KETODOL SOLUTION FOR INJECTION

Indications

• Management of moderate to severe pain
• Post-operative pain relief
• Short-term treatment of pain when oral therapy is not possible

Dosage

Adults: For adults, the initial dose is typically 10 mg

Mechanism of action

Ketorolac inhibits key pathways in prostaglandin synthesis which is crucial to its mechanism of action. It is a non-selective inhibitor of both COX-1 and COX-2 enzymes, with clinical efficacy primarily derived from its inhibition of COX-2. This enzyme converts arachidonic acid to prostaglandins, mediators of inflammation and pain. By blocking this pathway, ketorolac achieves analgesia and reduces inflammation.

Pharmacodynamics

As a non-selective NSAID, ketorolac acts by inhibiting COX-1 and COX-2 enzymes. COX-1 is constitutively active and present in various tissues, while COX-2 is inducible and primarily involved in inflammatory responses. While inhibition of COX-2 leads to the desired anti-inflammatory and analgesic effects, inhibition of COX-1 is associated with increased risks of gastrointestinal bleeding, ulceration, and other serious side effects. Therefore, ketorolac is recommended for short-term use only.

Pharmacokinetics

Ketorolac is well-absorbed following oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It has a volume of distribution of approximately 0.15 L/kg and is metabolized primarily in the liver via glucuronidation and hydroxylation. The elimination half-life is about 5 to 6 hours in healthy adults, and the drug is excreted mainly in urine, with about 90% of the dose recovered as metabolites.

Contra-indications

• Active or history of peptic ulcer disease
• History of gastrointestinal bleeding or perforation
• Severe renal impairment
• Hypersensitivity to ketorolac or other NSAIDs
• Concurrent use with other NSAIDs
• Labor and delivery
• Active bleeding conditions

Adverse effects

• Gastrointestinal bleeding
• Peptic ulcers
• Perforation of the gastrointestinal tract
• Renal impairment
• Cardiovascular events
• Headache
• Dizziness
• Nausea
• Abdominal pain

Interactions

• Anticoagulants (increased risk of bleeding)
• Other NSAIDs (increased risk of adverse effects)
• Lithium (reduced renal clearance)
• Methotrexate (increased toxicity)
• Diuretics (reduced effectiveness)

Precautions

• Use with caution in patients with a history of gastrointestinal disease
• Monitor renal function in long-term use
• Caution in the elderly due to increased risk of adverse effects
• Avoid in patients with a history of asthma or allergic reactions to NSAIDs

Pregnancy

Use is contraindicated during pregnancy, especially in the third trimester due to the risk of fetal harm and complications during delivery.

Breast-feeding

Caution is advised; ketorolac is excreted in breast milk and may affect the nursing infant.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• Tablets
• Injection solution

Indications

• Urinary tract infections
• Respiratory tract infections
• Gastrointestinal infections
• Bacterial pneumonia
• Otitis media

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines.

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Trimethamine inhibits the enzyme dihydrofolate reductase, which is crucial in the folate synthesis pathway. By blocking this enzyme, trimethamine effectively reduces the production of tetrahydrofolate, a form of folate necessary for the synthesis of nucleic acids and amino acids in bacteria. This inhibition leads to impaired bacterial growth and replication.

Pharmacodynamics

Trimethamine exhibits bactericidal activity, primarily against gram-positive and gram-negative bacteria. The drug is selective for bacterial dihydrofolate reductase, allowing for a wide therapeutic index. Its effect on folate metabolism leads to the disruption of DNA synthesis, essential for bacterial survival. The drug's effectiveness can be influenced by the presence of bacterial resistance mechanisms, which may include alterations in the target enzyme or increased efflux of the drug from bacterial cells.

Pharmacokinetics

Trimethamine is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It is widely distributed throughout body tissues, including the lungs, liver, and kidneys. The drug undergoes hepatic metabolism and is excreted primarily in the urine, both as unchanged drug and metabolites. The half-life of trimethamine is typically around 8 to 10 hours, but can be prolonged in patients with renal impairment.

Contra-indications

• Hypersensitivity to trimethoprim or any component of the formulation
• Severe renal impairment
• Pregnancy, particularly during the first trimester

Adverse effects

• Nausea
• Vomiting
• Rash
• Pruritus
• Anemia
• Hyperkalemia
• Elevated liver enzymes
• Renal impairment

Interactions

• May enhance the effects of anticoagulants, increasing the risk of bleeding
• Use with caution in patients receiving potassium-sparing diuretics due to the risk of hyperkalemia
• May reduce the efficacy of certain vaccines, including live bacterial vaccines

Precautions

• Monitor renal function, especially in patients with pre-existing renal disease
• Use cautiously in patients with a history of drug allergies
• Consider the risk of folate deficiency, particularly in long-term use

Pregnancy

Trimethoprim is contraindicated during the first trimester due to potential teratogenic effects. In later pregnancy, it should only be used if the potential benefit justifies the risk.

Breast-feeding

Trimethoprim is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place away from direct light. Keep out of reach of children.

Formulations

• Oral tablet
• Oral suspension
• Injection solution

Mechanism of action

Ketorolac inhibits key pathways in prostaglandin synthesis which is crucial to it's mechanism of action. Although ketorolac is non-selective and inhibits both COX-1 and COX-2 enzymes, it's clinical efficacy is derived from it's COX-2 inhibition. The COX-2 enzyme is inducible and is responsible for converting arachidonic acid to prostaglandins that mediate inflammation and pain. By blocking this pathway, ketorolac achieves analgesia and reduces inflammation. Ketorolac is administered as a racemic mixture; however, the "S" enantiomer is largely responsible for it's pharmacological activity.

Pharmacodynamics

Ketorolac is a non-selective NSAID and acts by inhibiting both COX-1 and COX-2 enzymes which are normally responsible for converting arachidonic acid to prostaglandins. The COX-1 enzyme is constitutively active and can be found in platelets, gastric mucosa, and vascular endothelium. On the other hand, the COX-2 enzyme is inducible and mediates inflammation, pain and fever. As a result, inhibition of the COX-1 enzyme is linked to an increased risk of bleeding and risk of gastric ulceration, while the desired anti-inflammatory and analgesic properties are linked to inhibition of the COX-2 enzyme. Therefore, despite it's effectiveness in pain management, ketorolac should not be used long-term since this increases the risk of serious adverse effects such as gastrointestinal bleeding, peptic ulcers, and perforations.