Why Mystinia Gravis Exhibits Greater Toxicity With Aminoglycosides

Aminoglycosides cause nephrotoxicity, and the relative toxicity of the various aminoglycosides can be correlated with the number of constituent amine groups that each contains; neomycin is the most nephrotoxic and streptomycin is the least. Although their polycationic structure prevents their entry into most cells, aminogly-cosides can diffuse from the tubular lumen across the apical membrane of proximal renal tubular cells following drug filtration through the glomerulus. Passage of the aminoglycosides across the apical membrane occurs via a saturable process of adsorption of polycationic aminoglycoside molecules to the proximal renal tubular lumen's anionic brush border and subsequent endocy-tosis and accumulation in lysosomes.

Once the drug is within the lysosomes, it will bind to anionic phospholipids, inhibiting lysosomal phospholi-pase A2. This leads to lysosomal distension, rupture, and release of acid hydrolases and the aminoglycoside into the cytosol. Free aminoglycoside then binds to other cellular organelles. Gentamicin accumulation in mitochondria displaces Ca++, leading to mitochondrial degeneration and cell necrosis. The necrotic cellular debris then sloughs off and is passed in the urine, leaving a denuded basement membrane. The development of toxicity depends upon the duration of aminoglycoside therapy and the mean trough blood plasma drug concentration. Nephrotoxicity is more likely in aminogly-coside-treated patients with gram-negative bacillary bacteremia than in those with staphylococcal bac-teremia. Nephrotoxicity is most common and most severe in patients with extrahepatic biliary obstruction, hepatitis, or cirrhosis.

The severity of aminoglycoside nephrotoxicity is additive with that of vancomycin, polymixin, gallium, furosemide, enflurane, cisplatin, and cephalosporins. Aminoglycoside nephrotoxicity is synergistic with that of amphotericin B and cyclosporine.

Even quite severe aminoglycoside-induced nephro-toxicity is nearly always reversible upon prompt discon tinuation of the drug. Verapamil and Ca++ can lessen the nephrotoxicity, but the latter may also inhibit the antibacterial effect of the aminoglycosides. Polyaspartic acid is a promising new agent that lessens aminoglyco-side nephrotoxicity, although it also may partially inhibit the drug's antibacterial activity.

Aminoglycosides accumulate in otolymph and can cause both vestibular and auditory ototoxicity, both of which can be irreversible. Uptake is driven by the concentration gradient between blood and the otolymph; this process is saturable. Sustained high concentrations in otolymph first destroy hair cells that are sensitive to high-frequency sounds. Streptomycin is more likely to cause vestibular toxicity than ototoxicity. The severity of aminoglycoside-induced ototoxicity is worsened by the coadministration of vancomycin, furosemide, bumetanide, and ethacrynic acid. Ca++ may lessen the ototoxic effect.

Aminoglycosides can cause neuromuscular junction blockade by displacing Ca++ from the neuromuscular junction, inhibiting the Ca++-dependent prejunctional release of acetylcholine and blocking postsynaptic acetylcholine receptor binding. This is usually clinically significant only in patients with myasthenia gravis, hypocalcemia, or hypermagnesemia or when the amino-glycoside is given shortly after the use of a neuromuscu-lar blocking agent. The neuromuscular blockade can be reversed by administration of intravenous calcium.

^ Study Questions

1. Many antibiotics appear to have as their mechanism of action the capacity to inhibit bacterial cell wall synthesis. This does NOT appear to be a mechanism of

(A) Aminoglycosides

(B) Penicillins

(C) Bacitracin

(D) Cephalosporins

2. Many antibiotics are not useful in treating infections in the central nervous system because they do not readily penetrate the blood-brain barrier. Which one of the following agents does get into the brain in reasonable concentrations?

(A) Penicillin G

(B) Ampicillin

(C) Cefotaxime

(D) Kanamycin

(E) Neomycin

3. Aminoglycoside antibiotics are frequently used in combination with the p-lactam antibiotics. Which of the following choices best explains the rationale for this use?

(A) The combination provides for a much greater spectrum of activity.

(B) A synergistic effect is often seen when the combination is employed.

(C) The p-lactam antibiotics prevent toxic effects of the aminoglycoside antibiotics.

(D) The combination decreases incidence of superinfections.

4. Patients with myasthenia gravis may exhibit greater toxicity to aminoglycosides than do patients without this condition. The most likely explanation is

(A) Aminoglycosides have muscarinic blocking properties.

(B) Aminoglycosides cause an increased metabolism of acetylcholine.

(C) Aminoglycosides cause a neuromuscular block by displacing Ca++ from the neuromuscular junction.

(D) Aminoglycosides inhibit second messenger activity at the neuromuscular junction.

5. As a class, the aminoglycoside antibiotics do not exhibit significant metabolism in the patient. The most likely reason is that

(A) Their chemical structure is unique and not prone to chemical reactions commonly seen in drug metabolism.

(B) The liver does not contain appropriate enzymes to break down the compounds.

(C) The body apparently lacks a necessary cofactor for the metabolism of aminoglycosides.

(D) Aminoglycosides do not readily get to the site of degradative enzymes.

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