AMINOGLUCOSIDOS, MECANISMO DE ACCIÓN, Efectos Adversos, Farmacocinética, INDICACIONES | PARTE 2

Mechanisms of Action and Toxicity of Aminoglycosides

Protein Synthesis and Membrane Function

• The discussion begins with the effects of aminoglycosides on protein synthesis, emphasizing that improper synthesis can lead to the production of dysfunctional proteins.

• These abnormal proteins are crucial for bacterial functions, such as transport and ATP production; their presence disrupts membrane integrity.

• Altered membrane permeability results in bactericidal effects, damaging bacteria through compromised structural integrity.

Dosing Strategies

• Effective treatment requires reaching a 25% concentration threshold for optimal antibacterial action; single doses are often recommended based on current studies.

• Repeated dosing may be beneficial but must be managed carefully to avoid adverse effects while maintaining therapeutic levels.

• Aminoglycosides exhibit a post-antibiotic effect, allowing continued efficacy even after drug concentrations drop below therapeutic levels.

Understanding Toxicity Mechanisms

• The nephrotoxic potential of aminoglycosides is linked to their accumulation in proximal tubular cells, leading to cellular dysfunction and apoptosis.

• Concentration in renal tubules can impair cell function due to inhibition of protein synthesis, exacerbated by concurrent use of other nephrotoxic drugs.

Renal Implications

• Nephrotoxicity varies among aminoglycosides; neomycin is particularly toxic when not used parenterally. Gentamicin remains a common choice despite its risks.

• Monitoring renal function is critical; clinicians should assess creatinine levels and drug concentrations in plasma during treatment.

Auditory and Vestibular Toxicity

• Aminoglycosides can affect cochlear and vestibular cells due to their positive charge, which facilitates cellular entry and potential atrophy.

• Both auditory and vestibular toxicities are generally reversible upon discontinuation of the drug unless prolonged exposure leads to irreversible damage over time.

Mechanism of Muscle Contraction and Pharmacology

Overview of Muscle Activation

• The process begins with the release of acetylcholine from the motor neuron, which is essential for muscle contraction by activating ion channels.

• Calcium ions enter the cell, crucial for muscle movement; calcium also facilitates vesicle movement in neurons, leading to increased acetylcholine release into the synaptic cleft.

Role of Acetylcholine

• Acetylcholine binds to sodium-dependent ligand channels, causing depolarization and subsequent muscle contraction as sodium enters the cell.

• Certain agents can block calcium entry into cells, competing with calcium due to their positive charge, which can inhibit acetylcholine release and disrupt muscle contraction.

Aminoglycosides: Usage and Mechanism

• Aminoglycosides are primarily used topically; they are not administered parenterally due to specific contraindications. They target gram-negative bacilli effectively.

• Key aminoglycosides include kanamycin, streptomycin, and neomycin; these are reserved for severe infections or when resistance is present.

Pharmacological Characteristics

• Aminoglycosides are second-line treatments for serious infections; they work synergistically with other antibiotics that inhibit cell wall synthesis.

• Commonly used aminoglycosides include gentamicin and amikacin; they have a post-antibiotic effect and require careful dosing based on infection severity.

Administration Guidelines

• Routes of administration vary: intramuscularly, intravenously (for severe cases), or topically. Dosing frequency typically ranges from every 6 hours to once daily depending on clinical context.

• The half-life of aminoglycosides is approximately 1.5 to 3 hours; distribution favors tissues like kidneys and ears but has limited penetration into cerebrospinal fluid unless meningitis is present.

Spectrum of Activity

• Aminoglycosides exhibit activity against various pathogens including E. coli and Staphylococcus aureus; understanding their spectrum helps guide effective treatment strategies.

Antibiotic Therapy Insights

Key Considerations in Antibiotic Treatment

• The discussion emphasizes the critical nature of treating patients with severe conditions such as sepsis, bacteremia, and febrile neutropenia. It highlights the importance of understanding which pathogens are involved, particularly focusing on gram-negative bacteria like E. coli and Pseudomonas.

• Complicated infections require careful consideration of antibiotic choices. Aminoglycosides are often used for resistant gram-negative bacilli, while beta-lactams must be administered based on their time-dependent efficacy.

• Beta-lactam antibiotics should be given every 8 to 12 hours depending on the specific drug (e.g., ceftriaxone). This timing is crucial to ensure effective treatment by allowing aminoglycosides to penetrate bacterial walls effectively.

• In cases of nosocomial pneumonia caused by gram-negative bacteria, a broad spectrum of coverage is necessary. Important pathogens include Staphylococcus aureus and various strains of E. coli.

• Meningitis treatment requires attention to specific pathogens like Pseudomonas or Acinetobacter. The discussion also mentions peritonitis related to dialysis as a significant concern in these patients.

Specific Antibiotics and Their Applications

• Gentamicin is highlighted as a first-line choice for certain infections; however, if resistance occurs, amikacin becomes the next option due to its broader antibacterial spectrum.

• Amikacin can treat tuberculosis and has high resistance levels against various bacteria. If both gentamicin and amikacin fail, streptomycin may be considered at higher doses.

• Neomycin is discussed primarily for topical applications in conjunctivitis or skin infections but also plays a role in surgical prophylaxis against intestinal flora contamination during surgeries.

Surgical Prophylaxis Strategies

• For surgical procedures involving the intestines, using oral kanamycin or paramycin helps clear intestinal flora before surgery to reduce infection risk post-operation.

• Proper preparation before manipulating the intestines significantly lowers the chances of postoperative complications such as sepsis from bacterial translocation.

Addressing Tuberculosis and Other Infections

• Streptomycin and kanamycin are noted for their effectiveness against tuberculosis; however, they have varying levels of activity compared to other treatments available.

• The conversation touches upon Francisella tularensis transmission via ticks and its implications for treating tularemia with appropriate antibiotics like streptomycin as first-line therapy.

Adverse Effects of Antibiotics

• Potential adverse effects associated with aminoglycosides include neuromuscular blockade when administered rapidly. Careful monitoring is essential during treatment administration to avoid complications.

• Chronic use can lead to peripheral neuritis or hypersensitivity reactions; thus, it’s vital that healthcare providers remain vigilant about these risks during long-term therapies such as those required for tuberculosis management.

Preparation for Surgery and Infection Control

Importance of Neomycin in Surgical Preparation

• Neomycin is highlighted as a crucial antibiotic for surgical patients, particularly effective against skin infections due to its coverage of both Gram-positive and Gram-negative bacteria.

• The discussion emphasizes the role of neomycin in preventing infections during surgery, especially in patients with hepatic encephalopathy.

Hepatic Encephalopathy and Bacterial Infections

• Patients with hepatic encephalopathy may develop connections between the portal vein and systemic circulation, allowing bacteria from the intestines to enter the bloodstream.

• Oral administration of antibiotics serves as a prophylactic measure to cleanse the intestines and prevent bacterial translocation.

Antibiotic Coverage for Gram-Negative Bacteria

Penicillins and Cephalosporins

• While penicillins can cover some Gram-negative bacteria, they are not first-line treatments; piperacillin is mentioned but not preferred.

• Third and fourth-generation cephalosporins are noted for their effectiveness against Gram-negative bacteria, including Pseudomonas aeruginosa.

Aminoglycosides Role

• Aminoglycosides provide good coverage for Gram-negative organisms and Pseudomonas but are considered second-line options.

• Streptomycin is mentioned as an aminoglycoside that covers resistant atypical bacilli but should be used cautiously.

Treatment Options for Gonorrhea

Addressing Resistant Strains

• For treating gonorrhea, when first-line therapies fail, alternatives like spectinomycin or neomycin may be utilized.

Anti-Pseudomonas Strategies

• The discussion concludes with a focus on anti-Pseudomonas medications, emphasizing the importance of beta-lactam inhibitors in treatment protocols.

Final Thoughts on Clinical Practice

Practical Insights

• The speaker humorously reflects on student life during clinical rotations while stressing the importance of understanding methodologies in research.