M-GENTANALGIN SYRUP (Each ml contains Gentamycin/ Metamizole sodium 21mg/163mg)

Indications

• Severe infections caused by Gram-negative bacteria
• Urinary tract infections
• Bacteremia
• Sepsis
• Pneumonia
• Intra-abdominal infections
• Skin and soft tissue infections

Dosage

Adults: The usual dosage for adults is 3 to 5 mg/kg/day divided into 3 doses, given intravenously or intramuscularly. Adjustments should be made based on renal function and severity of infection.

Mechanism of action

Gentamicin acts by binding to the bacterial 30S ribosomal subunit, leading to misreading of mRNA and subsequent production of nonfunctional or toxic peptides. This disrupts protein synthesis and leads to bacterial cell death. The drug enters bacterial cells in a three-phase process: first, ionic binding occurs with the cell membrane, increasing permeability. Second, energy-dependent transport allows the drug to access its intracellular target. Third, concentration-dependent killing is observed as gentamicin accumulates within the cell, amplifying its effects on protein synthesis and membrane integrity.

Pharmacodynamics

Gentamicin exhibits concentration-dependent bactericidal activity, meaning that its efficacy increases with higher concentrations. The pharmacodynamic properties highlight the rapid and delayed bactericidal effects, with membrane disruption occurring immediately followed by impaired protein synthesis. The drug's action is particularly effective against aerobic Gram-negative bacteria, while its effectiveness is significantly reduced in anaerobic conditions.

Pharmacokinetics

Gentamicin is poorly absorbed from the gastrointestinal tract; thus, it is typically administered intravenously or intramuscularly. It has a volume of distribution that reflects extensive tissue penetration, particularly in renal and gastrointestinal tissues. The elimination half-life ranges from 2 to 3 hours in healthy individuals, but it can be prolonged in patients with renal impairment. The drug is primarily eliminated by renal excretion, with dosage adjustments required in cases of renal dysfunction.

Contra-indications

• Hypersensitivity to gentamicin or other aminoglycosides
• Severe renal impairment
• Myasthenia gravis

Adverse effects

• Nephrotoxicity
• Ototoxicity (hearing loss, balance disorders)
• Neuromuscular blockade
• Allergic reactions (rash, pruritus)
• Peripheral neuropathy

Interactions

• Increased risk of nephrotoxicity with other nephrotoxic agents (e.g., cisplatin, vancomycin)
• Increased risk of ototoxicity with loop diuretics (e.g., furosemide)
• Synergistic effects with beta-lactam antibiotics

Precautions

• Monitor renal function during treatment
• Use caution in patients with pre-existing hearing loss
• Adjust dosage in patients with renal impairment
• Consider potential drug interactions

Pregnancy

Gentamicin should be used during pregnancy only if clearly needed, due to potential risk of fetal harm.

Breast-feeding

Gentamicin is excreted in breast milk, but is generally considered safe. Monitor for possible effects on the infant.

Storage

Store in a cool, dry place, away from light. Do not refrigerate or freeze.

Formulations

• Injection (solution for injection)
• Topical ointment
• Eye drops

Indications

• Severe pain
• Fever
• Spasm-related pain

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations for paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations for adults based on the clinical context.

Mechanism of action

The mechanism of action of metamizole is not fully understood. Its active metabolites, 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA), inhibit prostaglandin E2 (PGE2)-induced hyperalgesia. The anti-hyperalgesic effect of MAA may be mediated by guanosine 3',5'-cyclic monophosphate (cGMP) activation and ATP-sensitive potassium channel opening, while AA is associated with the activation of cannabinoid receptor type 1 (CB1). Metamizole is suggested to inhibit cyclooxygenase (COX)-3 with higher affinity than COX-1 or COX-2.

Pharmacodynamics

Metamizole exhibits strong analgesic and antipyretic effects, accompanied by spasmolytic properties. Unlike traditional NSAIDs, it has weak anti-inflammatory or antithrombotic capabilities. A significant adverse effect associated with metamizole is agranulocytosis, a serious condition characterized by a dangerously low neutrophil count, attributed to the formation of drug-dependent anti-neutrophil antibodies.

Pharmacokinetics

Metamizole is rapidly absorbed and metabolized in the liver, yielding active metabolites. It has a relatively short half-life and is excreted primarily via the kidneys. The pharmacokinetics can vary based on individual patient factors, including age and renal function.

Contra-indications

• Hypersensitivity to metamizole or any of its components
• History of agranulocytosis related to metamizole or other pyrazolones
• Severe hepatic impairment
• Severe renal impairment
• Active gastrointestinal bleeding

Adverse effects

• Agranulocytosis
• Hypotension
• Allergic reactions including skin rashes
• Gastrointestinal disturbances
• Dizziness
• Nausea
• Vomiting

Interactions

• May enhance the effects of other analgesics and anticoagulants
• Potential interaction with other medications that affect hematopoiesis
• May decrease the effectiveness of certain antihypertensive agents

Precautions

• Monitor blood counts regularly due to the risk of agranulocytosis
• Use with caution in patients with history of hypersensitivity reactions
• Caution in patients with renal or hepatic impairment
• Ensure hydration to prevent renal complications

Pregnancy

Metamizole should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Consult healthcare professionals for advice.

Breast-feeding

Metamizole is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

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

Formulations

• Oral tablets
• Intravenous injection
• Oral suspension

Mechanism of action

There are 3 key phases of aminoglycoside entry into cells. The first “ionic binding phase” occurs when polycationic aminoglycosides bind electrostatically to negatively charged components of bacterial cell membranes including with lipopolysaccharides and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acids and phospholipids within the cell membrane of Gram-positive bacteria. This binding results in displacement of divalent cations and increased membrane permeability, allowing for aminoglycoside entry. The second “energy-dependent phase I” of aminoglycoside entry into the cytoplasm relies on the proton-motive force and allows a limited amount of aminoglycoside access to its primary intracellular target - the bacterial 30S ribosome. This ultimately results in the mistranslation of proteins and disruption of the cytoplasmic membrane. Finally, in the “energy-dependent phase II” stage, concentration-dependent bacterial killing is observed. Aminoglycoside rapidly accumulates in the cell due to the damaged cytoplasmic membrane, and protein mistranslation and synthesis inhibition is amplified. The necessity of oxygen-dependent active transport explains why aminoglycosides are ineffective against anaerobic bacteria. Hence, aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modeling support this two-mechanism model. Inhibition of protein synthesis is a key component of aminoglycoside efficacy. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects including inhibition of translation, initiation, elongation, and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation. Mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above. Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/ ... Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. ... /Aminoglycosides/

Mechanism of action

The mechanism of action of metamizole is not fully understood. Its active metabolites, 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA), inhibit prostaglandin E2 (PGE₂)-induced hyperalgesia. It has been suggested that the anti-hyperalgesic effect of MAA is mediated by guanosine 3',5'-cyclic monophosphate (cGMP) activation and ATP-sensitive potassium channel opening, while the effects of AA are associated with the activation of cannabinoid receptor type 1 (CB1). Metamizole is classified in some sources as a weak non-steroidal anti-inflammatory drug (NSAID); however, evidence suggests that its analgesic effects do not depend on its anti-inflammatory properties. Although the inhibition of cyclooxygenase (COX) 2 may play a role in the central nervous system effects of metamizole, reports suggest that metamizole inhibits COX-3 with a higher affinity compared to COX-1 or COX-2.

Pharmacodynamics

Metamizole is a strong analgesic and antipyretic with spasmolytic properties. It has weak anti-inflammatory or antithrombotic properties and does not follow the same mechanism of action as conventional non-steroidal anti-inflammatory drugs (NSAIDs). Metamizole can lead to agranulocytosis, a life-threatening side effect where a patient’s neutrophil count falls below 500 cells per microliter. It has been shown that metamizole-induced agranulocytosis is caused by the development of drug-dependent anti-neutrophil antibodies requiring covalent binding of neutrophils to metamizole and its metabolites.