MOXIGLAX-KT EYE/EAR DROPS

Indications

• Bacterial infections
• Complicated skin and soft-tissue infections
• Pelvic inflammatory disease
• Respiratory tract infections
• Intra-abdominal infections

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: 400 mg once daily for 7-21 days, depending on the specific infection being treated.

Mechanism of action

Moxifloxacin's bactericidal effect is primarily due to its inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. By interfering with these enzymes, moxifloxacin prevents the replication, transcription, and repair of bacterial DNA. This mechanism is crucial for bacterial cell division and survival.

Pharmacodynamics

As a quinolone antibiotic, moxifloxacin is effective against a range of bacteria including aerobic Gram-positive organisms such as _Staphylococcus aureus_ and _Streptococcus pneumoniae_, as well as Gram-negative organisms like _Haemophilus influenzae_. It is known for its high affinity for bacterial DNA gyrase, which is approximately 100 times greater than its affinity for mammalian enzymes, making it selectively toxic to bacteria.

Pharmacokinetics

Moxifloxacin exhibits good oral bioavailability and is widely distributed in body tissues, reaching peak plasma concentrations approximately 1 to 2 hours after administration. The drug is primarily metabolized in the liver and excreted via the urine. The half-life of moxifloxacin is approximately 12 hours, allowing for once-daily dosing.

Contra-indications

• Acute myocardial infarction (risk factor for QT interval prolongation)
• Bradycardia (risk factor for QT interval prolongation)
• Congenital long QT syndrome (risk factor for QT interval prolongation)
• Electrolyte disturbances (risk factor for QT interval prolongation)
• Heart failure with reduced left ventricular ejection fraction (risk factor for QT interval prolongation)
• History of symptomatic arrhythmias (risk factor for QT interval prolongation)

Adverse effects

• Increased risk of infection
• Akathisia
• Angina pectoris
• Colitis associated with antibiotics
• Asthma
• Dehydration
• Gastritis
• Hyperlipidaemia
• Malaise
• Oedema
• Pelvic pain
• Thrombocytosis
• Vasodilation

Precautions

• May impair performance of skilled tasks (e.g. driving)
• Use with caution in patients with a history of seizures or CNS disorders

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk.

Breast-feeding

Manufacturer advises avoid-present in milk in animal studies.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Tablets 400 mg
• Injection solution 400 mg/250 ml
• Nebuliser solution 100 mg/1 ml

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

• Metabolic acidosis
• Acute kidney injury
• Cardiac arrest
• Severe lactic acidosis

Dosage

Children: Refer to BNF for Children for appropriate dosing in paediatric patients.

Adults: Refer to BNF for specific dosing guidelines based on clinical condition and severity of acidosis.

Mechanism of action

Tromethamine functions as a proton acceptor, interacting with hydrogen ions and their associated acid anions. It combines with lactic, pyruvic, and other metabolic acids, as well as carbonic acid, facilitating their excretion in urine. At physiological pH, tromethamine exists in both ionized and un-ionized forms, with the latter capable of penetrating cell membranes to neutralize intracellular acids. By reducing hydrogen ion concentration, tromethamine alters the bicarbonate:carbonic acid buffer system, increasing bicarbonate levels while decreasing carbon dioxide tension, which may lead to hypoventilation.

Pharmacodynamics

As an alkalinizing agent, tromethamine increases bicarbonate concentrations in the blood, thereby helping to correct metabolic acidosis. Its ability to act as a weak osmotic diuretic contributes to increased urine output and the excretion of electrolytes. This dual action is beneficial in managing conditions characterized by acid-base imbalances.

Pharmacokinetics

After intravenous administration, tromethamine is rapidly distributed in the body. It is primarily excreted unchanged in the urine, with its alkalinizing effects lasting until the body's regulatory mechanisms restore acid-base balance. The pharmacokinetics are influenced by the ionization state of the drug, which varies with pH levels.

Adverse effects

• Hypoventilation
• Hypoxia
• Fluid and electrolyte imbalances
• Metabolic alkalosis
• Nausea
• Vomiting

Precautions

• Use with caution in patients with respiratory depression
• Monitor patients for signs of fluid overload
• Assess electrolyte levels regularly during treatment

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether tromethamine is excreted in human milk. Caution should be exercised when administering tromethamine to a nursing mother.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Injection solution

Mechanism of action

The bactericidal action of moxifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. The fluoroquinolone antibiotic moxifloxacin has been associated with the acquired long QT syndrome and is used as a positive control in the evaluation of the QT-interval prolonging potential of new drugs. In common with other QT-prolonging agents, moxifloxacin is known to inhibit the hERG potassium K+ channel, but at present there is little mechanistic information available on this action. This study was conducted in order to characterise the inhibition of hERG current (I(hERG)) by moxifloxacin, and to determine the role in drug binding of the S6 aromatic amino-acid residues Tyr652 and Phe656. hERG currents were studied using whole-cell patch clamp (at room temperature and at 35-37 degrees C) in an HEK293 cell line stably expressing hERG channels. Moxifloxacin reversibly inhibited currents in a dose-dependent manner. We investigated the effects of different voltage commands to elicit hERG currents on moxifloxacin potency. Using a 'step-ramp' protocol, the IC50 was 65 uM at room temperature and 29 microM at 35 degrees C. When a ventricular action potential waveform was used to elicit currents, the IC50 was 114 microM. Block of hERG by moxifloxacin was found to be voltage-dependent, occurred rapidly and was independent of stimulation frequency. Mutagenesis of the S6 helix residue Phe656 to Ala failed to eliminate or reduce the moxifloxacin-mediated block whereas mutation of Tyr652 to Ala reduced moxifloxacin block by approximately 66%. Our data demonstrate that moxifloxacin blocks the hERG channel with a preference for the activated channel state. The Tyr652 but not Phe656 S6 residue is involved in moxifloxacin block of hERG, concordant with an interaction in the channel inner cavity. The bactericidal action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication, transcription, repair, and recombination. It appears that the C8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of Gram-positive bacteria compared to the C8-H moiety. The presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, associated with the NorA or pmrA genes seen in certain Gram-positive bacteria. Torsade de pointes (TdP) is increasingly recognized as a complication of drug therapy. The most common cause of drug-induced QT prolongation is inhibition of the rapidly activating component of the delayed potassium current (I(Kr)). Moxifloxacin, a widely used fluoroquinolone, is a weak I(Kr) inhibitor and has been associated with QT prolongation. Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I(Kr), expressed by HERG (the human ether-a-go-go-related gene). According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice and it should be used with caution in patients with predisposing factors for Torsades de pointes (TdP).

Pharmacodynamics

Moxifloxacin is a quinolone/fluoroquinolone antibiotic. Moxifloxacin can be used to treat infections caused by the following bacteria: Aerobic Gram-positive microorganisms: _Corynebacterium_ species, _Micrococcus luteus_, _Staphylococcus aureus_, _Staphylococcus epidermidis_, _Staphylococcus haemolyticus_, _Staphylococcus hominis_, _Staphylococcus warneri_, _Streptococcus pneumoniae_, and _Streptococcus viridans_ group. Aerobic Gram-negative microorganisms: _Acinetobacter lwoffii_, _Haemophilus influenzae_, and _Haemophilus parainfluenzae_. Other microorganisms: _Chlamydia trachomatis_. Moxifloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Moxifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria.

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.

Mechanism of action

Tromethamine is an alkalinizing agent which acts as a proton (hydrogen ion) acceptor. Tromethamine is a weak base; following IV injection, it attracts and combines with hydrogen ions and their associated acid anions and the resulting salts are excreted in urine. Tromethamine can combine with lactic, pyruvic, and other metabolic acids and with carbonic acid. ... At pH 7.4, approximately 70% of the tromethamine present in plasma is in the ionized (protonated) form; if pH is decreased from pH 7.4, the ionized fraction of the drug is increased. In contrast to the ionized fraction of tromethamine, which upon administration reacts only with acid in the extracellular fluids, the fraction of the dose which remains un-ionized at physiologic pH is thought to be capable of penetrating the cell membrane to combine with intracellular acid. Since administration of tromethamine reduces hydrogen ion concentration, there is a decrease in proton donor and an increase in proton acceptor concentrations in body buffers. In the bicarbonate:carbonic acid buffer, the concentration of dissolved carbon dioxide is decreased (at least until regulatory mechanisms compensate) and the concentration of bicarbonate is increased. The reduction of carbon dioxide tension removes a potent stimulus to breathing and may result in hypoventilation and hypoxia. Tromethamine ... acts as a weak, osmotic diuretic, increasing the flow of alkaline urine containing increased amounts of electrolytes. By removing protons from hydronium ions, ionization of carbonic acid is shifted so as to decrease pCO2 and to increase bicarbonate. Excess bicarbonate is then gradually excreted in kidney. /Tromethamine is an/ especially useful way to manage excessively high pCO2 in respiratory acidosis...