Tolfenamic acid

Tolfenamic acid is Non- Steroidal Anti inflammatory Drugs belonging to Analgesic and Anti inflammatory agents.

Tolfenamic acid is used in the treatment of Mild to moderate pain and acute migraine attacks.

Tolfenamic acid is Readily absorbed from the GI tract. Bioavailability: 85%. Time to peak plasma concentration: Approx 60-90 min and get distributed into breast milk (small amounts). Plasma protein binding: 99% and get Metabolised in the liver and get excreted via urine (approx 90%, as glucuronic acid conjugates) and faeces (approx 10%). Plasma half-life: Approx 2 hr.

The onset of action of Tolfenamic acid was within 1 hour.

The Tmax of Tolfenamic acid was within 2 to 4 hours

Tolfenamic acid shows common side effects like tremor, euphoria, fatigue, pulmonary infiltration, nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of Crohn’s disease and colitis, gastritis, pancreatitis

Tolfenamic acid is available in India, Germany, Canada, France, USA.

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 is available in the form of Capsules.

Tolfenamic acid is used in the treatment of Mild to moderate pain and acute migraine attacks.

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.

Tolfenamic acid is approved for use in the following clinical indications

Mild to moderate pain and acute migraine attacks.

200 mg when the first symptoms of migraine appear.

Treatment may be repeated once after 1 to 2 hours if a satisfactory response was not obtained initially.

Tolfenamic acid is available in the dosage strength of 250 mg.

Tolfenamic acid is available in the form of Capsules.

Tolfenamic acid is contraindicated in patients with:

Hypersensitivity to aspirin or other NSAID. Active or history of GI bleeding or ulceration, severe heart failure, history of GI bleeding or perforation related to previous NSAID therapy. Severe renal and hepatic impairment. Pregnancy (3rd trimester).

Take special care with Tolfenamic Acid Tablets if the patient are taking other NSAIDs including NSAIDs known as COX-2 inhibitors:

• have or have had asthma
• have decreased heart, liver or kidney function
• have or have had high blood pressure
• have had a gastrointestinal disease (Crohn’s disease or inflammation of the colon and rectum)
• have a connective tissue disease such as systemic lupus erythematosus (SLE)
• have cardiovascular disease, peripheral arterial disease and/or cerebrovascular disease
• have had a peptic ulcer, intestinal bleeding or perforation.

Tolfenamic acid may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

Risk Summary

Use of NSAIDs, including Tolfenamic acid, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Tolfenamic acid, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of Tolfenamic acid in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats and rabbits, there was no evidence of teratogenicity at exposures up to 5 and 10 times the MRHD, respectively. In rat studies with Tolfenamic acid, fetotoxicity (post implantation loss) was observed at exposures 2 times the MRHD, and delayed parturition and an increased incidence of stillbirth were noted at doses equivalent to the MRHD of Tolfenamic acid. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as Tolfenamic acid, resulted in increased pre- and post-implantation loss.

Increased risk of gastrointestinal bleeding with excessive alcohol ingestion. May slightly delay the rate, but not the extent of absorption with food.

• Common Adverse effects:

Swelling

Nausea

Vomiting

Diarrhoea Flatulence (wind)

Constipation

Indigestion

Stomach pain

Inflammation of the mouth or stomach

Worsening of gastrointestinal diseases (Crohn’s disease or inflammation of the colon and rectum) Rash

• Less Common Adverse effects:

Nettle rash

Visual disturbances

Pain in the eye and/or loss of vision

Headache

Sensation of pins and needles on the skin

Depression

Confusion

Tinnitus

Trembling or shaking

Feeling of elation

Dizziness

Vague feeling of weakness

• Rare Adverse effects

Exhaustion

Drowsiness

Slight pain when passing urine

Discoloration of urine (little more lemon coloured)

Decreased liver or kidney function

Sensitivity to light

• May increase the risk of bleeding with other NSAIDs or salicylates (e.g. aspirin), anticoagulants (e.g. warfarin), antiplatelet agents, corticosteroids, and SSRIs.
• May enhance the nephrotoxic effect of ciclosporin or tacrolimus.
• May reduce the effects of antihypertensive agents (e.g. ACE inhibitors, angiotensin II antagonists, β-blockers), diuretics (e.g. furosemide, thiazides), and mifepristone (consider avoiding Tolfenamic acid for at least 8-12 days after mifepristone use).
• May increase the plasma concentration of cardiac glycosides, lithium, aminoglycosides, and methotrexate.
• May prolong the half-life of oral hypoglycaemic agents, increasing the risk of hypoglycaemia. Metabolism and elimination may be reduced with probenecid.
• May increase the risk of haematological toxicity with zidovudine.

The common side effects of Tolfenamic acid include the following :

Swelling

Nausea

Vomiting

Diarrhoea Flatulence (wind)

Constipation

Indigestion

Stomach pain

Inflammation of the mouth or stomach

Worsening of gastrointestinal diseases (Crohn’s disease or inflammation of the colon and rectum) Rash

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.

• Pharmacodynamic

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.

• Pharmacokinetics

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Tolfenamic acid -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Tolfenamic acid
5. https://europepmc.org/article/med/6988203