Diclofenac sodium

Description

Diclofenac Sodium is an inhibitor of Cox-1 and Cox-2, it have been used in the treatment of pain associated with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

Chemical properties

Off-White Crystalline Solid

Originator

Voltaren,Fujisawa,Japan,1974

The Uses of Diclofenac sodium

Diclofenac sodium is a nonsteroidal anti-inflammatory compound and cyclooxygenase (COX) inhibitor. Oxidation of diclofenac sodium produces the metabolite 4'-hydroxy diclofenac) which demonstrates specific inhibition of Cox-2. Inhibition of Cox by diclofenac and 4'-hydroxy diclofenac suppresses prostaglandin E2 synthesis, producing anti-inflammatory and analgesic effects. Diclofenac is also shown to stabilize the native tetrameric conformation of transthyretin (TTR) fibrils, preventing the formation of insoluble amyloidogenic TTR deposits. Diclofenac Sodium is a substrate of CYP2C9. It is also used as an inhibitor of Cox-1 and Cox-2.

Definition

ChEBI: Diclofenac sodium is the sodium salt of diclofenac. It contains a diclofenac(1-).

Manufacturing Process

Four grams of N-chloroacetyl-N-phenyl-2,6-dichloroaniline and 4 grams of aluminum chloride are well mixed together and heated for 2 hours at 160°C. The melt is cooled and poured onto about 50 grams of ice while it is still warm. The oil which separates is dissolved in 50 ml of chloroform, the chloroform solution is washed with 10 ml of water, dried over sodium sulfate and concentrated under 11 torr. The residue is distilled. The 1-(2,6- dichlorophenyl)-2-indolinone melts at 126°-127°C. A solution of 186 grams of 1-(2,6-dichlorophenyl)-2-indolinone in 660 ml of ethanol and 660 ml of 2 N sodium hydroxide solution is refluxed for 4 hours. The solution is then cooled and left to stand for 4 hours at 0°-5°C. The crystals which form are filtered off and recrystallized from water. Diclofenac sodium melts at 283°-285°C. The yield is 97% of theoretical, according to US Patent 3,558,690.

brand name

Solaraze (Bioglan); Voltaren (Novartis);Aflamin;Alfamin;Allvoran;Artren;Blesin;B-voltaren;Cgp 9194;Chlorgyl;Ct-diclo;Dichloronic;Diclo attritin;Diclo spondril;Diclo-attritin;Diclo-burg;Diclo-phlohont;Diclo-puren;Diclo-recip;Dicloreum;Diclo-spondyril;Diclo-wolf;Dolobasan;Dolotrem;Doragon;Duravolten;Duvavotten;Feloran;Fenoflam;Flogofenac;Flogogenac;Forgenac;Inflamac;Klast;Monoflam;Myogit;Neuro-effekton;Neurofenac;Neuro-voltaren;Neviodin;Olfen;Panamor;Rewodina;Rheumalgen;Rheumavincin-n;Seecoren;Shignol;Silino;Sofarin;Thicataren;Toryxil;Tsudomin;Voltarene.

Therapeutic Function

Antiinflammatory

World Health Organization (WHO)

The World Health Organization currently has no information to suggest that diclofenac is less safe than other widely available non-steroidal antiinflammatory substances of this type, or that children are particularly liable to react adversely. It is registered in many countries in several dosage forms, including a 12.5 mg suppository indicated for juvenile arthritis.

Biochem/physiol Actions

Standard NSAID and cyclooxygenase (COX) inhibitor. Major metabolites are 4′-hydroxydiclofenac and 5′-hydroxydiclofenac. Has been used as substrate selective for CYP2C9.

Clinical Use

Diclofenac sodium is indicated for the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

Side Effects

Diclofenac sodium is used for the symptomatic relief of rheumatoid arthritis and osteoarthritis, including degenerative joint disease of the hip. Gastrointestinal problems (ulceration and bleeding) and adverse CNS reactions (dizziness and headache) are the most commonly encountered adverse effects.

Synthesis

Synthesis: Acylation of N-phenyl-2,6- dichloroaniline with chloroacetyl chloride gives the corresponding chloroacetanilide, which is fused with aluminum chloride to give 1-(2,6- dichlorophenyl)-2-indolinone. Hydrolysis of the indolinone with dilute aqueous-alcoholic sodium hydroxide affords the desired sodium salt directly.

Drug interactions

Potentially hazardous interactions with other drugs
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; concentration reduced by rifampicin.
Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparins, dabigatran and edoxaban - avoid long term use with edoxaban; increased risk of haemorrhage with IV diclofenac - avoid.
Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas enhanced.
Antiepileptics: possibly increased phenytoin concentration.
Ciclosporin: may potentiate nephrotoxicity; concentration increased by ciclosporin.
Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib.

Metabolism

Diclofenac sodium undergoes first-pass metabolism and It is then excreted in the form of glucuronide and sulfate conjugates, mainly in the urine (about 60%) but also in the bile (about 35%). then extensively metabolised to 4′-hydroxydiclofenac, 5-hydroxydiclofenac, 3′-hydroxydiclofenac, and 4′,5-dihydroxydiclofenac by glucuronidation of the intact molecule or more commonly by single and multiple hydroxylation followed by glucuronidation.

Storage

Store at RT