Chloramphenicol Flashcards
Be able to describe the mechanism of action of chloramphenicol.
a) Binds reversible to the 50S ribosomal subunit at a site that is near the site for erythromycin and clindamycin (competitive binding interactions occur among these drugs). It inhibits the peptidyl transferase activity of the ribosome and thus blocks peptide formation between the P and A site.
b) Inhibits peptide bond formation.
Be able to describe the therapeutic use of chloramphenicol.
a) Indicated for bacterial meningitis, typhoid fever, rickettsial infections, intraocular infections, and other serious infections where bacteriological evidence indicates it is an appropriate antibiotic.
Be able to describe the relationship between chloramphenicol sodium succinate and chloramphenicol.
a) Chloramphenicol sodium succinate is a prodrug for IV or IM administration that is hydrolyzed to chloramphenicol in the liver.
Be able to describe the metabolism of chloramphenicol sodium succinate.
a) Metabolized to its glucuronide in the liver. The glucuronide is pharmacologically inactive and is readily excreted by the kidneys. The reaction involves nucleophilic attack of the less hindered primary alcohol on UDPGA, catalyzed by glucuronyl transferase. Hydroxyl group is glucuronidated.
b) Also metabolized by reduction of the nitro group to an amino. The metabolite is less active than chloramphenicol.
Be able to describe the solubility characteristics and distribution of chloramphenicol.
a) The concentration achieved in brain and CSF is about 30-50% that of the plasma even when the meninges are not inflamed, and 89% when the meninges are inflamed.
Be able to describe the main bacterial resistance mechanisms to chloramphenicol.
a) Resistance to chloramphenicol results from 1) reduced membrane permeability 2) mutation of the 50S ribosomal subunit and 3) elaboration of chloramphenicol acetyltransferase, which acetylates one or both of the hydroxy groups to form metabolites that do not bind to the 50S ribosomal subunit.
Be able to describe the most serious potential toxicity of chloramphenicol, and how it limits the use of chloramphenicol.
a) Most serious toxicity of chloramphenicol is aplastic anemia. The effect usually becomes apparent weeks or months after chloramphenicol treatment has been stopped.
Be able to compare the risk of serious toxicity of chloramphenicol eye drops vs. oral chloramphenicol.
a) The highest risk is with oral chloramphenicol and the lowest risk occurs with eye drops.
Be able to describe how chloramphenicol toxicity can be minimized.
a) Blood levels should be monitored to keep chloramphenicol concentrations less than 25 ug/mL.
Be able to state whether or not chloramphenicol bone marrow suppression is a predictor of aplastic anemia.
a) Bone marrow suppression is due to impairment of mitochondrial function resulting from inhibition of protein synthesis. This effect is completely reversible once the drug is stopped and this does not predict future development of aplastic anemia.
b) One of the only ones that can inhibit protein synthesis in the mitochondria of the host.
Be able to describe the relationship between chloramphenicol bone marrow suppression and cumulative dose.
a) The effect occurs quite predictably once a cumulative dose of 20g has been given.
Be able to describe the relationship between chloramphenicol-induced childhood leukemia and length of treatment with chloramphenicol.
a) There is an increased risk of childhood leukemia, and the risk increases with length of treatment.
Be able to specify the risk of drug interactions with chloramphenicol and the mechanism involved.
a) Chloramphenicol inhibits cytochrome P450 so drug interactions can be expected with drugs that are metabolized by cytochrome P450.
Be able to describe the effect that inflammation of the meninges has on brain concentrations of chloramphenicol.
a) The concentration achieved in brain and CSF is about 30-50% that of the plasma even when the meninges are not inflamed, and 89% when the meninges are inflamed.
