Пиразинамид

Описание

Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.

Химические свойства

Crystalline Solid

Использование

Pyrazinamide is used therapeutically as an antitubercular agent. Pyrazinamide is used to form polymeric copper complexes, create pyrazine carboxamide scaffolds useful as FXs inhibitors, and as a component of mycobacteria identification kits. It is used to study liver toxicity prevention and mechanisms of resistance .

Показания

Pyrazinamide is a synthetic analogue of nicotinamide. Its exact mechanism of action is not known, although its target appears to be the mycobacterial fatty acid synthetase involved in mycolic acid biosynthesis. Pyrazinamide requires an acidic environment, such as that found in the phagolysosomes, to express its tuberculocidal activity. Thus, pyrazinamide is highly effective on intracellular mycobacteria. The mycobacterial enzyme pyrazinamidase converts pyrazinamide to pyrazinoic acid, the active form of the drug.A mutation in the gene (pncA) that encodes pyrazinamidase is responsible for drug resistance; resistance can be delayed through the use of drug combination therapy.

Антимикробная активность

It is principally active against actively metabolizing intracellular bacilli and those in acidic, anoxic inflammatory lesions. Activity against M. tuberculosis is highly pH dependent: at pH 5.6 the MIC is 8–16 mg/L, but it is almost inactive at neutral pH. Other mycobacterial species, including M. bovis, are resistant. Activity requires conversion to pyrazinoic acid by the mycobacterial enzyme pyrazinamidase, encoded for by the pncA gene, which is present in M. tuberculosis but not M. bovis. A few resistant strains lack mutations in pncA, indicating alternative mechanisms for resistance, including defects in transportation of the agent into the bacterial cell.

Приобретенная устойчивость

Drug resistance is uncommon and cross-resistance to other antituberculosis agents does not occur. Susceptibility testing is technically demanding as it requires very careful control of the pH of the medium, but molecular methods for detection of resistance-conferring mutations are available.

Общее описание

Pyrazinecarboxamide (PZA) occurs as a white crystalline powder that is sparingly soluble in water and slightly soluble in polar organic solvents. Its antitubercular properties were discovered as a result of an investigation of heterocyclic analogs of nicotinic acid, with which it is isosteric. Pyrazinamide has recently been elevated to first-line status in short-term tuberculosis treatment regimens because of its tuberculocidal activity and comparatively low short-term toxicity. Since pyrazinamide is not active against metabolically inactive tubercle bacilli, it is not considered suitable for long-term therapy. Potential hepatotoxicity also obviates long-term use of the drug. Pyrazinamide is maximally effective in the low pH environment that exists in macrophages (monocytes). Evidence suggests bioactivation of pyrazinamide to pyrazinoic acid by an amidase present in mycobacteria.

Реакции воздуха и воды

Water soluble.

Профиль реактивности

Pyrazinamide is a carbamate ester. Incompatible with strong acids and bases, and especially incompatible with strong reducing agents such as hydrides. May react with active metals or nitrides to produce flammable gaseous hydrogen. Incompatible with strongly oxidizing acids, peroxides, and hydroperoxides.

Фармацевтические приложения

Like isoniazid, pyrazinamide is a synthetic nicotinamide analog, although its mode of action is quite distinct.

Фармаколо?гия

Pyrazinamide is well absorbed from the GI tract and is widely distributed throughout the body. It penetrates tissues, macrophages, and tuberculous cavities and has excellent activity on the intracellular organisms; its plasma half-life is 9 to 10 hours in patients with normal renal function. The drug and its metabolites are excreted primarily by renal glomerular filtration.

Фармакокине?тика

Oral absorption: >90%
C_max 20–22 mg/kg oral: 10–50 mg/L after 2 h
Plasma half-life: c. 9 h
Plasma protein binding: c. 50%
It readily crosses the blood–brain barrier, achieving CSF concentrations similar to plasma levels. It is metabolized to pyrazinoic acid in the liver and oxidized to inactive metabolites, which are excreted in the urine, although about 70% of an oral dose is excreted unchanged.

Клиническое использование

Pyrazinamide is an essential component of the multidrug short-term therapy of tuberculosis. In combination with isoniazid and rifampin, it is active against the intracellular organisms that may cause relapse.

Побочные эффекты

Hepatotoxicity is the major concern in 15% of pyrazinamide recipients. It also can inhibit excretion of urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy.

Методы очистки

The amide crystallises from water, EtOH or 1:1 hexane/EtOH in four modifications viz -form, -form, -form and 
form. [R. & S.rum Acta Cryst 28B 1677 1972, Beilstein 25 III/IV 772.]