Tolfenamic acid

Tolfenamic acid, with the formula N-(2-methyl-3-chlorphenyl)-anthranilic acid, is a nonsteroidal anti-inflammatory agent.

In the information for tolfenamic acid, it is stated that this drug, being an NSAID, is effective in treating the pain associated with the acute attack of migraines in adults.

Studies have shown that tolfenamic acid presents a non-dose dependent partial inhibition of irritant-induced temperature rise as well as a dose-dependent inhibition of skin edema. By studying its NSAID properties more closely, it was noted a dose-related inhibition of serum thromboxane which indicated the inhibition of COX-1. In the same line, there was noted a inhibition of prostaglandin E2 synthesis which marks a related COX-2 inhibition. The maximal inhibition of thromboxane was greater than 80% as well as is proven to be a potent prostaglandin E inhibitor.

Tolfenamic acid inhibits the biosynthesis of prostaglandins, and it also presents inhibitory actions on the prostaglandin receptors. As commonly thought, the mechanism of action of tolfenamic acid is based on the major mechanism of NSAIDs which consists of the inhibition of COX-1 and COX-2 pathways to inhibit prostaglandin secretion and action and thus, to exert its anti-inflammatory and pain-blocking action. Nonetheless, some report currently indicates that tolfenamic acid inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes leading to an inhibition of even 25% of the chemotactic response. This activity is a not ligand specific additional anti-inflammatory mechanism of tolfenamic acid.

Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h. It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively. The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml. The bioavailability of tolfenamic acid is around 75%.

The volume of distribution is of 1.79-3.2 L/kg. When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg.

Tolfenamic acid presents high protein binding properties reaching 99.7% of the administered dose. Studies have studied the changes in protein binding depending on the presence of certain disorders that modify the dialysis equilibrium. These studies verify that modifications in blood creatinine, urea and bilirubin can significantly alter the concentration of unbound tolfenamic acid. The main binding structure is predicted to be related to lipid membrane structures.

Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates. Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose.

The estimated half-life of tolfenamic acid is 8.01-13.50 hours. When tested intravenously, the reported half-life was 6.1h.

The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg. When tested intravenously, the reported clearance rate was 72.4 ml.h/kg.

Tolfenamic acid has a relatively low acute toxicity with LD50 values in 200-1000 mg/kg. The metabolites of tolfenamic acid are reported to have an even less important toxicity. Some of the expected toxicity is related to the presence of gastrointestinal effects such as gut ulceration and renal papillitis.

• Livestock: Pneumonia- 1 ml/20 kg bodyweight & Acute Mastitis- 1 ml/10 kg body weight by IM at neck musculature or slowly at IV. Repeat once only after 48 hours if required.
• Dog: 1 ml/10 kg body weight by SC/IM injection and it may be repeated once only after 24 hours if required.
• Cat: 1 ml/10 kg body weight by SC injection and it may be repeated once only after 24 hours if required.
• Pig: 1 ml/20 kg body weight as a single IM injection in the neck musculature. Or, as directed by the Registered Veterinary Physician.