Pharmacology 3: Protein Synthesis Inhibitors
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Questions and Answers

What is a common therapeutic application for aminoglycosides?

  • Fungal infections
  • Chronic pain management
  • Viral infections
  • Infective endocarditis (correct)

    • How do low extracellular pH and anaerobic conditions affect aminoglycoside transport?

  • They have no effect on transport
  • They enhance transport by increasing the gradient
  • They inhibit transport by reducing the gradient (correct)
  • They facilitate oral absorption of aminoglycosides

    • Which aminoglycoside is typically administered topically due to its nephrotoxicity?

  • Gentamicin
  • Neomycin (correct)
  • Amikacin
  • Tobramycin

    • What is the primary reason aminoglycosides need to be given parenterally?

    <p>They are poorly absorbed after oral administration</p> Signup and view all the answers

    What is a significant cause of resistance to aminoglycosides?

    <p>Enzyme modification and inactivation</p> Signup and view all the answers

    What is the nature of the effect of aminoglycosides on bacteria?

    <p>Bactericidal and irreversible</p> Signup and view all the answers

    What is the primary mechanism of action of aminoglycosides?

    <p>Interference with ribosomal function</p> Signup and view all the answers

    Once daily dosing of aminoglycosides offers what potential advantage?

    <p>Practical dosing benefits</p> Signup and view all the answers

    Which part of the ribosome do aminoglycosides bind to?

    <p>30S subunit</p> Signup and view all the answers

    How should aminoglycosides be dosed for patients with low distribution into fatty tissue?

    <p>Based on lean body mass</p> Signup and view all the answers

    Aminoglycosides exhibit a concentration-dependent effect. What is the target Cmax for effective treatment?

    <p>8X to 10X times the MIC</p> Signup and view all the answers

    For patients with creatinine clearance greater than 60 mL/min, what is the recommended dose of aminoglycosides such as gentamicin or tobramycin?

    <p>5–7 mg/kg</p> Signup and view all the answers

    Which of the following is NOT a common aminoglycoside?

    <p>Penicillin</p> Signup and view all the answers

    What is a notable side effect associated with the use of aminoglycosides?

    <p>Nephrotoxicity</p> Signup and view all the answers

    What is a characteristic feature of the dosing regimen for aminoglycosides?

    <p>A single large dose is commonly used</p> Signup and view all the answers

    What structural feature is common in aminoglycosides?

    <p>A central hexose nucleus with two amino sugars</p> Signup and view all the answers

    What is the primary mechanism of action of aminoglycosides?

    <p>Disruption of bacterial peptide elongation</p> Signup and view all the answers

    Which aminoglycoside is generally used against pathogens resistant to Gentamicin and Tobramycin?

    <p>Amikacin</p> Signup and view all the answers

    How does pH influence the effectiveness of aminoglycosides?

    <p>Acidic environments may decrease their antimicrobial effect</p> Signup and view all the answers

    Which of the following is a common use of Neomycin?

    <p>Topical and oral use only</p> Signup and view all the answers

    Which aminoglycoside is actively used against visceral leishmaniasis?

    <p>Paromomycin</p> Signup and view all the answers

    What is the primary concern associated with aminoglycosides in patients with renal dysfunction?

    <p>Accumulation of the drug in the body</p> Signup and view all the answers

    Which aminoglycoside is most likely to cause vestibular toxicity?

    <p>Streptomycin</p> Signup and view all the answers

    What is a recommended practice for ensuring safe dosing of aminoglycosides?

    <p>Therapeutic drug monitoring of plasma levels</p> Signup and view all the answers

    What adverse effect is particularly risky in patients receiving large doses of aminoglycosides rapidly infused?

    <p>Neuromuscular paralysis</p> Signup and view all the answers

    How can ototoxicity from aminoglycosides particularly affect vulnerable populations?

    <p>It is especially harmful to pregnant women and their developing fetuses</p> Signup and view all the answers

    Concurrent use of which class of drugs can increase the risk of nephrotoxicity when administered with aminoglycosides?

    <p>Loop diuretics</p> Signup and view all the answers

    What is a common allergic reaction to topically applied neomycin?

    <p>Contact dermatitis</p> Signup and view all the answers

    Which of the following is NOT a reason for therapeutic drug monitoring of aminoglycosides?

    <p>To confirm the presence of drug in the system</p> Signup and view all the answers

    Why are aminoglycosides contraindicated in myasthenia gravis disease?

    <p>They can worsen muscle weakness.</p> Signup and view all the answers

    What is the primary clinical use of aminoglycosides?

    <p>Treatment against gram-negative enteric bacteria.</p> Signup and view all the answers

    In what circumstances are aminoglycosides almost always used in combination with β-lactam antibiotics?

    <p>To extend empirical coverage and utilize synergism.</p> Signup and view all the answers

    Which of the following is a common application of aminoglycosides for treating mycobacterial infections?

    <p>Streptomycin and amikacin.</p> Signup and view all the answers

    Which condition is NOT typically treated with aminoglycosides?

    <p>Viral hepatitis.</p> Signup and view all the answers

    What is the relationship between spectinomycin and aminoglycosides?

    <p>Spectinomycin is structurally related but lacks amino sugars.</p> Signup and view all the answers

    Which of the following infections can be treated with Gentamicin and Doxycycline?

    <p>Drug-resistant gonorrhea.</p> Signup and view all the answers

    When would aminoglycosides typically be discontinued during treatment?

    <p>After pathogen identification and susceptibility is determined.</p> Signup and view all the answers

    Study Notes

    Pharmacology 3: Protein Synthesis Inhibitors (Part 2)

    • Aminoglycosides are used to treat serious infections caused by aerobic gram-negative bacteria.
    • Their utility is limited by serious toxicities.
    • Structurally, aminoglycosides consist of two amino sugars linked to a central hexose nucleus via a glycosidic bond.
    • They are derived from Streptomyces species (ending in "-mycin") or Micromonospora species (ending in "-micin").
    • Aminoglycoside structure includes a 1-hexose ring (streptodine in streptomycin) and a 2-hexose ring (deoxystreptamine in other aminoglycosides), with various amino sugars attached via glycosidic linkages.
    • Common aminoglycoside agents include Streptomycin, Neomycin, Kanamycin, Amikacin, Gentamicin, Tobramycin, Sisomicin, Netilmicin, and Plazomicin.
    • These drugs are bactericidal, inhibiting protein synthesis by interfering with ribosomal function.
    • Aminoglycosides diffuse through porin channels and are then transported across the cytoplasmic membrane.
    • Once inside the cell, they irreversibly bind to the 30S ribosomal subunit, interfering with ribosomal assembly, causing the 30S subunit to misread the genetic code.
    • Aminoglycosides inhibit protein synthesis in at least three ways: disrupting the initiation complex, misreading mRNA, and breaking polysomes into nonfunctional monosomes.
    • Aminoglycosides are unique because they demonstrate irreversible bactericidal properties, unlike other antibiotics which are typically bacteriostatic.
    • Bactericidal effect of aminoglycosides is concentration dependent and requires Cmax to be 8X to 10X times the MIC.
    • They also exhibit a post-antibiotic effect (PAE). PAE is the continued bacterial suppression even after drug levels fall below the minimum inhibitory concentration.
    • Single large doses are now more commonly utilized than divided daily doses.
    • Aminoglycosides are often combined with a β-lactam antibiotic for a synergistic effect, particularly in the treatment of infective endocarditis (e.g., Enterococcus faecalis, Enterococcus faecium).
    • Low extracellular pH and anaerobic conditions inhibit transport by reducing the gradient.
    • The transport of aminoglycosides may be enhanced by cell wall-active drugs like penicillin or vancomycin.
    • Aminoglycosides are primarily used against aerobic gram-negative bacteria, especially when the isolate is drug-resistant or sepsis is suspected.

    Mechanism of Action

    • Aminoglycosides are used in combination with β-lactams to enhance coverage against gram-positive pathogens and to take advantage of the synergistic effect.
    • Combination therapy using aminoglycosides is used in treating drug-resistant infections such as Mycobacterium tuberculosis infections and brucellosis caused by Brucella species, in combination with doxycycline in the case of brucellosis.
    • Other uses include Pseudomonas (Amikacin > tobramycin > gentamicin) and Klebsiella (amikacin = gentamicin > tobramycin) infections.
    • Aminoglycosides are used as empiric therapy when the pathogen is unknown or when broader spectrum therapy is desired.
    • Treatment with aminoglycosides is usually discontinued once the causative organism is known in favor of less toxic alternatives

    Clinical Uses

    • Aminoglycosides are most commonly used with empiric therapy in combination with other antibacterial drugs.
    • Once the organism and its susceptibility are determined, less toxic antibiotics are used to complete the treatment course.
    • Aminoglycosides are used in combination therapy as a first-line option for tularemia caused by Francisella tularensis and plague caused by Yersinia pestis.

    Resistance

    • Resistance to aminoglycosides can occur via efflux pumps, decreased uptake (via porins), and/or enzymatic modification/inactivation of the drugs.
    • The enzymes responsible for inactivation often have specificities for particular aminoglycosides, decreasing the risk of cross-resistance.

    Pharmacokinetics

    • Aminoglycosides are highly polar and do not absorb effectively via oral intake.
    • All aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum levels.
    • Neomycin is administered topically for skin infections or orally for bowel preparation before colorectal surgery.
    • Aminoglycosides after intramuscular injection, typically peak in the blood within 30-90 minutes.
    • Once-daily dosing with aminoglycosides is safe and effective if the creatinine clearance is greater than 60 mL/min.
    • Dosing of patients with creatinine clearance less than 60 mL/min is determined by a different method.

    Distribution

    • Aminoglycosides have similar pharmacokinetic (PK) properties.
    • Tissue concentrations can be subtherapeutic, and penetration into fluids varies.
    • Due to their low distribution into fat tissue, aminoglycosides are dosed based on lean body mass, not total body weight.
    • Cerebrospinal fluid (CSF) concentrations may be inadequate, even with inflamed meninges.
    • Intrathecal administration may be needed for CNS infections.
    • All aminoglycosides cross the placental barrier and can accumulate in fetal plasma and amniotic fluid.

    Elimination

    • Over 90% of parenteral aminoglycosides are excreted unchanged in the urine.
    • Accumulation in patients with renal dysfunction requires dose adjustments.
    • Traditionally, divided dosing of aminoglycoside therapy is common in patients with normal renal function, while single-dose administration may be preferred.

    Adverse Effects

    • Therapeutic drug monitoring of plasma levels for aminoglycosides (Gentamicin, Tobramycin, and Amikacin) is crucial to ensure adequate dosing and minimize dose-related toxicities.
    • Ototoxicity is a concern, often presenting as vestibular or auditory issues, and can manifest as deafness. Vertigo may also occur, especially with Streptomycin.
    • Nephrotoxicity can range from mild reversible renal impairment to severe acute tubular necrosis, particularly in the elderly and those with renal insufficiency.
    • Concurrent use with loop diuretics or other nephrotoxic antimicrobial agents potentiates nephrotoxicity and should be avoided. Neomycin, tobramycin, and gentamicin are the most nephrotoxic among commonly used agents.
    • Allergic reactions, such as contact dermatitis, can result from topical neomycin application.
    • Neuromuscular paralysis can be triggered by high doses infused rapidly or concurrent administration with neuromuscular blockers. This is a concern, especially for patients with myasthenia gravis, which may require prior administration of calcium gluconate or neostigmine (Ach-esterase Inh).
    • Aminoglycosides should be used with caution in persons with a history of myasthenia gravis, due to potential worsening of neuromuscular effects.

    Spectinomycin

    • Spectinomycin is an aminocyclitol antibiotic, structurally related to but different from the other aminoglycosides.
    • It lacks amino sugars and glycosidic bonds and lacks the specific ribosomal binding site of other aminoglycosides.
    • Spectinomycin is active in vitro against many Gram-positive and Gram-negative organisms, but is not used often due to better alternatives.
    • It is primarily used as an alternative in cases of drug-resistant gonorrhea or in penicillin-allergic patients.

    Summary of Aminoglycosides

    • Aminoglycosides bind to the 30S ribosomal subunit, disrupting bacterial peptide elongation and leading to bacterial death.
    • The microbial activity of aminoglycosides is pH-dependent, with acidic environments decreasing their antimicrobial effect.
    • Aminoglycosides are typically chosen when higher spectrum antibacterial cover is needed, combined with other drugs for synergy, with patients with drug allergies, or with suspected drug-resistant infections. They are commonly combined with another drug, to increase microbial coverage or synergistic effect.
    • They are chosen over alternatives once suspected organism and sensitivities are known.

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    Pharmacology 3: Protein Synthesis Inhibitors Part 2 PDF

    Description

    Explore the essential details of aminoglycosides, a class of antibiotics used to combat serious infections from aerobic gram-negative bacteria. This quiz will cover their structure, function, common agents, and toxicity issues, essential for understanding their role in pharmacology.

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