Hepatitis chloramphenicol

Monitoring Monitoring serum levels is important because of the variability of chloramphenicol s pharmacokinetics. Monitor serum concentrations weekly monitor more often in patients with hepatic dysfunction, in therapy more than 2 weeks, or with potentially interacting drugs. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug-drug interactions. 

Age In newborn infants, the glomerular filtration rate and tubular transport is immature, which takes 5 to 7 months to mature. Also, the hepatic drug metabolism capacity is also inadequate (that is why chloramphenicol can produce grey baby syndrome ), and due to the higher permeability of blood brain barrier, certain drugs attain high concentration in the CNS. 

Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines. Active chloramphenicol (about 10% of the total dose administered) and its inactive degradation products (about 90% of the total) are eliminated in the urine. A small amount of active drug is excreted into bile and feces. The systemic dosage of chloramphenicol need not be altered in renal insufficiency, but it must be reduced markedly in hepatic failure. Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d. 

Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides. 

Chloramphenicol Prevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Use is rare in the developed world because of serious toxicities Oral, IV hepatic clearance (half-life 2.5 h) dosage is 50-100 mg/kg/d in four divided doses Toxicity Dose-related anemia, idiosyncratic aplastic anemia, gray baby syndrome... 

The ability of liver to biotransform chloramphenicol has been also demonstrated in several fish species. In pertinent studies, various metabolic pathways were determined and chloramphenicol-glucuronide, chloramphenicol-base, chloramphenicol-alcohol, and chloramphenicol-oxamate were the main metabolites observed (34, 35). Following hepatic biotransformation, a large proportion of the administered dose was excreted in the urine. 

Following oral or parenteral administration, thiamphenicol is well absorbed and rapidly and extensively distiibuted in the tissues of most animal species. Thiamphenicol is primarily excreted in the urine but small amounts are found in feces as well. It is excreted almost entirely in the unchanged form. Unlike chloramphenicol, thiamphenicol may not be an optimal substrate for the hepatic microsomal enzyme glucuronyl transferase. In rabbits and rats, more than 90% of the administered dose was excreted unchanged. However, a higher level of glucuronidation occurred in swine. 

Burke, J. T., W. A. Virgin, R. J. Sherertz, K. L. Sanders, M. R. Blum, and F. A. Sarubbi. 1982. Pharmacokinetics of intravenous chloramphenicol sodium succinate in adult patients with normal renal and hepatic function. J. Pharmacokin. Biopharrrl0 601-614. 

Incompatibilities of metoclopramide depend on drug concentration, pH, and temperature. It is incompatible with cephalosporins, chloramphenicol, sodium bicarbonate, doxorubicin, cisplatin, and cyclophosphamide. Caution should be exercised with simultaneous administration of metoclopramide with lithium, sym-pathomimetics, antidepressants, bromocriptine, and carbamazepine. Omperazole interacts with tolbutamide, clarithromycin, and phenytoin. Coadministration of rantidine and cisapride increases the plasma concentration of rantidine. Abuse of senna laxative has been reported and may cause hepatitis.176-178... 

Age Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to the toxic effects of chloramphenicol (see p. 320) and sulfonamides (see p. 289). Young children should not be treated with tetracyclines (see p. 311) which affect bone growth, or fluoroquinolones (see p. 323), which interfere with cartilage growth. 

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