Phenylbutazone: Uses, Warnings, Pharmacodynamics, Mechanism of Action and Adverse Effects in Humans

It is an NSAID drug that was discontinued for human use due to its harmful side effects.

It is used for veterinary use; This drug is used today to treat fever, pain, and inflammatory conditions associated with the musculoskeletal system in animals (horses, dogs, others).

Phenylbutazone became available for use in humans for the treatment of rheumatoid arthritis and gout in 1949. However, it is no longer approved, and therefore not marketed, for any human use.

Phenylbutazone Toxicity Warnings

Phenylbutazone was introduced in 1949 for the treatment of rheumatoid arthritis (RA) and related disorders.

At present, it is no longer manufactured for human use, but is still used in veterinary medicine (used mainly in horses and dogs), for which hepatotoxicity has been described.

Side effects were recorded in up to 45% of recipients and severe reactions in 10-15% of patients forced its withdrawal from the market several years ago. More than 100 cases of liver injury were described, with an incidence of manifest hepatotoxicity of 1–5%.

Most of the patients who developed phenylbutazone hepatotoxicity were adults who took the drug for 1-6 weeks. Men and women seemed to be affected equally; most were over 30 years old and a third were over 60 years old.

Almost half had signs of hypersensitivity such as fever, rash, and eosinophilia. Hepatocellular injury predominated in two thirds of the cases, with cholestasis in one third. Hepatic granulomas were found in 30% of patients undergoing liver biopsy.

The relatively short fixed latency period, a rapid response to re-exposure, and the high incidence of allergic manifestations and granulomatous hepatitis suggested an immune mechanism.

However, intrinsic toxicity was more likely to explain the injury that was seen in children who received an overdose, as well as in some experimental models. The prognosis for phenylbutazone hepatotoxicity depends on the morphological form of the lesion.

Those with cholestatic features or granulomas generally recovered within a few weeks or months, although one case progressed to chronic cholestasis .

A fatality rate of 25% was recorded for those with severe liver necrosis. In mice, liver and kidney cell tumors developed in long-term carcinogenicity studies.

Oxyphenbutazone is the hydroxy derivative of phenylbutazone and one of its active metabolites. It shares a similar toxicity profile with the parent compound and is currently not marketed.

Other pyrazolone derivatives that have been developed and chemically related to phenylbutazone include azapropazone and feprazone.

Pharmacodinámica

Phenylbutazone is a synthetic derivative of pyrazolone. It is a non-hormonal anti-inflammatory antipyretic compound that was helpful in treating inflammatory conditions.

The apparent analgesic effect is probably related primarily to the compound’s anti-inflammatory properties and arises from its ability to reduce prostaglandin H and prostacyclin production.

Prostaglandins act on a variety of cells such as vascular smooth muscle cells that cause constriction or dilation, on platelets that cause aggregation or disaggregation, and on spinal neurons that cause pain.

Prostacyclin causes platelet breakdown of vascular constriction.

Mechanism of action

Phenylbutazone binds and inactivates prostaglandin H synthase and prostacyclin synthase through peroxide-mediated deactivation (H2O2). Reduced prostaglandin production leads to reduced inflammation of the surrounding tissues.

Pharmacokinetics

Phenylbutazone is readily absorbed from the gastrointestinal tract and peak plasma concentrations occur approximately 2 hours after ingestion.

It is also easily absorbed when administered rectally. Phenylbutazone is widely distributed in body fluids and tissues; it diffuses into the synovial fluid, crosses the placenta, and small amounts enter the CNS and breast milk.

It is 98% bound to plasma proteins. It is extensively metabolized in the liver by oxidation and by conjugation with glucuronic acid.

Oxyphenbutazone, gamma-hydroxyphenbutazone, and p, gamma-dihydroxyphenylbutazone are formed by oxidation, but only small amounts appear in the urine and the rest are further metabolized.

It is mainly excreted in the urine as metabolites , although about a quarter of a dose can be excreted in the faeces.

Adverse effects in humans

The adverse effects of this drug are:

  • Sickness.
  • Vomiting
  • Epigastric discomfort.
  • Diarrhea.
  • Edema due to salt retention.
  • Rashes.
  • Dizziness
  • Drowsiness.
  • Headache.
  • Blurry vision.

The most serious reactions include:

  • Gastric irritation with ulceration and gastrointestinal bleeding.
  • Ulcerative stomatitis.
  • Hepatitis.
  • Jaundice .
  • Hematuria.
  • nephritis.
  • Renal insufficiency.
  • Pancreatitis.
  • Ocular toxicity.
  • Goiter

Phenylbutazone can precipitate heart failure and can also cause an acute pulmonary syndrome with dyspnea and fever and enlargement of the salivary gland ( parotitis ).

Hypersensitivity reactions have also been reported including asthma, and severe generalized reactions, including:

  • Lymphadenopathy
  • Erythema multiforme.
  • Stevens-Johnson syndrome.
  • Toxic epidermal necrolysis.
  • Exfoliative dermatitis.

The most serious adverse effects of phenylbutazone are related to bone marrow depression and include agranulocytosis and aplastic anemia.

Leukopenia, pancytopenia, hemolytic anemia, and thrombocytopenia can also occur. These adverse haematological reactions have resulted in restrictions on the indications for the use of phenylbutazone and its subsequent delisting from the market for human use.

Blood disorders can develop shortly after starting treatment or can occur suddenly after prolonged treatment, and regular hematological monitoring should be carried out.