Chloramphenicol

Protein synthesis inhibitor, chloramphenicol, and thiamphenicol

1. C hloramphenicol Jagir R. Patel Asst Professor Dept.: pharmacology

2. Introduction Chloramphenicol was initially obtained from Streptomyces Venezuela It was soon synthesized chemically and the commercial product now is all synthetic It has a nitrobenzene substitution, which is probably responsible for the antibacterial activity and its intensely bitter taste.

3. Anti bacterial spectrum Chloramphenicol is primarily bacteriostatic , though high concentrations Have been shown to exert cidal effect on some bacteria . Chloramphenicol was highly active against Salmonella including S. typhi , but resistant strains are now rampant . It is more active than tetracyclines against H. influenzne (though many have now developed resistance ), B. pertussis , Klebsiella, N.meningitidis and anaerobes including Bact. fragilis . It is less active against gram-positive cocci, spirochetes , certain Enterobacteriaceae and Chlamydia . Entamoeba and Plasmodia are not inhibited .

4. Mechanism

5. Mechanism of action

6. Mechanism of Resistance Resistance to chloramphenicol is caused by

7. P harmacokinetics Duration:   Typhoid: 8-10 days; meningitis: 7-10 days; brain abscess: Up to 4 wk. Absorption :  Readily absorbed with peak plasma concentrations after 1 or 2 hr (oral ). Distribution :  Distributed widely into tissues and fluids, CSF, eye, crosses the placenta and enters the breast milk. Protein-binding: 60 %. Metabolism :  Hydrolysed to the free drug in the GI tract (palmitate); liver by conjugation with glucuronic acid, lungs and kidneys after parenteral admin (sodium succinate ). Excretion :   Via the urine, via the bile (3%), via the faeces (1% as inactive form); 1.5-4 hr (elimination half-life).

8. Adverse effects Hypersensitive reactions : sin rashes, fever, and angioedema GIT : nausea, vomiting, diarrhoea Anemias: Patients may experience dose-related anemia, hemolytic anemia (seen in patients with glucose-6-phosphate dehydrogenase deficiency ), and aplastic anemia. [Note: Aplastic anemia is independent of dose and may occur after therapy has ceased.] Bone marrow suppression : T he most serious ADV of chloramphenicol, is on bone marrow, it occurs in two ways D ose dependent reversible suppression, which manifests anemia, leukopenia, and thrombocytopenia . Non dose related : which is fatal

9. Gray baby syndrome Gray baby syndrome  (also termed  Gray  or  Grey syndrome ) is a rare but serious side effect that occurs in newborn infants Pathophysiology Due to lack of The  UDP- glucuronyl transferase enzyme system of infants, especially premature infants, is immature and incapable of metabolizing the excessive drug load. Insufficient renal excretion of the unconjugated drug.

10. S ymptoms Loss of appetite Vomiting Ashen gray color of the skin Hypotension (low blood pressure) Cyanosis (blue discolouration of lips and skin) Hypothermia Cardiovascular collapse Abdominal distension Irregular respiration Increased blood lactate

11. Drug Interactions Paracetamol + chloramphenicol = enhances bioavailability of chloramphenicol by 28 % Chloramphenicol is potent enzyme inhibitor and inhibits metabolism of warfarin = increase risk of bleeding Morphine = respiratory depression Chorpropamide = increase hypoglycaemia Chloramphenicol + Penicillins can cause antibiotic antagonism .

12. Therapeutic uses Anaerobic infections : B.fragilis , in combination with metronidazole for treatment of brain, lungs, intra abdominal, or pelvic abscess Eye and ear infections B rucellosis Because of its toxic side effects , chloramphenicol is used only to suppress infections that cannot be treated effectively with other antibiotics. Such infections typically include (1) Typhoid fever (2) Meningococcal infections in cephalosporin-allergic patients (3) Serious H . influenzae infections, particularly in cephalosporin-allergic patients (4) Anaerobic infections (e.g., those originating in the pelvis or intestines) Anaerobic or mixed infections of the CNS (6) Rickettsial infections in pregnant patients, tetracycline-allergic patients, and renally impaired patients Oral : 50mg/kg, ear drops: 5% 2-3 drops, eye drops: 0.5% drops

13. Precautions & M onitoring effects Chloramphenicol can cause bone marrow suppression (dose-related) with resulting pancytopenia ; rarely, the drug leads to aplastic anemia (not related to dose). Hypersensitivity reaction s may include skin rash and, in extremely rare cases, angioedema or anaphylaxis . Chloramphenicol therapy may lead to gray baby syndr ome in neonates ( especially premature infants). This dangerous reaction, which stems partly from inadequate liver detoxification of the drug, is manifested by vomiting, gray cyanosis, rapid and irregular respirations , vasomotor collapse, and in some cases death.

14. Chloramphenicol formulations

15. T hiamphenicol Thiamphenicol  (also known as  thiophenicol  and  dextrosulphenidol ) is an antibiotic. It is the  methyl- sulfonyl  analogue of chloramphenicol and has a similar spectrum of activity, but is 2.5 to 5 times as potent . Pharmacokinetics Absorption:   Peak serum concentrations: 2 hr. Distribution:   Diffuses into the CSF, across the placenta, into breast milk and into the lungs. Protein binding: 10%. Half-life: 2-3 hr, increased in renal impairment. Metabolism :  Undergoes little or no conjugation with glucuronic acid in the liver. Excretion:   Excreted in the urine mainly as unchanged drug (70%); small amount excreted in bile and faeces.

16. Cont.… Interactions : Drugs that depress bone marrow function. Indications oral only 1.5gm daily divided dose Sexually transmitted diseases; Susceptible infections Gonorrhoea

17. Adverse effects of chloramphenicol Adverse effects of Chloramphenicol- BIG Super Hypersensitivity B- Bone marrow depression I- Irritative effects like nausea, vomiting, diarrhoea, pain on injection G- Gray baby syndrome Super - super infections Hypersensitivity reactions like rashes, fever, angioedema