Diclofenac

1. Drug Name

• Generic Name: Diclofenac

• Brand Names: Voltaren, Cataflam, Zipsor, Cambia, and Flector (topical patch)

2. Drug Classification

• Class: Nonsteroidal Anti-inflammatory Drug (NSAID)

• Subclass: Acetic acid derivative

3. Mechanism of Action

• Diclofenac works by inhibiting both COX-1 and COX-2 enzymes, with a slightly higher selectivity for COX-2.

• By blocking COX enzymes, it reduces the synthesis of prostaglandins, key mediators of inflammation, pain, and fever.

• The reduction of prostaglandin E2 and other inflammatory mediators results in decreased sensitivity of peripheral pain receptors and reduced inflammation.

• Diclofenac may also inhibit lipoxygenase pathways and reduce intracellular accumulation of arachidonic acid, contributing further to its anti-inflammatory effects.

4. Pharmacokinetics

• Absorption: Bioavailability varies with formulation; generally, oral bioavailability is about 50-60% due to significant first-pass metabolism. Peak plasma concentration is reached within 1-2 hours.

• Distribution: Volume of distribution (Vd) is around 0.12-0.17 L/kg, with high protein binding (99%) to albumin.

• Metabolism: Extensively metabolized in the liver, primarily through CYP2C9 and CYP3A4 pathways.

• Excretion: Half-life (t½) of about 1-2 hours in immediate-release forms; longer in extended-release forms. Primarily excreted in urine (65%) and feces (35%) as metabolites.

• Special Considerations: Elderly patients may have slower elimination, necessitating caution with dosing, especially in those with renal or hepatic impairment.

5. Indications

• Primary Indications:

  • Management of pain and inflammation in conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

  • Acute pain management in conditions like dysmenorrhea, musculoskeletal injuries, and postoperative pain.

• Off-Label Uses:

  • Migraine prophylaxis in acute cases (e.g., diclofenac powder for oral solution).

• Specific Populations:

  • Particularly useful in adults for inflammatory and degenerative joint diseases; not typically first-line for pediatric patients except under specific indications and careful monitoring.

6. Dosage and Administration

• Adults:

  • Osteoarthritis: 100-150 mg/day in divided doses.

  • Rheumatoid arthritis: 150-200 mg/day in divided doses.

  • Dysmenorrhea: 50 mg every 8 hours as needed.

• Pediatric: Not commonly recommended; however, for conditions requiring NSAIDs, dosing should be calculated based on weight, typically 1-3 mg/kg/day in divided doses.

• Route: Available in oral (tablets, capsules), topical (gels, patches), and parenteral (intramuscular) forms.

• Dosing Adjustments:

  • Renal and hepatic impairment: Use cautiously and with lower doses, as clearance may be reduced.

• Maximum Safe Dose: Generally limited to 150 mg/day for chronic use to minimize gastrointestinal and cardiovascular risks.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to diclofenac or other NSAIDs.

  • History of asthma, urticaria, or allergic reactions triggered by NSAIDs.

  • Active gastrointestinal bleeding or peptic ulcer disease.

  • Severe heart failure, renal failure, or hepatic failure.

• Relative Contraindications:

  • Caution in patients with cardiovascular disease, mild renal or hepatic dysfunction, or a history of GI bleeding.

8. Warnings and Precautions

• Black Box Warning:

  • Increased risk of cardiovascular thrombotic events, myocardial infarction, and stroke.

  • Increased risk of gastrointestinal bleeding, ulceration, and perforation.

• Special Warnings:

  • Pregnancy: Contraindicated in the third trimester due to the risk of premature closure of the ductus arteriosus.

  • Lactation: Generally not recommended due to limited data; alternate NSAIDs with a safer profile may be preferred.

• Monitoring Parameters:

  • Renal and liver function for patients on long-term therapy, especially in older adults.

  • Periodic CBC for patients with long-term therapy to monitor for GI bleeding.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Gastrointestinal discomfort, nausea, indigestion, diarrhea.

  • Headache, dizziness, and drowsiness.

• Less Common but Clinically Significant:

  • Hypertension, fluid retention, and edema.

  • Skin reactions, including rash and photosensitivity.

• Rare/Serious Adverse Reactions:

  • Anaphylactic reactions, angioedema.

  • Severe skin reactions (Stevens-Johnson Syndrome, toxic epidermal necrolysis).

  • Hepatotoxicity and acute renal failure, particularly with chronic use or in susceptible patients.

10. Drug Interactions

• Major Drug Interactions:

  • Anticoagulants (e.g., warfarin): Increased risk of bleeding.

  • Antihypertensives (e.g., ACE inhibitors, beta-blockers): May decrease antihypertensive efficacy.

  • Lithium and Methotrexate: Can increase serum concentrations and toxicity.

• Food-Drug Interactions:

  • Food delays absorption but may reduce gastrointestinal irritation.

• Interactions with Lab Tests:

  • May cause elevated liver enzyme tests and interfere with some renal function tests.

11. Clinical Pharmacology

• Diclofenac’s pharmacodynamics primarily involve its inhibition of COX enzymes, thereby reducing inflammation, pain, and fever.

• Diclofenac has greater selectivity for COX-2 compared to other NSAIDs, providing a balance between efficacy and reduced GI toxicity, although risks still exist at higher doses and with prolonged use.

12. Special Populations

• Pregnancy: Category C (1st and 2nd trimesters); Category D (3rd trimester). Avoid during the third trimester due to risks to fetal cardiovascular development.

• Lactation: Generally avoided due to limited safety data; safer NSAIDs are preferred during breastfeeding.

• Geriatrics: Increased risk of GI and renal side effects; lower doses are advised with close monitoring of kidney and liver function.

• Renal/Hepatic Dysfunction: Dose adjustments are necessary. Monitoring of renal and liver function is recommended in patients with compromised organ function.

13. Therapeutic Uses

• First-Line Therapy: Used for pain and inflammation in osteoarthritis, rheumatoid arthritis, and other inflammatory conditions.

• Second-Line or Adjunctive Therapy: Sometimes combined with other analgesics for enhanced pain relief, especially in severe cases such as postoperative pain or cancer-related pain.

14. Monitoring and Follow-Up

• Recommended Lab Tests: Baseline and periodic liver function tests, renal function tests for patients on long-term therapy.

• Patient-Reported Symptom Checklists: GI symptoms, signs of bleeding, and any unusual fatigue or jaundice (suggesting liver issues).

• Monitoring of Therapeutic and Toxic Levels: Regular clinical evaluation of symptoms and side effects.

15. Overdose Management

• Symptoms of Overdose: Nausea, vomiting, abdominal pain, drowsiness, headache, and in severe cases, metabolic acidosis, renal failure, or respiratory depression.

• Treatment Protocols:

  • Activated charcoal within 1-2 hours for recent ingestion.

  • IV fluids, acid-base balance correction, and symptomatic care.

  • There is no specific antidote; hemodialysis is ineffective due to high protein binding.

16. Patient Counseling Information

• Advise patients to take diclofenac with food or milk to reduce gastrointestinal irritation.

• Inform them of potential signs of serious side effects, like stomach pain, dark stools, or yellowing of the skin, which require immediate medical attention.

• Patients should avoid alcohol while taking diclofenac to reduce the risk of gastrointestinal bleeding.