KETOROLAC

1. Drug Name

• Generic Name: Ketorolac

• Brand Names: Toradol, Acular (for ophthalmic use), and others.

2. Drug Classification

• Class: Non-Steroidal Anti-Inflammatory Drug (NSAID)

• Subclass: Pyrroziline carboxylic acid derivative

3. Mechanism of Action

Ketorolac is a potent NSAID that provides analgesia and anti-inflammatory effects by inhibiting the cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2.

• COX Inhibition: Ketorolac acts primarily through the inhibition of COX enzymes, blocking the conversion of arachidonic acid to prostaglandins. Prostaglandins are involved in promoting inflammation, pain, and fever. By inhibiting both COX-1 and COX-2, ketorolac reduces these processes.

• Pain Relief (Analgesic Effect): Ketorolac is particularly effective for moderate to severe pain and is commonly used as a short-term option for post-surgical pain due to its strong analgesic effects. Its analgesic activity is related to both peripheral and central mechanisms of prostaglandin inhibition.

• Anti-inflammatory Effect: The anti-inflammatory action is similar to other NSAIDs, where the inhibition of prostaglandins reduces the inflammatory response in conditions like arthritis.

• Antipyretic Effect: Ketorolac has minimal antipyretic effects compared to other NSAIDs, as it is primarily used for analgesia.

4. Pharmacokinetics

• Absorption: Ketorolac is rapidly absorbed following oral or parenteral administration. Bioavailability after oral administration is approximately 100%, and peak plasma concentrations occur within 30 minutes to 1 hour after oral administration. Intramuscular (IM) administration achieves higher peak plasma concentrations than oral doses.

• Distribution: The volume of distribution (Vd) of ketorolac is approximately 0.15 L/kg. It is highly protein-bound (approximately 99%), primarily to albumin, which affects its distribution in patients with low protein levels or liver dysfunction.

• Metabolism: Ketorolac is extensively metabolized in the liver through the cytochrome P450 enzyme system (particularly CYP2C9). The primary metabolites are inactive, and the drug undergoes phase I (hydroxylation) and phase II (conjugation) metabolic pathways.

• Excretion: The elimination half-life (t½) of ketorolac is approximately 5 to 9 hours after oral administration. The drug is excreted primarily in the urine (approximately 90%) as inactive metabolites, with a small fraction excreted unchanged. Ketorolac clearance is reduced in patients with renal impairment, requiring dose adjustments.

• Special Considerations: In patients with impaired renal function, the clearance of ketorolac is significantly reduced, which may increase the risk of toxicity. Lower doses or alternative treatments may be required.

5. Indications

• Primary Indications:

  • Short-term management of moderate to severe pain, typically following surgery (e.g., post-operative pain).

  • Pain management in musculoskeletal conditions such as strains and sprains.

  • Acute gouty arthritis (off-label use).

  • Post-renal colic pain.

• Off-Label Uses:

  • Ophthalmic use: Ketorolac ophthalmic solution is used to treat postoperative inflammation and to reduce swelling after cataract surgery.

  • Menstrual pain (dysmenorrhea): Ketorolac has been used off-label for dysmenorrhea in women.

• Specific Populations: Ketorolac is typically used in adults and requires careful monitoring when used in patients with compromised renal, hepatic, or cardiovascular health.

6. Dosage and Administration

• Adult Dosing:

  • Oral: 10 mg every 4 to 6 hours as needed. The maximum daily dose should not exceed 40 mg.

  • Intramuscular (IM): 30 mg every 6 hours as needed. Maximum dose is 120 mg/day.

  • Intravenous (IV): 30 mg every 6 hours as needed. Maximum dose is 120 mg/day.

  • Ophthalmic (Acular): 1 drop in the affected eye 4 times daily for up to 4 days post-surgery.

• Pediatric Dosing:

  • For children 2 years and older, the dose is based on body weight, typically 0.5 mg/kg every 6 hours, with a maximum dose of 5 mg/kg/day.

• Renal Impairment: Ketorolac is contraindicated in patients with severe renal dysfunction (e.g., creatinine clearance <30 mL/min). In patients with mild to moderate renal impairment, the dose should be reduced by half.

• Hepatic Impairment: Ketorolac should be used with caution in patients with liver disease due to its metabolism in the liver. Dose adjustments may be necessary based on the severity of hepatic dysfunction.

• Maximum Safe Dose: The maximum recommended daily dose is 40 mg for oral administration and 120 mg for IM/IV administration.

7. Contraindications

• Absolute Contraindications:

  • Active peptic ulcer disease or history of gastrointestinal bleeding.

  • Severe renal insufficiency (creatinine clearance <30 mL/min).

  • Hypersensitivity to ketorolac or other NSAIDs.

  • History of gastrointestinal bleeding or perforation related to previous NSAID therapy.

  • Pregnancy, especially in the third trimester (due to risk of premature closure of the ductus arteriosus in the fetus).

• Relative Contraindications:

  • Patients with cardiovascular disease or hypertension (due to potential for fluid retention and increased blood pressure).

  • Patients with a history of asthma, urticaria, or other allergic-type reactions to NSAIDs.

8. Warnings and Precautions

• Black Box Warnings:

  • Serious gastrointestinal (GI) bleeding, ulceration, and perforation risk, particularly in elderly patients or those with a history of GI issues.

  • Increased risk of cardiovascular thrombotic events, including myocardial infarction and stroke, particularly with long-term use or in patients with existing cardiovascular disease.

• Special Warnings:

  • Renal Function: Ketorolac can cause renal impairment, especially in patients with pre-existing kidney disease. Renal function should be monitored during therapy.

  • Hepatic Function: Liver function should be monitored, especially in patients with known hepatic disease, as ketorolac is metabolized by the liver.

  • Pregnancy: Ketorolac is contraindicated in the third trimester due to fetal risks (e.g., premature closure of the ductus arteriosus). It should be used with caution in the first and second trimesters, only if the potential benefit justifies the risk.

  • Lactation: Ketorolac is excreted in breast milk, and should only be used in breastfeeding women if the benefits outweigh the risks.

• Monitoring Parameters:

  • Monitor renal function (serum creatinine, urine output), especially in the elderly or those with renal disease.

  • Regular monitoring for signs of gastrointestinal bleeding, such as melena, hematemesis, or abdominal pain.

9. Adverse Effects

• Common Adverse Effects:

  • Nausea and dyspepsia

  • Abdominal pain

  • Headache

  • Dizziness

• Less Common but Clinically Significant Side Effects:

  • Gastrointestinal issues: Ulcers, gastrointestinal bleeding, perforation, and pancreatitis.

  • Renal impairment: Decreased renal function, fluid retention, and edema.

  • Cardiovascular effects: Hypertension, increased risk of myocardial infarction or stroke with prolonged use.

• Rare/Serious Adverse Reactions:

  • Anaphylaxis

  • Stevens-Johnson syndrome

  • Toxic epidermal necrolysis (TEN)

  • Severe renal failure

  • Gastrointestinal perforation or bleeding, which can be fatal

10. Drug Interactions

• Major Drug Interactions:

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

  • ACE inhibitors/ARBs: Reduced effectiveness of blood pressure medications and an increased risk of renal dysfunction.

  • Lithium: Ketorolac can increase lithium serum levels, potentially leading to lithium toxicity.

  • Diuretics (e.g., furosemide): Enhanced nephrotoxic effect when used with ketorolac.

• Food-Drug Interactions:

  • Ketorolac should be taken with food or milk to reduce the risk of gastrointestinal irritation.

• Lab Test Interactions:

  • Ketorolac may increase liver enzyme levels, and affect tests related to renal function (e.g., serum creatinine).

11. Clinical Pharmacology

Ketorolac's potent analgesic effects are due to its inhibition of COX enzymes, reducing prostaglandin synthesis. Unlike many NSAIDs, ketorolac is more commonly used in acute pain settings and for post-operative pain, where stronger pain relief is needed. Its side effect profile and potential for gastrointestinal and renal toxicity restrict its use to short-term management.

12. Special Populations

• Pregnancy: Category C (avoid in third trimester).

• Lactation: Excreted in breast milk; use with caution.

• Pediatrics: Dosage adjustments are based on weight and renal function; should be used cautiously.

• Elderly: Increased risk of gastrointestinal bleeding and renal impairment; lower doses may be necessary.

13. Therapeutic Uses

• First-Line Indications: Postoperative pain, acute pain (e.g., musculoskeletal injuries), and renal colic.

• Second-Line Indications: Short-term management of moderate to severe pain in non-surgical settings.

14. Monitoring and Follow-Up

• Regular monitoring of renal function and gastrointestinal symptoms is necessary during prolonged therapy. Blood pressure should also be monitored in patients with cardiovascular risk factors.

15. Overdose Management

• Symptoms of Overdose: Drowsiness, dizziness, headache, nausea, vomiting, gastrointestinal bleeding, and renal failure.

• Treatment Protocols: Activated charcoal may be used if ingestion is within 1 hour. Symptomatic treatment is provided, with IV fluids, renal function monitoring, and management of any bleeding.

16. Patient Counseling Information

• Patients should be advised to take ketorolac with food to reduce stomach upset and to avoid alcohol, which increases the risk of gastrointestinal bleeding.

• Inform patients of the potential for kidney and gastrointestinal side effects, especially with prolonged use.