PHENYLBUTAZONE
Chemistry - A synthetic pyrazolone derivative related chemically to aminopyrine, phenylbutazoneoccurs as a white to off-white, odorless crystalline powder that has a pKa of 4.5. It is very slightlysoluble in water and 1 gram will dissolve in 28 ml of alcohol. It is tasteless at first, but has a slightlybitter after-taste.
Both phenylbutazone and oxyphenbutazone cross the placenta and are excreted into milk.
The serum half-life in the horse ranges from 3.5-6 hours, and like aspirin is dose-dependent.
Therapeutic efficacy however, may last for more than 24 hours however, probably due to the irreversible binding of phenylbutazone to cyclooxygenase. In horses and other species, phenylbutazone is nearly completely metabolized, primarily to oxphenbutazone (active) and gamma-hy-droxyphenylbutazone. Oxyphenbutazone has been detected in horse urine for up to 48 hours after asingle dose. Phenylbutazone is more rapidly excreted into alkaline than into acidic urine .
Other serum half-lives reported for animals are: Cattle » 40 - 55 hrs; Dogs » 2.5 - 6 hrs; Swine »2 - 6 hrs.; Rabbits » 3 hrs..
Contraindications/Precautions - Phenylbutazone is contraindicated in patients with a history of, or preexisting hematologic or bone marrow abnormalities, preexisting GI ulcers, and in foodproducing animals or lactating dairy cattle. Cautious use in both foals and ponies is recommendedbecause of increased incidences of hypoproteinemia and GI ulceration. Foals with a heavy parasiteburden or that are undernourished may be more susceptible to development of adverse effects.
Phenylbutazone may cause decreased renal blood flow and sodium and water retention, andshould be used cautiously in animals with preexisting renal disease or CHF.
Because phenylbutazone may mask symptoms of lameness in horses for several days followingtherapy, it can be used by unethical individuals to disguise lameness for "soundness" exams.
States may have different standards regarding the use of phenylbutazone in track animals. Completeelimination of phenylbutazone in horses may take 2 months and it can be detected in the urine for atleast 7 days following administration.
Although phenylbutazone has shown no direct teratogenic effects, rodent studies have demonstrated reduced litter sizes, increased neonatal mortality, and increased stillbirth rates.
Phenylbutazone should therefore be used in pregnancy only when the potential benefits of therapyoutweigh the risks associated with it.
Phenylbutazone is contraindicated in patients demonstrating previous hypersensitivity reactions toit, and should be used very cautiously in patients that have a history of allergies to other drugs.
While phenylbutazone is apparently a safer drug to use in horses and dogs than in people, seriousadverse reactions can still occur. Toxic effects that have been reported in horses include oral and GIerosions and ulcers, hypoalbuminemia, diarrhea, anorexia, and renal effects (azotemia, renalpapillary necrosis). Unlike humans, it does not appear that phenylbutazone causes much sodiumand water retention in horses at usual doses, but edema has been reported. In dogs however, phenylbutazone may cause sodium and water retention, and diminished renal blood flow.
Phenylbutazone-induced blood dyscrasias have also been reported in dogs.
Do not administer injectable preparation IM or SQ, as it is very irritating (swelling, to necrosis andsloughing). Intracarotid injections may cause CNS stimulation and seizures.
Therapy should be halted at first signs of any toxic reactions (e.g., anorexia, oral lesions, depression, reduced plasma proteins, increased serum creatinine or BUN, leukopenia, or anemias).
The use of sucralfate or the H2 blockers (cimetidine, ranitidine) have been suggested for use intreating the GI effects. Misoprostol, a prostaglandin E analog, may also be useful in reducing thegastrointestinal effects of phenylbutazone.
Overdosage - Manifestations (human) of acute overdosage with phenylbutazone include, a promptrespiratory or metabolic acidosis with compensatory hyperventilation, seizures, coma, and acutehypotensive crisis. In an acute overdose, symptoms of renal failure (oliguric, with proteinuria andhematuria), liver injury (hepatomegaly and jaundice), bone marrow depression, and ulceration (andperforation) of the GI tract may develop. Other symptoms reported in humans include: nausea, vomiting, abdominal pain, diaphoresis, neurologic and psychiatric symptoms, edema, hypertension, respiratory depression, and cyanosis.
Standard overdose procedures should be followed (empty gut following oral ingestion, etc.).
Supportive treatment should be instituted as necessary and intravenous diazepam used to helpcontrol seizures. Monitor fluid therapy carefully, as phenylbutazone may cause fluid retention.
Phenylbutazone and oxyphenbutazone can induce hepatic microsomal enzymes and increase themetabolism of drugs affected by this system (e.g., digitoxin & phenytoin). Conversely, othermicrosomal enzyme inducers (e.g., barbiturates, promethazine, rifampin, corticosteroids, orchlorpheniramine, diphenhydramine) may decrease the plasma half-life of phenylbutazone.
Phenylbutazone may increase the plasma half-life of penicillin G or lithium. Phenylbutazoneadministered concurrently with hepatotoxic drugs may increase the chances of hepatotoxicitydeveloping.
Phenylbutazone may antagonize the increased renal blood flow effects caused by furosemide.
Concurrent use with other NSAIDs may increase the potential for adverse reactions developing, however many clinicians routinely use phenylbutazone concomitantly with flunixin in horses.
Laboratory Test Interference - Phenylbutazone and oxyphenbutazone may interfere with thyroid function tests by competing with thyroxine at protein binding sites or by inhibiting thyroidiodine uptake.
Storage, Stability, Compatibility
Oral products should be stored in tight, child-resistant containers if possible. The injectable product should be stored in a cool place (46 - 56° F) or kept refrigerated.Pharmacology - PHENYLBUTAZONE
Phenylbutazone has analgesic, anti-inflammatory, antipyrexic, and mild uricosuricproperties. The proposed mechanism of action is by the inhibition of cyclooxygenase, therebyreducing prostaglandin synthesis. Other pharmacologic actions phenylbutazone may induce includereduced renal blood flow and decreased glomerular filtration rate, decreased platelet aggregation, and gastric mucosal damage.Pharmacokinetics - PHENYLBUTAZONE
Following oral administration, phenylbutazone is absorbed from both thestomach and small intestine. The drug is distributed throughout the body with highest levels attained in the liver, heart, lungs, kidneys, and blood. Plasma protein binding in horses exceeds 99%.Both phenylbutazone and oxyphenbutazone cross the placenta and are excreted into milk.
The serum half-life in the horse ranges from 3.5-6 hours, and like aspirin is dose-dependent.
Therapeutic efficacy however, may last for more than 24 hours however, probably due to the irreversible binding of phenylbutazone to cyclooxygenase. In horses and other species, phenylbutazone is nearly completely metabolized, primarily to oxphenbutazone (active) and gamma-hy-droxyphenylbutazone. Oxyphenbutazone has been detected in horse urine for up to 48 hours after asingle dose. Phenylbutazone is more rapidly excreted into alkaline than into acidic urine .
Other serum half-lives reported for animals are: Cattle » 40 - 55 hrs; Dogs » 2.5 - 6 hrs; Swine »2 - 6 hrs.; Rabbits » 3 hrs..
Uses, Indications
One manufacturer lists the following as the indications for phenylbutazone:"For the relief of inflammatory conditions associated with the musculoskeletal system in dogs andhorses." (Package Insert; Butazolidin® ¯ Coopers). It has been used primarily for the treatmentof lameness in horses and occasionally as an analgesic/anti-inflammatory, antipyrexic in dogs, cattle, and swine.Contraindications/Precautions - Phenylbutazone is contraindicated in patients with a history of, or preexisting hematologic or bone marrow abnormalities, preexisting GI ulcers, and in foodproducing animals or lactating dairy cattle. Cautious use in both foals and ponies is recommendedbecause of increased incidences of hypoproteinemia and GI ulceration. Foals with a heavy parasiteburden or that are undernourished may be more susceptible to development of adverse effects.
Phenylbutazone may cause decreased renal blood flow and sodium and water retention, andshould be used cautiously in animals with preexisting renal disease or CHF.
Because phenylbutazone may mask symptoms of lameness in horses for several days followingtherapy, it can be used by unethical individuals to disguise lameness for "soundness" exams.
States may have different standards regarding the use of phenylbutazone in track animals. Completeelimination of phenylbutazone in horses may take 2 months and it can be detected in the urine for atleast 7 days following administration.
Although phenylbutazone has shown no direct teratogenic effects, rodent studies have demonstrated reduced litter sizes, increased neonatal mortality, and increased stillbirth rates.
Phenylbutazone should therefore be used in pregnancy only when the potential benefits of therapyoutweigh the risks associated with it.
Phenylbutazone is contraindicated in patients demonstrating previous hypersensitivity reactions toit, and should be used very cautiously in patients that have a history of allergies to other drugs.
Adverse Effects, Warnings
The primary concerns with phenylbutazone therapy in humans include its bone marrow effects (agranulocytosis, aplastic anemia), renal and cardiovascular effects(fluid retention to acute renal failure), and GI effects (dyspepsia to perforated ulcers). Other seriousconcerns with phenylbutazone include, hypersensitivity reactions, neurologic, dermatologic, andhepatic toxicities.While phenylbutazone is apparently a safer drug to use in horses and dogs than in people, seriousadverse reactions can still occur. Toxic effects that have been reported in horses include oral and GIerosions and ulcers, hypoalbuminemia, diarrhea, anorexia, and renal effects (azotemia, renalpapillary necrosis). Unlike humans, it does not appear that phenylbutazone causes much sodiumand water retention in horses at usual doses, but edema has been reported. In dogs however, phenylbutazone may cause sodium and water retention, and diminished renal blood flow.
Phenylbutazone-induced blood dyscrasias have also been reported in dogs.
Do not administer injectable preparation IM or SQ, as it is very irritating (swelling, to necrosis andsloughing). Intracarotid injections may cause CNS stimulation and seizures.
Therapy should be halted at first signs of any toxic reactions (e.g., anorexia, oral lesions, depression, reduced plasma proteins, increased serum creatinine or BUN, leukopenia, or anemias).
The use of sucralfate or the H2 blockers (cimetidine, ranitidine) have been suggested for use intreating the GI effects. Misoprostol, a prostaglandin E analog, may also be useful in reducing thegastrointestinal effects of phenylbutazone.
Overdosage - Manifestations (human) of acute overdosage with phenylbutazone include, a promptrespiratory or metabolic acidosis with compensatory hyperventilation, seizures, coma, and acutehypotensive crisis. In an acute overdose, symptoms of renal failure (oliguric, with proteinuria andhematuria), liver injury (hepatomegaly and jaundice), bone marrow depression, and ulceration (andperforation) of the GI tract may develop. Other symptoms reported in humans include: nausea, vomiting, abdominal pain, diaphoresis, neurologic and psychiatric symptoms, edema, hypertension, respiratory depression, and cyanosis.
Standard overdose procedures should be followed (empty gut following oral ingestion, etc.).
Supportive treatment should be instituted as necessary and intravenous diazepam used to helpcontrol seizures. Monitor fluid therapy carefully, as phenylbutazone may cause fluid retention.
Drug Interactions
Both phenylbutazone and the active metabolite oxyphenbutazone are highlybound to plasma proteins and may displace other highly bound drugs. This mechanism may affectserum levels and duration of actions of phentoin, valproic acid, oral anticoagulants, otherantiinflammatory agents, sulfonamides, and the sulfonylurea antidiabetic agents.Phenylbutazone and oxyphenbutazone can induce hepatic microsomal enzymes and increase themetabolism of drugs affected by this system (e.g., digitoxin & phenytoin). Conversely, othermicrosomal enzyme inducers (e.g., barbiturates, promethazine, rifampin, corticosteroids, orchlorpheniramine, diphenhydramine) may decrease the plasma half-life of phenylbutazone.
Phenylbutazone may increase the plasma half-life of penicillin G or lithium. Phenylbutazoneadministered concurrently with hepatotoxic drugs may increase the chances of hepatotoxicitydeveloping.
Phenylbutazone may antagonize the increased renal blood flow effects caused by furosemide.
Concurrent use with other NSAIDs may increase the potential for adverse reactions developing, however many clinicians routinely use phenylbutazone concomitantly with flunixin in horses.
Laboratory Test Interference - Phenylbutazone and oxyphenbutazone may interfere with thyroid function tests by competing with thyroxine at protein binding sites or by inhibiting thyroidiodine uptake.