Pharmacological properties of the drug Pyrazinamide
Pyrazinamide is used to treat tuberculosis (tuberculostatic). It inhibits the development of Mycobacterium tuberculosis at the stage of intracellular division. Pyrazinamide is especially effective during the first months of treatment. It is always prescribed in combination with other tuberculostatics (isoniazid, ethambutol, rifampicin) in order to prevent the development of pyrazinamide-resistant strains of Mycobacterium tuberculosis . Pyrazinamide is completely absorbed from the gastrointestinal tract. The maximum concentration in the blood is achieved 2 hours after oral administration. Pyrazinamide is widely distributed in body tissues and fluids. It is metabolized in the liver, its main metabolite is also active against Mycobacterium tuberculosis . Pyrazinamide and its metabolites are excreted mainly by the kidneys. Pyrazinamide is completely absorbed from the gastrointestinal tract. In the cerebrospinal fluid, almost the same concentration is achieved as in the blood serum. The main metabolite is pharmacologically active pyrazinoic acid. 70% of the drug is excreted in the urine.
Note!
The description of the drug Rifampicin / Isoniazid / Pyrazinamide / Ethambutol on this page is a simplified author’s version of the apteka911 website, created on the basis of the instructions for use. Before purchasing or using the drug, you should consult your doctor and read the manufacturer's original instructions (attached to each package of the drug).
Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide to prescribe the drug, as well as determine the dose and methods of its use.
Use of the drug Pyrazinamide
The usual dose of pyrazinamide for adults is 15–30 mg/kg/day; the maximum daily dose should not exceed 2 g. There may be cases of using an increased dose, that is, 50–70 mg/kg/day 2–3 times a week. When taken twice a week, the maximum daily dose should not exceed 4 g; when taken three times a day, this dose should not exceed 3 g. The usual dose of Pyrazinamide for children is 15–30 mg/kg/day; the maximum daily dose should not exceed 2 g. It is possible to use an increased dose - 50–70 mg/kg/day 2–3 times a week. When prescribed 2 times a week, the maximum daily dose should not exceed 4 g; when prescribed 3 times a week, the maximum dose should not exceed 3 g. In elderly patients, pyrazinamide is usually treated in doses close to the lower limit of the usual dose for adults. The usual dose of pyrazinamide for patients with moderate renal impairment is 12–20 mg/kg/day. Treatment with doses of 40 mg/kg/day 3 times a week and 60 mg/kg/day 2 times a week is also possible. Pyrazinamide should be avoided in patients with creatinine clearance ≤50 ml/min. For patients on hemodialysis or peritoneal dialysis, the usual adult dose is prescribed. Doses of 40 mg/kg/day 3 times a week and 60 mg/kg/day 2 times a week can also be used, but it is advisable to use them 24 hours before the start of dialysis. If patients with liver dysfunction take regular doses, pyrazinamide accumulates in the body. Therefore, such patients need to be treated with lower doses. The tablets are taken with water as a single dose after breakfast. Ideal body weight is always used to calculate the daily dose.
Pyrazinamide[edit | edit code]
Chemical properties[edit | edit code]
Pyrazinamide
(pyrazinoic acid amide) is a synthetic analogue of nicotinamide.
The structural formula of pyrazinamide is as follows: Structural formula of pyrazinamide
Antimicrobial activity[edit | edit code]
In vitro, pyrazinamide exhibits bactericidal activity only at low pH, due to which it acts on Mycobacterium tuberculosis located in the acidic environment of phagosomes (Jacobs, 2000). The MIC of pyrazinamide for intracellularly located Mycobacterium tuberculosis is 12.5 μg/ml. With monotherapy with pyrazinamide, resistance to it quickly develops. The target of the drug appears to be fatty acid synthase 1, which is involved in the synthesis of mycolic acids (Zimhony et al., 2000).
Pyrazinamide
Pharmacokinetics[edit | edit code]
Pyrazinamide is well absorbed from the gastrointestinal tract. 2 hours after oral administration at a dose of 500 mg, the serum concentration of the drug is 9-12 mcg/ml, and after 8 hours - 7 mcg/ml. In the absence of kidney disease, T/2 is 9-10 hours. Pyrazinamide penetrates well into tissues and biological fluids, including the lungs, liver and CSF. The drug is metabolized by hydrolysis to pyrazinoic acid, which is then hydroxylated. The resulting 5-hydroxypyrazinoic acid is excreted by the kidneys, mainly through glomerular filtration.
Application[edit | edit code]
Pyrazinamide is an important component of short-term (6-month) combination anti-tuberculosis therapy (British Thoracic Association, 1983; Bass et al., 1994).
For adults and children it is prescribed orally at a dose of 15-30 mg/kg/day (but not more than 2 g/day) in one dose. The drug is effective and safe when administered 2-3 times a week (the single dose is increased).
Side effects[edit | edit code]
The most dangerous effect is the hepatotoxic effect. When taken at a dose of 40-50 mg/kg/day, clinically significant liver damage occurs in 15% of patients; in 2-3% of cases, jaundice is observed, and occasionally - liver necrosis with a fatal outcome. The first sign of liver damage is an increase in aminotransferase activity. Modern treatment regimens, which involve taking the drug at a dose of 15-30 mg/kg/day, are much safer (Girling, 1978). However, liver function is assessed in all patients before starting therapy. During treatment, the examination is periodically repeated and when the first signs of hepatotoxicity appear, pyrazinamide is discontinued. For any liver dysfunction, pyrazinamide is prescribed only in the most extreme cases.
Almost all patients experience hyperuricemia due to decreased urate excretion; attacks of gout are possible. Other side effects include arthralgia, decreased appetite, nausea, vomiting, painful urination, malaise and fever. Since pyrazinamide has not been proven to be non-teratogenic, this drug is not prescribed to pregnant women in the United States (Bass et al., 1994). However, some international organizations allow the use of pyrazinamide during pregnancy.
Side effects of the drug Pyrazinamide
The doctor should inform the patient about possible side effects and first aid if they occur. The most serious side effects are liver dysfunction (jaundice, liver enlargement, asymptomatic increase in liver transaminases, isolated cases of acute liver atrophy and death), which depends on the dose. Nausea, anorexia and arthralgia (with or without increased serum uric acid concentrations) are common side effects of pyrazinamide therapy. Less commonly noted are vomiting, myalgia and arthralgia with hyperthermia, hypersensitivity reactions (skin rash, urticaria, itching, photosensitivity), sideroblastic anemia and thrombocytopenia. Sometimes side effects of pyrazinamide therapy include acne, pellagra, pain when urinating (dysuria) and inflammation of the kidneys (interstitial nephritis).
Side effects
From the organ of vision: optic neuritis (unilateral or bilateral), which is manifested by impaired perception of red and green colors, narrowing of visual fields, decreased visual acuity up to complete blindness), development of central or peripheral scotoma, retinal hemorrhage, optic nerve atrophy .
From the immune system: anaphylactic reactions/anaphylaxis, including anaphylactic shock, angioedema, bronchospasm, interstitial pneumonitis, lymphadenopathy, vasculitis, rheumatoid syndrome.
From the skin and subcutaneous tissue: skin rash (including morbilliform, maculopapular dermatitis, purpura or exfoliative dermatitis), flushing, urticaria, itching, dermatitis, toxic epidermal necrolysis/toxic-allergic dermatitis, Stevens-Johnson syndrome, erythema multiforme, possible exacerbation of symptoms systemic lupus erythematosus or the appearance of lupus-like syndrome, hot flashes, pemphigoid (bubble) reaction, acne, photosensitivity.
From the nervous system: dizziness, headache, depression, confusion, disorientation, impaired coordination of movements, hallucinations, convulsions, increased seizures in patients with epilepsy, ataxia, myasthenia, peripheral neuropathy, peripheral neuritis, paresthesia, paresis, hyperreflexia, toxic encephalopathy , memory impairment, sleep disturbance, mood changes, increased excitability, irritability, euphoria, insomnia, cerebral hemorrhages, psychotic reactions (including toxic psychoses), ranging from minor personality changes to significant mental disorders, which, as a rule, disappeared when the drug was discontinued ; hearing loss and tinnitus in patients with renal failure.
From the blood and lymphatic system: neutropenia, leukopenia, thrombocytopenia, eosinophilia, anemia, including hemolytic and aplastic anemia, sideroblastic anemia, erythrocyte vacuolization, agranulocytosis, thrombocytopenic purpura, hypercoagulability, intravascular coagulation syndrome, tendency to form blood clots, splenomegaly, porphyria, increased serum iron concentrations, lymphadenopathy.
From the respiratory organs and mediastinal organs: infiltrates in the lungs with or without eosinophilia, pneumonitis, difficulty breathing, shortness of breath, dry cough.
Cardiac disorders: pericarditis, myocarditis, arterial hypertension, decreased blood pressure, palpitations, tachycardia, pain behind the sternum and in the heart area, discomfort in the heart area, increased myocardial ischemia in the elderly, feeling of heat, facial flushing.
From the digestive tract: lack of appetite, decreased appetite, metallic taste in the mouth, dyspepsia, heartburn, dry mouth, nausea, vomiting, diarrhea, constipation, pain/discomfort in the abdomen/epigastric area, stomach, exacerbation of peptic ulcer, acute pancreatitis , erosive gastritis, pseudomembranous colitis. Hepatobiliary system: liver dysfunction/liver damage, increased levels of liver transaminases, bilirubin, thymol test; hepatitis, discomfort in the right hypochondrium, jaundice, fulminant liver failure, which can lead to the development of necrosis (especially over the age of 35 years), bilirubinuria, hepatomegaly; in isolated cases, the occurrence of acute liver atrophy depends on the dose.
From the kidneys and urinary tract: interstitial nephritis, difficulty urinating, acute renal failure, increased levels of urea and creatinine, nephronecosis, dysuria, pain when urinating, in rare cases - myoglobinuric renal failure due to rhabdomyolysis.
Metabolic disorders: uric acid diathesis, exacerbation of gout; hyperuricemia, pyridoxine deficiency, which affects the conversion of tryptophan into nicotinic acid, pellagra, acidosis, porphyria.
Endocrine disorders: gynecomastia in men, menorrhagia in women, Cushing's syndrome, menstrual irregularities, adrenal insufficiency in patients with adrenal dysfunction, hyperglycemia.
From the musculoskeletal system: arthralgia, joint swelling, joint stiffness, myalgia, rhabdomyolysis, gout attacks.
General disorders: increased body temperature, drug fever, malaise, chills, flu-like symptoms, weakness, swelling, malaise, tendency to bleed and hemorrhage, pellagra, herpes, lacrimation, orange-red color of urine, feces, saliva, sputum, sweat , mucus, withdrawal syndrome that may occur when you stop taking the drug, including headache, insomnia, irritability, nervousness.
Special instructions for the use of the drug Pyrazinamide
If the patient feels well, then it is very important to take the drug regularly and complete the full course of treatment. During treatment with Pyrazinamide, basic liver function tests and uric acid levels should be monitored. Liver function tests should be performed every 2 to 4 weeks and/or if any clinical signs or symptoms of liver failure occur. Pyrazinamide delays renal excretion of urate, which may manifest as hyperuricemia, usually without signs of gout. If symptoms of liver dysfunction or hyperuricemia (acute gout) are present, treatment should be discontinued. In patients with kidney failure, pyrazinamide may accumulate in the body. Pyrazinamide should be administered with caution to patients with diabetes mellitus, as the treatment of diabetes mellitus may become more difficult during therapy with pyrazinamide. In patients with porphyria, pyrazinamide can cause acute attacks of porphyria. Pyrazinamide should be administered with caution to patients with known hypersensitivity to ethionamide, isoniazid, niacin, or other chemically similar medicinal products, as such patients may also be hypersensitive to pyrazinamide. During pregnancy and breastfeeding. Although there is no evidence of harmful effects of pyrazinamide on the fetus, the risk cannot be excluded. During pregnancy, pyrazinamide can be taken only if the potential benefit to the mother outweighs the possible risk to the fetus. Pyrazinamide is excreted into breast milk in small quantities, so breastfeeding is not recommended during treatment with the drug.
Drug interactions Pyrazinamide
Patients should avoid drinking alcoholic beverages during treatment with pyrazinamide, as this medicine may increase the harmful effects of alcohol. Concomitant use of pyrazinamide and isoniazid may reduce the serum concentration of isoniazid, especially in patients with poor metabolism of isoniazid. Concomitant use of pyrazinamide and ethionamide increases the risk of liver damage, especially in patients with diabetes. During treatment with this drug combination, you should have regular laboratory tests to measure your liver function. If any signs of liver dysfunction occur, treatment with this combination of drugs should be discontinued. Pyrazinamide reduces the metabolism of cyclosporine and thereby reduces the level of cyclosporine in the blood serum. In patients treated with cyclosporine, serum cyclosporine levels should be monitored from the initiation of pyrazinamide therapy to its discontinuation. Concomitant use of pyrazinamide and phenytoin may increase serum concentrations of phenytoin and, accordingly, signs of phenytoin toxicity may occur. Pyrazinamide may reduce the effectiveness of drugs used to treat gout and drugs that help remove uric acid from the body (allopurinol, colchicine, probenecid, sulfinpyrazone). This may increase serum uric acid levels in patients with gout taking pyrazinamide. To control hyperuricemia, it may be necessary to change the dosage of these drugs if anti-gout drugs and a drug that promotes uric acid elimination are used concomitantly with pyrazinamide. Concomitant use of pyrazinamide and allopurinol may reduce the metabolism of pyrazinamide metabolites. The metabolism of pyrazinamide itself does not change significantly. Zidovudine may significantly reduce serum pyrazinamide levels and increase the risk of anemia. Pyrazinamide interferes with the Acetest and Ketostix tests, as it turns the color of the sample red-brown. Pyrazinamide may interfere with the determination of serum iron concentrations using the Ferrochem II device.
