Piroxicam

Description

Piroxieam is a non-steroidal anti-inflammatory drug, of the oxieam class. A contact and photocontact sensitizer, which induced contact dermatitis in a physieal therapist. Piroxieam generally cross reacts with thiosalicylic acid and also with thiomersal. Cross sensitivity is not observed to tenoxicam.

Chemical properties

Off-White to Pale Yellow Solid

Originator

Amida, Euphoric Pharmaceuticals

The Uses of Piroxicam

Piroxicam is used in inflammatory and degenerative diseases of the musculoskeletal system that are accompanied by painful symptoms. It is used for rheumatic heart disease, nonspecific infectious polyarthritis, gouty arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, arthrosis, back pain, neuralgia, myalgia, and other diseases associated with inflammation.

The Uses of Piroxicam

Non-steroidal anti-inflammatory with long half-life. Cyclooxygenase inhibitor. Clinically useful NSAID

The Uses of Piroxicam

Piroxicam is an effective and potent inhibitor of prostaglandin synthesis and a Cox-1 and Cox-2 inhibitor. Studies show that Piroxicam blocks release of platelet ADP, and inhibits Cox-1 more potently than Cox-2.

Indications

For treatment of osteoarthritis and rheumatoid arthritis.

Background

A cyclooxygenase inhibiting, non-steroidal anti-inflammatory agent (NSAID) that is well established in treating rheumatoid arthritis and osteoarthritis and used for musculoskeletal disorders, dysmenorrhea, and postoperative pain. Its long half-life enables it to be administered once daily.

Definition

ChEBI: A monocarboxylic acid amide resulting from the formal condensation of the carboxy group of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide with the exocyclic nitrogen of 2-aminopyridine.

Indications

Piroxicam (Feldene) is indicated for the treatment of rheumatoid arthritis and osteoarthritis. Piroxicam is a nonspecific COX inhibitor that has a much higher affinity for COX-1 than COX-2. This may account for the large proportion (over 30%) of patients receiving long-term therapy who have reported side effects.Adverse GI reactions have been the most frequently reported side effect, but edema, dizziness, headache, rash, and changes in hematological parameters have also occurred in 1 to 6% of patients. Piroxicam can cause serious GI bleeding, ulceration, and perforation, particularly in the elderly, if the recommended dosage is exceeded or if aspirin is being taken concurrently.

Manufacturing Process

189.6 g (3.51 mol) of sodium methoxide in 1.4 L of dry dimethylsulfoxide was stirred at room temperature (~ 25°C), while under a dry nitrogen atmosphere. To the stirred slurry, there were then added in one complete portion 300 g (1.17 moles) of methyl 3-oxo-1,2-benzoisothyazolin-2-acetate 1,1-dioxide (Chemische Berichte, vol. 30, p. 1267 (1897)) and flask containing the system was then immediately immersed in an ice-methanol bath. The resulting deep red solution was cooled to 30°C and the ice bath removed. The solution was then stirred under dry nitrogen at 30°C for 4 min, cooled quickly to 18°C and then immediately poured into 4.8 L of 3 N hydrochloric acid solution admixed with ice. The resulting slurry was stirred for 15 min, filtered, then washed with water to give 250 g of crude product. Recrystallization from a chloroform-ethanol mixture (1:1) in the presence of charcoal, then afforded a 61% yield of methyl 3,4-dihydro-4-oxo-2H-1,2benzothiazine-3-carboxylate 1,1-dioxide, melting point 173-174°C after two recrystallizations from isopropanol.
A 22 L round-bottomed flask charged with 800 g (3.13 moles) of methyl 3,4dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, 3.2 l of water, 9.6 l of 95% ethanol, 673 ml of methyl iodide (1.53 kg, 10.87 moles) and 3.14 L of 1 N aqueous sodium hydroxide. The reaction mixture was then stirred for 30 min at room temperature, under nitrogen atmosphere and then solution was stored for 23 h. The slurry was then chilled at 0°C and filtered. After washing the filter cake twice with water, ethanol and then diethyl ether there were obtained 537 g of methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2benzothiazine-3-carboxylate 1,1-dioxide, melting point 165°-168°C after recrystallization from 1.25 L of acetonitrile.
In 3 L round-bottomed flask there were placed methyl 3,4-dihydro-2-methyl4-oxo-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, 2-aminopyridin and dry xylene. Nitrogen gas was then bubbled into the suspension for 5 min, then the reaction mixture was heated to begin a period of slow distillation, with complete solution effected during the first 10 min of heating. After 5.5 h, the period of slow distillation was discontinued and reaction mixture was allowed to heat at reflux for approximately 16 h. After that the reaction mixture was cooled to room temperature and filtered. The solid material was crystallized from chloroform with methanol and againe from methanol and then there were obtained piroxicam, melting point 197°-200°C, dec.

brand name

Feldene (Mack/Pfizer, Germany), Brexidol (Pharmacia & Upjohn, Germany), Brexin (Pharmacia & Upjohn, Austria), Doblexan (Organon, Spain), Durapirox (Durachemie, Germany), Piro-Phlogont (Azupharma, Germany), Ruvamed (Coup, Greece).

Therapeutic Function

Antiinflammatory, Analgesic

General Description

Piroxicam (Feldene) is the most widely used oxicam becauseof its once-daily dosing schedule. It is well absorbedafter oral administration and has a plasma half-life of 50hours, thus requiring a dose of only 20 to 30 mg oncedaily. It undergoes extensive hepatic metabolism, catalyzedby CYP2C9 to give 5-hydroxypiroxicam as its majormetabolite. Several piroxicam prodrugshave been synthesized via derivatization of the enol alcoholgroup (amipiroxicam, droxicam, and pivoxicam) to reducepiroxicam-induced GI irritation.

Biological Activity

Anti-inflammatory; highly selective inhibitor of COX-1 (ratio of IC 50 values for COX-2/COX-1 ~ 600).

Biochem/physiol Actions

Cyclooxygenase inhibitor.

Pharmacokinetics

Piroxicam is in a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). Piroxicam works by reducing hormones that cause inflammation and pain in the body. Piroxicam is used to reduce the pain, inflammation, and stiffness caused by rheumatoid arthritis and osteoarthritis.

Clinical Use

NSAID and analgesic. Piroxicam, the first of a new class of NSAIDs known as “oxicams,” was introduced in 1979 for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout, and acute musculoskeletal disorders. This compound was the result of a long and intensive effort to develop a potent NSAID having a novel structure and a plasma half-life sufficiently long to maintain continuous therapeutic blood levels on a once-a-day dosing regimen. Piroxicam is a potent competitive inhibitor of cyclooxygenase and lowers blood levels of prostaglandins in humans. Its ability to inhibit the infiltration of polymorphonuclear leukocytes into inflamed joints has been demonstrated in animals. Its potency and long plasma half-life of 40 h in humans allow for once-a-day dosing at 20 mg. A high incidence of gastric irritation results from this agent.

Synthesis

Piroxicam, 1,1-dioxid-4-hydroxy-2-methyl-N-2-pyradyl-2H-1,2-benzothiazine- 3-carboxamide (3.2.78), is synthesized from saccharin (3.2.70). Two methods for saccharin synthesis are described. It usually comes from toluene, which is sulfonated by chlorosulfonic acid, forming isomeric 4- and 2-toluenesulfonyl chlorides. The isomeric products are separated by freezing (chilling). The liquid part, 2-toluenesulfonyl chloride (3.2.68) is separated from the crystallized 4-toluenesulfochloride and reacted with ammonia, giving 2-toluenesulfonylamide (3.2.69). Oxidation of the product with sodium permanganate or chromium (VI) oxide in sulfuric acid gives saccharin—o-sulfobenzoic acid imide (3.2.70).

An alternative way for making saccharin is from methyl ester o-aminobenzoic (anthranylic acid). This undergoes diazotization using nitrous acid, and the resulting diazonium salt (3.2.71) is reacted with sulfur dioxide in the presence of copper dichloride, forming the methyl ester o-sulfobenzoic acid (3.2.72). Reaction of the resulting product with chlorine gives o-chlorosulfonylbenzoic acid methyl ester (3.2.73), which upon reaction with ammonium gives o-sulfonylamidobenzoic acid methyl ester (3.2.74). In the presence of hydrogen chloride, the resulting product undergoes cyclization into saccharin (3.2.70).

Veterinary Drugs and Treatments

In dogs, piroxicam may be beneficial in reducing the pain and inflammation associated with degenerative joint disease, but there are safer alternatives available. Its primary use is in dogs as adjunctive treatment of bladder transitional cell carcinoma. It may also be of benefit in squamous cell carcinomas, mammary adenocarcinoma, and transmissible venereal tumor (TVT). There is some use of it in cats for its anti-tumor effects, but it must be used with extreme caution in this species.

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia.
Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage).
Antibacterials: possibly increased risk of convulsions with quinolones.
Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparins, dabigatran and edoxaban - avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas enhanced.
Antiepileptics: possibly increased phenytoin concentration.
Antivirals: increased risk of haematological toxicity with zidovudine; concentration increased by ritonavir.
Ciclosporin: may potentiate nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect; hyperkalaemia with potassium-sparing diuretics.
Lithium: excretion decreased.
Pentoxifylline: increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity.

Absorption

Well absorbed following oral administration.

Metabolism

Renal

Metabolism

Piroxicam metabolism is mainly via cytochrome P450 CYP 2C9 in the liver by hydroxylation of the pyridyl ring of the piroxicam side-chain, followed by conjugation with glucuronic acid.
It is excreted mainly in the urine with smaller amounts in the faeces. Enterohepatic recycling occurs. Less than 5% of the dose is excreted unchanged in the urine and faeces.

Side Effects

The more common side effects that can occur with piroxicam include:

diarrhea

dizziness

headache

heartburn

Toxicity

Symptoms of overdose include drowsiness, nausea, stomach pain, and/or vomiting.