Description
Diflunisal is more
potent than aspirin but produces fewer side effects and has a biological half-life three to four times greater than that
of aspirin. It is rapidly and completely absorbed on oral administration, with peak plasma levels being achieved within
2 to 3 hours of administration. It is highly bound (99%) to plasma proteins after absorption. Its elimination half-life is
8 to 12 hours, and it is excreted into urine primarily as glucuronide conjugates. The most frequently reported side
effects include disturbances of the GI system (e.g., nausea, dyspepsia, and diarrhea), dermatological reactions, and
CNS effects (e.g., dizziness and headache).
Chemical Properties
White Solid
Originator
Dolobid,Morson,UK,1978
Uses
As a prostaglandin synthetase inhibitor, diflunisal exhibits analgesic, fever-reducing, and
anti-inflammatory action. It is used for long- and short-lasting symptomatic relief of low
to moderate pain in osteoarthritis and rheumatoid arthritis.
Uses
Salicylate; non-selective cyclo-oxygenase inhibitor; antipyretic; analgesic; anti- inflammatory.
Definition
ChEBI: Diflunisal is an organofluorine compound comprising salicylic acid having a 2,4-difluorophenyl group at the 5-position. It has a role as a non-steroidal anti-inflammatory drug and a non-narcotic analgesic. It is an organofluorine compound and a monohydroxybenzoic acid. It is functionally related to a salicylic acid and a 1,3-difluorobenzene.
Manufacturing Process
A mixture of 10 g of 4-(2',4'-difluorophenyl)-phenol and 27.2 g of potassium
carbonate is exposed to carbon dioxide at 1,300 psi and 175°C. The dark
mass obtained from this carbonation is then dissolved in 300 ml of water and
200 ml of methylene chloride and the two layers separated. The water layer is
then extracted with 100 ml of methylene chloride and then acidified with 2.5
N hydrochloric acid. This mixture is then filtered and the cake dried in vacuo
to yield 5.32 g of the crude product. The crude product is then recrystallized
from benzene-methanol. An additional crystallization of this semipure material
from benzene-methanol yields analytically pure 2-hydroxy-5-(2',4'-
difluorophenyl)-benzoic acid (MP 210-211°C).
Brand name
Dolobid (Merck).
Therapeutic Function
Analgesic, Antiinflammatory
General Description
Diflunisal (Dolobid), is a longer acting and more potent drugthan aspirin because of its hydrophobic, 2,4-difluorophenylgroup attached to the 5-position of the salicyclic acid. In alarge-scale comparative study with aspirin, it was also bettertolerated with less GI complications than aspirin. It ismarketed in tablet form for treating mild to moderate postoperativepain as well as RA and OA.
Diflunisal is highly protein bound. Its metabolism is subjectto a dose-dependent, saturable, and capacity-limitedglucuronide formation. This unusual pharmacokineticprofile is a result of an enterohepatic circulation and the reabsorptionof 65% of the drug and its glucuronides, followedby cleavage of its unstable, acyl glucuronide back tothe active drug. Thus, diflunisal usage in patients with renalimpairment should be closely monitored.
Mechanism of action
Diflunisal is a weak inhibitor of both COX-1
and COX-2.
Pharmacology
Peak plasma concentrations are reached
within 2 to 3 h after oral dosing. Diflunisal is
strongly bound to plasma protein (> 99 %), has
a long elimination half-life (8–12 h) and nonlinear
elimination kinetics. Hence, it is used with
an initial loading dose (1000 mg) and a lower
maintenance dose (500–1000 mg/d).
Clinical Use
Diflunisal (pKa 3.3) was introduced in the United States in 1982 and has gained considerable acceptance as an
analgetic and as a treatment of rheumatoid arthritis and osteoarthritis. Diflunisal is metabolized primarily to ether and
ester glucuronide conjugates.
Side effects
The main side effects are gastrointestinal disturbances,
headache and rash.
Synthesis
Diflunisal, 2??,4??-difluoro-4-hydroxy-3-byphenylcarboxylic acid (3.2.5), is
synthesized from a diazonium salt, which is synthesized from 2,4-difluoroaniline and
isoamyl nitrite, and anisole in the presence of copper (I) salts by the classic scheme of
making diaryls. The resulting 4-(2,4-difluorophenyl)anisole (3.2.3) is demethylated by
hydrogen iodide into 4-(2,4-difluorophenyl)-phenol (3.2.4). This product is reacted with
carbon dioxide in the presence of a base according to the Kolbe¨CSchmitt phenol carboxylation method, giving diflunisal (3.2.5) [64¨C67].
References
[1] KF TEMPERO SL S VJ Cirillo. Diflunisal: a review of pharmacokinetic and pharmacodynamic properties, drug interactions, and special tolerability studies in humans.[J]. British journal of clinical pharmacology, 1977, 4 S1: 31S-36S. DOI:
10.1111/j.1365-2125.1977.tb04511.x
