Pyrazinamide
Encyclopedia
Pyrazinamide is a drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

 used to treat tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

. The drug is largely bacteriostatic, but can be bacteriocidal on actively replicating tuberculosis bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

.

Abbreviations

The abbreviations PZA and Z are standard, and used commonly in the medical literature.

Dosing and presentation

  • 20–25 mg/kg daily, or
  • 50–70 mg/kg three times a week.


The British Thoracic Society
British Thoracic Society
The British Thoracic Society was formed in 1982 by the amalgamation of the British Thoracic Association and the Thoracic Society. It is a registered charity and a company limited by guarantee.-Function:...

 guidelines are for 1.5 g daily for patients weighing less than 50 kg, and 2 g daily for patients weighing 50 kg or more.

Pyrazinamide is a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...

 and is available in a wide variety of presentations. Pyrazinamide tablets are usually 500 mg and form the bulkiest part of the standard tuberculosis treatment regimen. Pyrazinamide tablets are so large that some patients find them impossible to swallow: pyrazinamide syrup is an option for these patients.

Pyrazinamide is also available as part of fixed dose combinations with other TB drugs such as isoniazid
Isoniazid
Isoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...

 and rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...

 (Rifater
Rifater
Rifater is a fixed dose combination tablet manufactured by Aventis used in the treatment of tuberculosis. Each tablet contains 120 mg rifampicin, 50 mg isoniazid and 300 mg pyrazinamide....

is an example).

Pharmacokinetics

Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis
Tuberculous meningitis
Tuberculous meningitis is also known as TB meningitis or tubercular meningitis.Tuberculous meningitis is Mycobacterium tuberculosis infection of the meninges—the system of membranes which envelops the central nervous system. It is the most common form of CNS tuberculosis.-Clinical features:Fever...

. It is metabolised by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 and the metabolic products are excreted by the kidneys.

Pyrazinamide is routinely used in pregnancy in the UK and the rest of the world; the WHO recommend its use in pregnancy; and there is extensive clinical experience to show that it is safe. In the U.S., pyrazinamide is not used in pregnancy, citing insufficient evidence of safety. Pyrazinamide is removed by haemodialysis and therefore doses should always be given at the end of a dialysis session.

Medical uses

Pyrazinamide is only used in combination with other drugs such as isoniazid
Isoniazid
Isoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...

 and rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...

 in the treatment
Tuberculosis treatment
Tuberculosis treatment refers to the medical treatment of the infectious disease tuberculosis .The standard "short" course treatment for TB is isoniazid, rifampicin , pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months...

 of Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...

. It is never used on its own. It has no other indicated medical uses
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...

. In particular, it is not used to treat other mycobacteria; Mycobacterium bovis
Mycobacterium bovis
Mycobacterium bovis is a slow-growing , aerobic bacterium and the causative agent of tuberculosis in cattle...

and Mycobacterium leprae
Mycobacterium leprae
Mycobacterium leprae, also known as Hansen’s coccus spirilly, mostly found in warm tropical countries, is a bacterium that causes leprosy . It is an intracellular, pleomorphic, acid-fast bacterium. M. leprae is an aerobic bacillus surrounded by the characteristic waxy coating unique to mycobacteria...

are innately resistant to pyrazinamide. Pyrazinamide is used in the first two months of treatment to reduce the duration of treatment required. Regimens not containing pyrazinamide must be taken for nine months or more.

Pyrazinamide in conjunction with rifampin is a preferred treatment for latent tuberculosis
Latent tuberculosis
Also called latent tuberculosis infection, latent TB or LTBI.Latent tuberculosis is where a patient is infected with Mycobacterium tuberculosis, but does not have active tuberculosis disease. Patients with latent tuberculosis are not infectious, and it is not possible to get TB from someone with...

.

Pyrazinamide is a potent antiuricosuric drug and consequently has an off-label use
Off-label use
Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...

 in the diagnosis of causes of hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...

 and hyperuricosuria
Hyperuricosuria
Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia...

. It acts on URAT1.

Mechanism of action

Pyrazinamide is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...

 that stops the growth of Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...

.

M. tuberculosis has the enzyme pyrazinamidase which is only active in acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...

ic conditions. Pyrazinamidase converts pyrazinamide to the active form, pyrazinoic acid
Pyrazinoic acid
Pyrazinoic acid is a pyrazinamide metabolite....

 which accumulates in the bacilli. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase
Fatty acid synthase
Fatty acid synthase is an enzyme that in humans is encoded by the FASN gene.Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis...

 (FAS) I, which is required by the bacterium to synthesise fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...

s although this has been discounted. It was also suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I. Pyrazinoic acid binds to the ribosomal protein S1 (RpsA) and inhibits trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.

Mutations in the pncA and rpsA genes are responsible for pyrazinamide resistance in M. tuberculosis.

Side effects

The most common (approximately 1%) side effect of pyrazinamide is joint pains (arthralgia), but this is not usually so severe that patients need to stop taking the pyrazinamide. The arthralgia can be distressing to patients, but is never harmful.

The most dangerous side effect of pyrazinamide is hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...

, which is dose related. The old dose for pyrazinamide was 40–70 mg/kg daily and the incidence of drug-induced hepatitis has fallen significantly since the recommended dose has been reduced. In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol
Ethambutol
Ethambutol is a bacteriostatic antimycobacterial drug prescribed to treat tuberculosis. It is usually given in combination with other tuberculosis drugs, such as isoniazid, rifampicin and pyrazinamide....

), pyrazinamide is the most common cause of drug-induced hepatitis. It is not possible to clinically distinguish pyrazinamide-induced hepatitis from hepatitis caused by isoniazid or rifampicin; test dosing is required (this is discussed in detail in tuberculosis treatment
Tuberculosis treatment
Tuberculosis treatment refers to the medical treatment of the infectious disease tuberculosis .The standard "short" course treatment for TB is isoniazid, rifampicin , pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months...

)

Other side effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 include nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

 and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...

, sideroblastic anemia
Sideroblastic anemia
Sideroblastic anemia or sideroachrestic anemia is a disease in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells . It may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can evolve into hematological malignancies...

, skin rash, urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...

, pruritus
Itch
Itch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...

, hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...

, dysuria
Dysuria
In medicine, specifically urology, dysuria refers to painful urination.Difficult urination is also sometimes described as dysuria.It is one of a constellation of irritative bladder symptoms, which includes urinary frequency and haematuria....

, interstitial nephritis
Interstitial nephritis
Interstitial nephritis is a form of nephritis affecting the interstitium of the kidneys surrounding the tubules...

, malaise
Malaise
Malaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...

; rarely porphyria
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...

, and fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

.

Chemical synthesis

Pyrazinamide can by synthesized from o-phenylenediamine
O-Phenylenediamine
o-Phenylenediamine is a organic compound with the formula C6H42. This aromatic diamine is an important precursor to many heterocyclic compounds...

 and glyoxal
Glyoxal
Glyoxal is an organic compound with the formula OCHCHO. This yellow colored liquid is the smallest dialdehyde . Its tautomer acetylenediol is unstable.-Production:...

:

See also

  • Tuberculosis
    Tuberculosis
    Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

  • Mycobacterium tuberculosis
    Mycobacterium tuberculosis
    Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...

  • Tuberculosis treatment
    Tuberculosis treatment
    Tuberculosis treatment refers to the medical treatment of the infectious disease tuberculosis .The standard "short" course treatment for TB is isoniazid, rifampicin , pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months...

  • Tuberculosis diagnosis
    Tuberculosis diagnosis
    Tuberculosis is diagnosed by finding Mycobacterium tuberculosis bacteria in a clinical specimen taken from the patient. While other investigations may strongly suggest tuberculosis as the diagnosis, they cannot confirm it.-Diagnosis:...

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