Pyrazinamide is a medication used to treat

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in w ...

. For active tuberculosis, it is often used with rifampicin, isoniazid, and either

streptomycin Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, ''Mycobacterium avium'' complex, endocarditis, brucellosis, ''Burkholderia'' infection, plague, tularemia, and rat bite fever ...

ethambutol Ethambutol (EMB, E) is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat ''Mycobacterium av ...

. It is not generally recommended for the treatment of latent tuberculosis. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. Common side effects include nausea, loss of appetite, muscle and joint pains, and rash. More serious side effects include

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...

liver toxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...

, and sensitivity to sunlight. It is not recommended in those with significant liver disease or porphyria. It is unclear if use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

is safe but it is likely okay during

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

. Pyrazinamide is in the antimycobacterial class of medications. How it works is not entirely clear. Pyrazinamide was first made in 1936, but did not come into wide use until 1972. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. Pyrazinamide is available as a generic medication.

Medical uses

Pyrazinamide is only used in combination with other drugs such as isoniazid and rifampicin in the treatment of '' Mycobacterium tuberculosis'' and as directly observed therapy (DOT). It is never used on its own. It has no other indicated medical uses. In particular, it is not used to treat other mycobacteria; '' Mycobacterium bovis'' and '' Mycobacterium leprae'' are innately resistant to pyrazinamide. Pyrazinamide is used in the first 2 months of treatment to reduce the duration of treatment required. Regimens not containing pyrazinamide must be taken for 9 months or more. Pyrazinamide is a potent antiuricosuric drug and consequently has an

off-label use Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although m ...

in the diagnosis of causes of hypouricemia and hyperuricosuria. It acts on URAT1.

Adverse effects

The most common (roughly 1%) side effect of pyrazinamide is

joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

s (arthralgia), but this is not usually so severe that patients need to stop taking it. Pyrazinamide can precipitate

flares by decreasing renal excretion of uric acid. The most dangerous side effect of pyrazinamide is

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

, 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 to 12–30 mg/kg daily. In the standard four-drug regimen (isoniazid, rifampicin, 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) Other side effects include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

, anorexia,

sideroblastic anemia Sideroblastic anemia, or sideroachrestic anemia, is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorpora ...

skin rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

urticaria Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...

pruritus Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...

dysuria Dysuria refers to painful or uncomfortable urination. It is one of a constellation of ''irritative'' bladder symptoms (also sometimes referred to as lower urinary tract symptoms), which includes nocturia and urinary frequency. Diagnosis The c ...

interstitial nephritis Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules ...

, malaise, rarely porphyria, and

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

Pharmacokinetics

Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis. It is metabolised by the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

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

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...

(WHO) recommends its use in pregnancy; and extensive clinical experience shows that it is safe. In the US, pyrazinamide is not used in pregnancy, citing insufficient evidence of safety. Pyrazinamide is removed by haemodialysis, so doses should always be given at the end of a dialysis session.

Mechanism of action

Pyrazinamide is a prodrug that stops the growth of ''M. tuberculosis''. Pyrazinamide diffuses into the granuloma of ''M. tuberculosis'', where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid. Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. 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 Fatty acid synthase (FAS) 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. It is not a single enzyme but a whole enzymatic system composed of two iden ...

(FAS) I, which is required by the bacterium to synthesize

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

s although this has been discounted. The accumulation of pyrazinoic acid was also suggested to disrupt membrane potential and interfere with energy production, necessary for survival of ''M. tuberculosis'' at an acidic site of infection. However, since an acidic environment is not essential for pyrazinamide susceptibility and pyrazinamide treatment does not lead to intrabacterial acidification nor rapid disruption of membrane potential, this model has also been discounted. Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation, but more detailed experiments have shown that it does not have this activity. The current hypothesis is that pyrazinoic acid blocks synthesis of

coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...

. Pyrazinoic acid binds weakly to

aspartate decarboxylase Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

('' PanD''), triggering its degradation. This is an unusual mechanism of action in that pyrazinamide does not directly block the action of its target, but indirectly triggers its destruction.

Resistance

Mutations in the ''

pncA PncA is a gene encoding pyrazinamidase in ''Mycobacterium'' species. Pyrazinamidase converts the drug pyrazinamide to the active form pyrazinoic acid. There is a strong correlation between mutations in pncA and resistance of ''M. tuberculosis ...

'' gene of ''M. tuberculosis'', which encodes a pyrazinamidase and converts pyrazinamide to its active form pyrazinoic acid, are responsible for the majority of pyrazinamide resistance in ''M. tuberculosis'' strains. A few pyrazinamide-resistant strains with mutations in the ''rpsA'' gene have also been identified. However, a direct association between these ''rpsA'' mutations and pyrazinamide resistance has not been established. The pyrazinamide-resistant ''M. tuberculosis'' strain DHMH444, which harbors a mutation in the carboxy terminal coding region of ''rpsA'', is fully susceptible to pyrazinoic acid and pyrazinamide resistance of this strain was previously associated with decreased pyrazinamidase activity. Further, this strain was found to be susceptible to pyrazinamide in a mouse model of tuberculosis. Thus, current data indicate that ''rpsA'' mutations are not likely to be associated with pyrazinamide resistance. Currently, three main methods of testing are used for pyrazinamide resistance: 1) phenotypic tests where a tuberculosis strain is grown in the presence of increasing concentrations of pyrazinamide, 2) measuring levels of pyrazinamidase enzyme produced by the tuberculosis strain, or 3) looking for mutations in the ''

'' gene of tuberculosis. Concerns exist that the most widely used method for phenotypic resistance testing may overestimate the number of resistant strains. Global resistance of tuberculosis to pyrazinamide has been estimated to be in 16% of all cases, and 60% of people with

multidrug-resistant tuberculosis Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some ...

Abbreviations

The abbreviations PZA and Z are standard, and used commonly in the medical literature, although best practice discourages the abbreviating of drug names to prevent mistakes.

Presentation

Pyrazinamide is a

generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...

, and is available in a wide variety of presentations. Pyrazinamide tablets form the bulkiest part of the standard tuberculosis treatment regimen. Pyrazinamide tablets are so large, some people find them impossible to swallow: pyrazinamide syrup is an option. Pyrazinamide is also available as part of fixed-dose combinations with other TB drugs such as isoniazid and rifampicin ('' Rifater'' is an example).

History

Pyrazinamide was first discovered and patented in 1936, but not used against tuberculosis until 1952. Its discovery as an antitubercular agent was remarkable since it has no activity against tuberculosis''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

'', due to not being active at a neutral pH, so would ordinarily not be expected to work ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

''. However,

nicotinamide Niacinamide or Nicotinamide (NAM) is a form of vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) ma ...

was known to have activity against tuberculosis and pyrazinamide was thought to have a similar effect. Experiments in mice at Lederle and Merck confirmed its ability to kill tuberculosis and it was rapidly used in humans.

References

External links

* {{portal bar, Medicine Anti-tuberculosis drugs Carboxamides Enones Prodrugs Pyrazines World Health Organization essential medicines Wikipedia medicine articles ready to translate