Pyrazinamide

Pyrazinamide (generic) is used primarily as an adjunct to other drugs in treating tuberculosis. This drug s mechanism of action against M. tuberculosis is unknown. Problems associated with pyrazinamide include hepatotoxicity and lower-extremity joint pain. 

Therapeutic Function Antibacterial (tuberculostatic) Chemical Name Pyrazinecarboxamide Common Name — 

Trade Name Manufacturer Country Year Introduced 

166 Parts of pyrazine-2,3-dicarboxamide (1 mol) is slurried in 1,000 parts of 1 N aqueous sodium hydroxide. The reaction mixture is heated at 95°C to 98°C until a clear solution results. Thereupon the mixture is cooled with ice to about 5°C and acidified to approximately a pH of 1. The cold reaction mixture is allowed to stand until precipitation of the pyrazine-2-car-boxamide-3 arboxylic acid is substantially complete whereupon it is recovered by filtration and dried at 50°C to 60°C. 

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Rifampicin, the only commercially available ansamacroHde, is manufactured by MerreU Dow under the tradename Rifadin, and by CIBA under the trade name Rimactane. Rifampicin is also suppHed in combination with isoniazid or pyrazinamide [98-96-4]. The rifampicin—isoniazid combination is known as Rifamate (MerreU Dow), Rifinah (MerreU Dow), and Rimactazid (CIBA) the rifampicin—pyrazinamide as Rifater (MerreU Dow). Several other rifamycin derivatives including rifabutin and rifapentine are undergoing clinical studies. 

Numerous other methods are available for the preparation of amino derivatives, and these include direct synthesis (see Section 2.14.3.2) and more traditional transformations such as the Hofmann reaction. Aminopyrazine has been prepared from pyrazinamide (60G1807) and 2-aminoquinoxaline from the corresponding carboxamide (71JOC1158). The... 

Before the discovery of streptomycin, pyrazinamide (126) was one of the front runners in the treatment of tuberculosis. A broad spectrum of biological activity has been associated with pyrazine derivatives, ranging from the herbicidal activity of (127) to antibiotic activity... 

Parts of pyrazine-2arboxylic acid is heated in a reaction vessel provided with an intake for Inert gas. The reaction mixture is heated in a bath held at 220°C and nitrogen is introduced. The solid material melts and effervesces and sublimed pyrazinamide vapors are carried out of the reaction vessel in the nitrogen stream. They are introduced into a suitably cooled condenser, condensing in the form of a white sublimate. After the reaction is proceeding vigorously the bath temperature is raised to 255 C and then gradually and slowly allowed to drop to 190°C over a period of time sufficient to permit the reaction to go substantially to completion. The sublimed pyrazinamide, if desired, is further purified by recrystallization from water or alcohol. 

Tear-Efrin - Phenylephrine HCI Tebacin acid - Aminosalicylic acid Tebertin - Inosine Teberus Ethionamide Tebesium - Isoniazid Tebilon - Isoniazid Tebloc - Loperamide HCI Tebrezid - Pyrazinamide Techlon - Pentoxifylline Teclinazets - Tetracycline T-E Cypionate - Estradiol cypionate Tedarol - Triamcinolone Tedarol - Triamcinolone acetonide Tedarol - Triamcinolone diacetate Teejel - Choline salicylate Tefsiel - Tegafur... 

The initial phase must contain three or more of the following drugp isoniazid, rifampin, and pyrazin-amide, along with either ethambutol or streptomycin. The CDC recommends treatment to begin as soon as possible after the diagnosis of tuberculosis. The treatment recommendation regimen is for the administration of rifampin, isoniazid, and pyrazinamide for a minimum of 2 months (8 weeks), followed by rifampin and isoniazid for 4 months (16 weeks) in areas with a low incidence of tuberculosis. In areas of high incidence of tuberculosis, the CDC recommends the addition of streptomycin or ethambutol for the first 2 months. 

Hepatotoxicily is the principal adverse reaction seen witii pyrazinamide use Symptoms of hepatotoxicily may range from none (except for slightly abnormal hepatic function tests) to a more severe reaction such as jaundice Nausea, vomiting, diarrhea, myalgia, and rashes also may be seen. 

Older adults are particularly susceptible to a potentially fatal hepatitis when taking isoniazd, especially if they consume alcohol on a regular basis. Two other antitubercular drugs rifampin and pyrazinamide, can cause liver dysfunction in the older adult. Careful observation and monitoring for signs of liver impairment are necessary (eg, increased serum aspartate transaminase, increased serum alanine transferase, increased serum bilirubin, and jaundice). 

PYRAZINAMIDE Patients should have baseline liver functions tests to use as a comparison when monitoring liver function during pyrazinamide therapy. The nurse should monitor the patient closely for symptoms of a decline in hepatic functioning (ie, yellowing of the skin, malaise, liver tenderness, anorexia, or nausea). The primary health care provider may order periodic liver function tests. Hepatotoxicity appears to be dose related and may appear at any time during therapy. 

Pyrazinamide Notify the primary health care provider if any of the following occurs nausea, vomiting, loss of appetite fever, malaise, visual changes, yellow discoloration of the skin, or severe pain in the knees, feet, or wrists. (Note Pain in these areas may be a sign of active gout.)... 

Ms. Burns has received a diagnosis of tuberculosis. She is concerned because her primary health care provider has informed her that the treatment regimen consists of three drugs, isoniazid, rifampin, and pyrazinamide, taken for the next 2 months, followed by a 4-month treatment regimen with two of the drugs. 

Pyrazinamid (Hefa Rifater (Marion Merrell )- J Pyramide (Sankyo)... 

Pyrazinamid "Lederle" GB Rifater (Hoechst)-comb. Merrell)-comb. 

CjjHjjOj 35363-65-6) see Dimethisterone methyl pyrazine-2-carboxylate (QH N202 6164-79-0) see Pyrazinamide 5-methyl-2-pyrazinecarboxylic acid (QHfiN202 5521-55-1) see Adpimox Glipizide 5-methylpyrazine-2-carboxylic acid see under 5-methyl-2-pyrazinecarboxylic acid... 

QHgN2 95-54-5) see Benperidol Droperidol Mibefradil hydrochloride Pyrazinamide Tiabendazole Tibezonium iodide... 

Fig. 5.17 Antitubercular compounds (see text also for details of antibiotics) A, PAS B, isoniazid C, ethionamide D, pyrazinamide E, prothionamide F, thiaeetazone G, ethambutol.

Mycobacterium tuberculosis Rifampicin + isoniazid + ethambutol + pyrazinamide ... 

Pyrazinamide is a structural analogue of isoniazid and is converted to the active acid derivative intracellularly by a nicotinamidase. Pyrazinamide resistance has been linked to reduced levels of nicotinamidase but the genetic determinants of resistance have not been fully elucidated. 

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