due to Pyrazinamide ’s weak MAO inhibition and the relatively few published case reports of the interaction. Although not fully investigated, it has been proposed that the reaction has a genetic component and may only be significant in poor or intermediate acetylators since Pyrazinamide is primarily inactivated by acetylation.

• Histamine-containing food: Pyrazinamide may also inhibit diamine oxidase resulting in headache, sweating, palpitations, flushing, diarrhea, itching, wheezing, dyspnea or hypotension to histamine-containing foods (eg, skipjack, tuna, saury, other tropical fish).

Management: Manufacturer’s labeling recommends avoiding histamine-containing foods; corticosteroids and antihistamines may be administered if histamine intoxication occurs

• Common Adverse effects

Hyperuricaemia, leading to acute gout; anorexia, nausea, vomiting.

• Less Common Adverse effects:

Aggravation of peptic ulcer, arthralgia, malaise, fever, sideroblastic anaemia, thrombocytopenia, dysuria.

• Rare Adverse effects

Photosensitivity, pellagra, rash.

Antagonises the effect of uricosuric agents (e.g., probenecid, sulfinpyrazone). May reduce the contraceptive effect of oestrogens. May inactivate oral typhoid vaccine. May increase the serum concentration of ciclosporin. May enhance the hepatotoxic effect of rifampicin.

The common side effects of Pyrazinamide include the following

Constipation, Diarrhea, Heartburn, pain in the back, arm, or legs, Headache, joint pain.

Symptoms: Liver toxicity and hyperuricaemia.

Management: Empty the stomach by gastric lavage if necessary. Employ general supportive measures. May give benzodiazepine if there is evidence of CNS stimulation and probenecid for hyperuricaemia.

Pharmacodynamic

Pyrazinamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of the infection and the susceptibility of the infecting organism. Its activity appears to partly depend on the conversion of the drug to pyrazinoic acid (POA), which lowers the pH of the environment below that which is necessary for growth of Mycobacterium tuberculosis.

Pharmacokinetics

● Absorption: Readily absorbed from the GI tract. Time to peak plasma concentration: Approx 2 hr.

● Distribution: Widely distributed in body fluids and tissues, diffuses in the CSF and enters breast milk. Plasma protein binding: 50%.

● Metabolism: Undergoes hepatic metabolism via hydrolysis to pyrazinoic acid (major active metabolite) and subsequently hydroxylated to 5-hydroxypyrazinoic acid (major excretory product).

● Excretion: Via urine by glomerular filtration (approx 70% mainly as metabolites, approx 4% as unchanged drug). Half-life: Approx 9-10 hr.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Pyrazinamide -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Pyrazinamide
• https://europepmc.org/article/med/6988203