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Chemistry

Aminoglycosides

Understanding the chemical and physical properties of aminoglycosides like gentamicin is essential for comprehending their pharmacokinetic behavior, mechanism of action, and analytical methods used in therapeutic drug monitoring (TDM)

Chemical Properties of Aminoglycosides

  • Definition: Aminoglycosides are a class of antibiotics composed of amino-modified glycosides (sugars) linked by glycosidic bonds
  • Structure: Each aminoglycoside molecule consists of an aminocyclitol ring (usually 2-deoxystreptamine) connected to various amino sugars
  • Functional Groups: Multiple amino and hydroxyl groups, giving them strong basic properties
  • Molecular Weight: Typically ranges from 400 to 600 Da
  • Chemical Stability: Generally stable in aqueous solutions, but can be affected by pH and temperature

Physical Properties of Aminoglycosides

  • Appearance: White or off-white powders
  • Solubility: Highly water-soluble due to the presence of multiple polar amino and hydroxyl groups
  • Partition Coefficient (Log P): Low Log P values indicate poor lipid solubility
  • Ionization: Aminoglycosides are polycationic at physiological pH, meaning they have multiple positive charges
  • Hygroscopicity: Some aminoglycosides are hygroscopic, meaning they readily absorb moisture from the air

Specific Chemical and Physical Properties of Gentamicin

  • Structure: Gentamicin is a mixture of closely related aminoglycoside antibiotics, primarily gentamicin C1, C1a, and C2
  • Molecular Formula
    • Gentamicin C1: \(C_{21}H_{43}N_5O_7\)
    • Gentamicin C1a: \(C_{20}H_{41}N_5O_7\)
    • Gentamicin C2: \(C_{20}H_{41}N_5O_6\)
  • Molecular Weight: Approximately 477.60 g/mol for gentamicin C1
  • Appearance: White to off-white powder
  • Solubility: Highly soluble in water, slightly soluble in ethanol, and practically insoluble in chloroform and ether
  • pKa Values: Gentamicin has multiple pKa values due to the presence of several amino groups
  • Partition Coefficient (Log P): Low Log P value indicates poor lipid solubility

Pharmacokinetic Implications

  • Absorption: Poor oral absorption due to high polarity and charge
    • Primarily administered intravenously or intramuscularly
  • Distribution: Limited distribution into tissues and body fluids
    • Low volume of distribution (Vd)
    • Does not readily cross the blood-brain barrier
  • Protein Binding: Low protein binding (less than 30%)
    • Most of the drug exists in the free, active form in the plasma
  • Metabolism: Minimal metabolism
    • Primarily excreted unchanged in the urine
  • Excretion: Primarily eliminated by glomerular filtration in the kidneys
    • Renal impairment significantly affects drug clearance

Mechanism of Action and Structure-Activity Relationship (SAR)

  • Mechanism of Action: Aminoglycosides inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit
    • This binding interferes with mRNA translation and causes misreading of the genetic code
  • Structure-Activity Relationship (SAR)
    • The presence of multiple amino groups is crucial for binding to the negatively charged ribosomal RNA
    • The specific arrangement of amino sugars and the aminocyclitol ring determines the spectrum of activity and susceptibility to bacterial resistance mechanisms

Analytical Considerations in TDM

  • Analytical Methods
    • Immunoassays: Commonly used for routine TDM due to their ease of use and high throughput
    • Chromatography: HPLC with UV or fluorescence detection can be used to separate and quantify individual gentamicin components
    • Mass Spectrometry: LC-MS/MS provides high sensitivity and specificity for gentamicin quantification
  • Sample Preparation
    • Protein precipitation or solid-phase extraction (SPE) may be used to remove interfering substances from the sample
  • Calibration and Quality Control
    • Use appropriate calibrators and quality control materials to ensure accurate and reliable results
  • Interferences
    • Other antibiotics and drugs can interfere with aminoglycoside assays
    • Hemolysis and lipemia can also affect assay performance
    • Cross reactivity can occur between aminoglycosides within certain immunoassays

Clinical Significance in TDM

  • Therapeutic Drug Monitoring (TDM)
    • TDM is essential for optimizing aminoglycoside therapy and minimizing the risk of toxicity
    • Aminoglycosides have a narrow therapeutic index, meaning that the therapeutic and toxic concentrations are close together
    • TDM is used to monitor peak and trough concentrations:
      • Peak Concentrations: Reflect the maximum drug level in the body and are associated with efficacy
      • Trough Concentrations: Reflect the minimum drug level in the body and are associated with toxicity
  • Dosage Adjustments
    • Dosage adjustments are based on TDM results and patient-specific factors, such as renal function and infection severity
  • Monitoring for Toxicity
    • Assess renal function (serum creatinine, creatinine clearance)
    • Monitor for ototoxicity (hearing loss, tinnitus, vertigo)
  • Specific considerations
    • Aminoglycoside concentrations can be higher in patients with ascites
    • High doses can be more effective to treat infection, but must balance the risk of nephrotoxicity and ototoxicity

Key Terms

  • Aminoglycosides: A class of antibiotics composed of amino-modified glycosides
  • Gentamicin: An aminoglycoside antibiotic used to treat bacterial infections
  • Therapeutic Drug Monitoring (TDM): Measurement of drug concentrations to optimize therapy
  • Peak Concentration: The maximum drug level in the body after administration
  • Trough Concentration: The minimum drug level in the body before the next dose
  • Pharmacokinetics: The study of how the body affects a drug (ADME)
  • Mechanism of Action: The way in which a drug produces its therapeutic effect
  • Structure-Activity Relationship (SAR): The relationship between the chemical structure of a drug and its biological activity
  • Nephrotoxicity: Kidney damage
  • Ototoxicity: Hearing loss or vertigo
  • Hydrophilic: Having an affinity for water; water-loving
  • Hydrophobic: Lacking affinity for water; water-fearing
  • Therapeutic index: Ratio of a drug’s toxic level to the level that provides therapeutic benefits