kashdoc21
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chloramphenicol - according to kaplan notes says - inhibits only mitochondrial pr synth and not cytoplasmic syn
can someone explain pl...
pr synth takes place in cytoplasm / mitochondria?
inprokaryotes transcription and translation can occur simultaneously ... can not link it correctly
pl explain !!!
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| po
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Mechanism of Action
* Chloramphenicol inhibits protein synthesis in bacteria and, to a lesser extent, in eukaryotic cells. The drug readily penetrates bacterial cells, probably by facilitated diffusion.
* Chloramphenicol acts primarily by binding reversibly to the 50 S ribosomal subunit. Although binding of tRNA at the codon recognition site on the 30 S ribosomal subunit is thus undisturbed, the drug appears to prevent the binding of the amino-acid-containing end of the aminoacyl tRNA to the acceptor site on the 50 S ribosomal subunit. The interaction between peptidyltransferase and its amino acid substrate cannot occur, and peptide bond formation is inhibited
* Chloramphenicol also can inhibit mitochondrial protein synthesis in mammalian cells, perhaps because mitochondrial ribosomes resemble bacterial ribosomes (both are 70 S) more than they do the 80 S cytoplasmic ribosomes of mammalian cells.
* The peptidyltransferase of bovine mitochondrial ribosomes, but not cytoplasmic ribosomes, is susceptible to the inhibitory action of chloramphenicol. Mammalian erythropoietic cells seem to be particularly sensitive to the drug.
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| po
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Adverse effects
* Chloramphenicol inhibits the synthesis of proteins of the inner mitochondrial membrane that are synthesized in mitochondria, by inhibiting the ribosomal peptidyltransferase. These include subunits of cytochrome c oxidase, ubiquinone-cytochrome c reductase, and the proton-translocating ATPase. Much of the toxicity observed with this drug can be attributed to these effects
Adverse effects cont.
Hematologic Toxicity
* The most important adverse effect of chloramphenicol is on the bone marrow.
* Chloramphenicol affects the hematopoietic system in two ways:
o by an non-dose-related idiosyncratic response manifested by aplastic anemia, leading in many cases to fatal pancytopenia.
o by a dose-related toxic effect that presents as anemia, leukopenia, or thrombocytopenia, and
Hematologic Toxicity cont
aplastic anemia
* It seems to occur more commonly in individuals who undergo prolonged therapy and especially in those who are exposed to the drug on more than one occasion.
* A genetic predisposition is suggested by the occurrence of pancytopenia in identical twins. Although the incidence of the reaction is low-1 in approximately 30,000 or more courses of therapy-the fatality rate is high when bone-marrow aplasia is complete, and there is a higher risk of acute leukemia in those who recover
* The risk of aplastic anemia does not contraindicate the use of chloramphenicol in situations in which it is necessary; however, it emphasizes that the drug should never be employed in undefined situations or in diseases readily, safely, and effectively treatable with other antimicrobial agents.
Very
important
Reversible bone marrow suppression
* A second, and dose-related, toxic hematologic effect of chloramphenicol is a common and predictable (but reversible) erythroid suppression of the bone marrow.
* probably due to inhibitory action of the drug on mitochondrial protein synthesis.
* It occurs regularly when plasma concentrations are 25 mg/ml or higher and is observed with the use of large doses of chloramphenicol, prolonged treatment, or both.
Reversible bone marrow suppression
* The clinical picture is marked initially by reticulocytopenia, which occurs 5 to 7 days after the initiation of therapy, followed by a decrease in hemoglobin, an increase in plasma iron, cytoplasmic vacuolation of early erythroid forms and granulocyte precursors, and normoblastosis with a shift to early erythrocyte forms
Gray baby syndrome
* Fatal chloramphenicol toxicity may develop in neonates, especially premature babies, when they are exposed to excessive doses of the drug.
* The illness, the gray baby syndrome, usually begins 2 to 9 days after treatment is started.
* The manifestations in the first 24 hours are vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose, green stools. Soon they become flaccid, turn an ashen-gray color, and become hypothermic
Gray baby syndrome cont
* Two mechanisms are apparently responsible for chloramphenicol toxicity in neonates
* (1) failure of the drug to be conjugated with glucuronic acid, owing to inadequate activity of glucuronyl transferase in the liver, which is characteristic of the first 3 to 4 weeks of life; and (2) inadequate renal excretion of unconjugated drug in the newborn.
* both exchange transfusion and charcoal hemoperfusion have been used to treat overdose with chloramphenicol in infants.
Hypersensitivity Reactions
* Although relatively uncommon, macular or vesicular skin rashes occur as a result of hypersensitivity to chloramphenicol. Fever may appear simultaneously or be the sole manifestation.
* Angioedema is a rare complication. Jarisch-Herxheimer reactions have been observed shortly after institution of chloramphenicol therapy for syphilis, brucellosis, and typhoid fever.
Other adverse effects
* Nausea, vomiting, unpleasant taste, diarrhea, and perineal irritation may follow the oral administration of chloramphenicol. Among the rare toxic effects produced by this antibiotic are blurring of vision and digital paresthesias. Optic neuritis occurs in 3% to 5% of children
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| drbcshah
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Thanks for Question kashdoc and answer to po
Brilliant work
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