Description
Phenindione is an anticoagulant and vitamin K antagonist. It inhibits the reduction of vitamin K
1 epoxide to vitamin K
1 by vitamin K
1 epoxide reductase in rat liver homogenates in a concentration-dependent manner.
In vivo, phenindione (500 mg/kg) inhibits prothrombin synthesis and conversion of vitamin K
1 epoxide to vitamin K
1 in rats by 50 and 57%, respectively. Dietary administration of phenindione (4 mg/kg per day) inhibits aortic atherosclerosis or intracardial thrombosis in rat models of diet-induced atherosclerosis or intravascular thrombosis, respectively.
Chemical Properties
light yellow fluffy fine flakes
Uses
Oral anticoagulant (indanedione).
Uses
Like coumarin derivatives, phenindione, a compound of the indandione class, acts by altering
biosynthesis of coagulant proteins in the liver. It is used for preventing and treating thrombosis,
thrombophlebitis, and thromboembolism. However, because of a number of side
effects such as polyurea, polydipsia, tachycardia, and others, it is rarely used in practical medicine.
Definition
ChEBI: Phenindione is a beta-diketone and an aromatic ketone. It has a role as an anticoagulant. It derives from a hydride of an indane.
brand name
Hedulin (Sanofi Aventis).
Clinical Use
Anticoagulant
Synthesis
Phenindione, 3-phenylindan-1,3-dion (24.1.16), is synthesized in two ways.
The first consists of condensating benzaldehyde with phthalide in the presence of sodium
ethoxide. Evidently, the resulting phenylmethylenphthalide (24.1.15) rearranges under the
reaction conditions to give the desired phenindione (24.1.16). The second method consists of
condensation of phenylacetic acid with phthalic anhydride, forming phenylmethylenphthalide
(24.1.15), which rearranges further in the presence of sodium ethoxide to phenindione.
Drug interactions
Potentially hazardous interactions with other drugs There are many significant interactions with
coumarins. Prescribe with care with regard to the
following:
Anticoagulant effect enhanced by: alcohol,
amiodarone, anabolic steroids, aspirin, aztreonam,
bicalutamide, cephalosporins, chloramphenicol,
cimetidine, ciprofloxacin, dronedarone, fibrates,
clopidogrel, cranberry juice, danazol, dipyridamole,
disulfiram, fibrates, grapefruit juice, levofloxacin,
macrolides, metronidazole, nalidixic acid, neomycin,
norfloxacin, NSAIDs, ofloxacin, paracetamol,
penicillins, ritonavir, rosuvastatin, sulphonamides,
thyroid hormones, testosterone, tetracyclines,
tigecycline, tramadol, trimethoprim.
Anticoagulant effect decreased by: oral
contraceptives, rifamycins, vitamin K.
Anticoagulant effects enhanced/reduced by: anion
exchange resins, corticosteroids, dietary changes,
enteral feeds.
Analgesics: increased risk of bleeding with IV
diclofenac and ketorolac - avoid.
Anticoagulants: increased risk of haemorrhage with
apixaban, dabigatran, edoxaban and rivaroxaban -
avoid.
Ciclosporin: there have been a few reports of altered
anticoagulant effect; decreased ciclosporin levels have
been seen rarely
Metabolism
Hepatically metabolised. Metabolites of phenindione
often colour the urine pink or orange.
Purification Methods
Crystallise the dione from EtOH (m 156o) or CHCl3 (m 148-150o). [Beilstein 7 H 808, 7 III 4100, 7 IV 2570.]
References
[1] P REN. Mechanism of action of anticoagulants: correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K1 from vitamin K1 epoxide.[J]. Journal of Pharmacology and Experimental Therapeutics, 1977, 201 3: 541-546.
[2] E DAVIDSON G A G A N HOWARD. The effect of phenindione on rats fed diets which produce thrombosis or experimental atherosclerosis.[J]. British journal of experimental pathology, 1962, 43: 418-423.
