Usage
- Tolfenamic acid is prescribed for the treatment of migraine headaches and mild to moderate pain, including primary dysmenorrhea (painful menstruation). It may also be used off-label for vascular headaches. Veterinary uses include the treatment of pain and inflammation in various animals.
- Pharmacological Classification: Non-Steroidal Anti-Inflammatory Drug (NSAID)
- Mechanism of Action: Tolfenamic acid primarily inhibits cyclooxygenase (COX-1 and COX-2) enzymes. These enzymes are responsible for the production of prostaglandins, which mediate inflammation and pain. The drug also exhibits direct antagonistic action on prostaglandin receptors and inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes, further contributing to its anti-inflammatory effects.
Alternate Names
- N-(2-methyl-3-chlorophenyl) anthranilic acid
- Brand Names: Clotan, Tolfem, Tufnil, Migrex (and various veterinary formulations)
How It Works
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Pharmacodynamics: Tolfenamic acid exerts analgesic (pain-relieving), anti-inflammatory, and antipyretic (fever-reducing) effects by inhibiting prostaglandin and leukotriene synthesis. It binds strongly to plasma proteins (approximately 99%).
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Pharmacokinetics:
- Absorption: Tolfenamic acid is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached in approximately 60-90 minutes. Absorption is delayed when taken orally, with a mean lag time of about 32 minutes. Food or milk can increase the rate of absorption. Antacids containing aluminum hydroxide can decrease absorption, while those with magnesium hydroxide can increase it. The bioavailability is around 75-85%.
- Distribution: The volume of distribution is 1.79-3.2 L/kg. High concentrations are found in plasma, digestive tract, liver, lungs, and kidneys. The drug exhibits a linear pharmacokinetic profile.
- Metabolism: Tolfenamic acid is metabolized in the liver and undergoes enterohepatic circulation.
- Elimination: Primarily eliminated via renal excretion (about 90%) and feces. The plasma half-life is approximately 2 hours, but the mean life in ruminants can range from 8 to 15 hours.
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Mode of Action: Tolfenamic acid inhibits COX-1 and COX-2 enzymes, reducing prostaglandin synthesis. It also acts as a direct antagonist on prostaglandin receptors and inhibits leukotriene B4 chemotaxis.
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Receptor binding, enzyme inhibition, or neurotransmitter modulation: COX-1 and COX-2 enzyme inhibition, prostaglandin receptor antagonism.
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Elimination pathways: Primarily renal excretion and some fecal excretion.
Dosage
Standard Dosage
Adults:
- Migraine: 200 mg at the onset of symptoms; may repeat once after 1-2 hours if needed.
- Mild to Moderate Pain: 100-200 mg three times daily.
- Maximum daily dose: Should not exceed 600mg per day.
Children:
- A pediatric dosage regimen has not yet been established. Not recommended for use in patients under 18 years of age.
Special Cases:
- Elderly Patients: Use the lowest effective dose for the shortest possible duration due to increased risk of adverse effects, particularly gastrointestinal bleeding and perforation. Monitor closely.
- Patients with Renal Impairment: Dose adjustments may be necessary. Avoid use in severe renal impairment.
- Patients with Hepatic Dysfunction: Use with caution due to potential for increased adverse effects. Close monitoring of liver function tests is necessary. Dose adjustments may be necessary.
- Patients with Comorbid Conditions: Use with extreme caution in patients with asthma, bronchospasm, bleeding disorders, cardiovascular diseases, peptic ulceration, hypertension, liver or heart problems, systemic lupus erythematosus, or inflammatory bowel disease.
Clinical Use Cases
The primary clinical use cases for humans are migraine and mild to moderate pain. The dosage guidelines mentioned above apply. The drug is not typically used in the clinical settings you listed (intubation, surgical procedures, mechanical ventilation, ICU, emergency situations). In veterinary medicine, tolfenamic acid is utilized for various conditions, such as acute inflammation associated with respiratory diseases and acute mastitis in cattle and pigs.
Dosage Adjustments
- Dose modifications may be necessary for patients with renal or hepatic dysfunction. Geriatric patients generally require lower doses.
Side Effects
Common Side Effects:
- Gastrointestinal discomfort (indigestion, nausea, vomiting, diarrhea, stomach pain)
- Dizziness, headache, drowsiness
- Dysuria (painful urination), particularly in males
Rare but Serious Side Effects:
- Gastrointestinal bleeding or perforation
- Peptic ulcers
- Allergic reactions (rash, itching, angioedema)
- Stevens-Johnson syndrome
- Blood disorders
- Liver or kidney damage
- Pulmonary infiltration
- Confusion, depression, hallucinations
- Hypertension
- Increased risk of bleeding
- Heart attack or stroke
Long-Term Effects:
- Chronic kidney disease
- Gastrointestinal problems (ulcers, bleeding)
- Cardiovascular complications (heart attack, stroke)
Adverse Drug Reactions (ADR):
Any rare or serious side effect as listed above requires immediate intervention.
Contraindications
- Hypersensitivity to tolfenamic acid or other NSAIDs
- Active gastrointestinal bleeding or ulceration
- History of gastrointestinal bleeding or perforation related to previous NSAID therapy
- Severe heart failure, liver failure, or renal failure
- Third trimester of pregnancy
Drug Interactions
- Other NSAIDs (including aspirin): Increased risk of gastrointestinal side effects and bleeding.
- Anticoagulants (e.g., warfarin): Increased risk of bleeding.
- Antihypertensives, diuretics: Decreased antihypertensive effect.
- Cardiac glycosides (e.g., digoxin): Increased plasma glycoside levels.
- Lithium, Methotrexate: Increased plasma concentration.
- Mifepristone: Decreased therapeutic effect of mifepristone.
- Quinolone antibiotics: Increased risk of convulsions.
- Zidovudine: Increased risk of hematological toxicity.
- Ciclosporin, diuretics, tacrolimus: Increased risk of nephrotoxicity.
- SSRIs, antiplatelets: Increased risk of bleeding.
- Corticosteroids: Increased risk of gastrointestinal bleeding.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Contraindicated in the third trimester. Use only if clearly necessary during the first and second trimesters, and minimize dose and duration. May make it more difficult to become pregnant.
- Breastfeeding: Avoid if possible, as NSAIDs can be excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: COX-1 and COX-2 inhibitor, prostaglandin receptor antagonist, inhibits leukotriene B4 chemotaxis
- Side Effects: Gastrointestinal issues, dizziness, headache, dysuria; rarely, GI bleeding, ulcers, allergic reactions, liver/kidney damage
- Contraindications: Hypersensitivity to NSAIDs, active GI ulcers, severe heart/liver/renal failure, third trimester of pregnancy
- Drug Interactions: Other NSAIDs, anticoagulants, antihypertensives, lithium, methotrexate, quinolone antibiotics
- Pregnancy & Breastfeeding: Avoid in third trimester and during breastfeeding; use with caution in first and second trimesters if clearly necessary.
- Dosage: Migraine: 200 mg initially, may repeat once after 1-2 hours. Mild to moderate pain: 100-200 mg tid. Adjust for renal/hepatic impairment.
- Monitoring Parameters: Renal and liver function, blood pressure, signs of GI bleeding.
Popular Combinations
Generally, tolfenamic acid is not combined with other NSAIDs due to the increased risk of adverse events. Specific combinations are not commonly used or recommended.
Precautions
- General Precautions: Screen for allergies, history of GI ulcers, heart/liver/kidney disease, bleeding disorders, asthma.
- Specific Populations: See “Special Cases” under Dosage. Avoid in children under 18. Menstruating individuals should use with caution due to the risk of dysmenorrhea exacerbation.
- Lifestyle Considerations: Advise patients about potential dizziness/drowsiness and driving restrictions. Alcohol and smoking may exacerbate GI risks.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tolfenamic Acid?
A: For adults, 200 mg at the onset of a migraine, which may be repeated once after 1-2 hours if needed. For mild to moderate pain, 100-200 mg three times daily. Not established for children. Dose adjustments may be needed in elderly, renally impaired, or hepatically impaired patients.
Q2: What are the common side effects of Tolfenamic Acid?
A: Common side effects include gastrointestinal issues (nausea, vomiting, diarrhea, stomach pain), dizziness, headache, and dysuria.
Q3: Is Tolfenamic Acid safe during pregnancy?
A: Tolfenamic acid is contraindicated in the third trimester. It should only be used in the first and second trimesters if clearly necessary and the benefits outweigh the risks.
Q4: Can Tolfenamic Acid be taken with other NSAIDs?
A: Concomitant use of Tolfenamic acid with other NSAIDs, including aspirin, is generally not recommended due to the increased risk of gastrointestinal and bleeding complications.
Q5: How does Tolfenamic Acid interact with anticoagulants?
A: Tolfenamic acid can increase the risk of bleeding when taken with anticoagulants, such as warfarin. Close monitoring and dose adjustments may be necessary.
Q6: What are the contraindications to using Tolfenamic Acid?
A: Contraindications include hypersensitivity to NSAIDs, active gastrointestinal bleeding or ulceration, severe heart/liver/renal failure, and the third trimester of pregnancy.
Q7: What should I monitor in patients taking Tolfenamic Acid?
A: Monitor for signs of gastrointestinal bleeding (e.g., black stools, coffee-ground vomit), changes in renal or liver function tests, and blood pressure changes.
Q8: Can Tolfenamic Acid be used in children?
A: A pediatric dosing regimen has not been established, and use in children under 18 is generally not recommended.
Q9: What are signs of Tolfenamic Acid overdose?
A: Signs of overdose include headache, nausea, vomiting, gastrointestinal bleeding, drowsiness, dizziness, and occasionally convulsions. In severe cases, acute renal failure and liver damage can occur.
