1. Chloramphenicol

2. CHLORAMPHENICOL
Chloramphenicol was initially obtained from streptomyces venezuelae in
Yellowish white crystalline solid.
Nitrobenzene substitution responsible for the antibacterial activity.
It is bacteriostatic but in high concentration exert cidal effect.

3. CHLORAMPHENICOL
Structure:

4. MECHANISM OF ACTION Inhibits bacterial protein synthesis
Interferring with 'transfer' of the elongating peptide chain to the newly attached aminoacyl-tRNA at the ribosome-mRNA complex.
It specifically attaches to the 50S ribosome
Hinder the access of aminoacyl-tRNA to the acceptor site for amino acid incorporation.
Probably by acting as a peptide analogue, it prevents formation of peptide bonds.
At high doses, it can inhibit mammalian mitochondrial protein synthesis as well.

5. Step 2 – transpeptidation Step 3 – tRNA leaves P site
Step 1 – AA binds to A
Step 2 – transpeptidation X
Protein synthesis
50S
30S P A
Step 3 – tRNA leaves P site
Step 4 – translocation

6. X X A Inhibits protein synthesis
Binds reversibly to 50S; Inhibits peptidyl transferase X
Protein synthesis X P A
30S
Inhibits transfer of elongating peptide chain to newly attached aminoacyl tRNA at A site

7. ANTIMICROBIAL SPECTRUM
Primarily bacteriostatic
At high concentrations exert cidal effect on some bacteria, e.g. H. influenzae.
Broad-spectrum antibiotic
Active against nearly the same range of organisms (gram-positive and negative bacteria, rickettsiae, mycoplasma) as tetracyclines.

8. Notable differences between these two are:
(a) Highly active against Salmonella including S. typhi,
(b) More active than tetracyclines against
H. Influenzae, B. pertussis, Klebsiella, N. Meningitis and anaerobes including Bact. fragilis.
(c) Less active against
Gram-positive cocci, spirochetes, certain enterobacteriaceae and chlamydia.
Entamoeba and Plasmodia are not inhibited.
Like tetracyclines, it is ineffective against Mycobacteria, Pseudomonas, many Proteus, viruses and fungi.

9. RESISTANCE
Due to acquisition of R plasmid encoded for an acetyl transferase an enzyme which inactivates chloramphenicol.
Acetyl-chloramphenicol does not bind to the bacterial ribosome.
Decreased permeability (chloramphenicol appears to enter bacterial cell both by passive as well as facilitated diffusion)
Lowered affinity of bacterial ribosome for chloramphenicol

10. PHARMACOKINETICS Rapidly and completely absorbed after oral ingestion.
50-60% bound to plasma proteins
Widely distributed.
Freely penetrate serous cavities and blood-brain barrier
Crosses placenta and is secreted in bile and milk.
Excreted unchanged in urine.
Plasma t1/2 is 3-5 hours in adults.

11. ADVERSE EFFECTS 1 . Bone marrow depression
Cause of aplastic anaemia (characterised by pancytopenia resulting from failure of the bone marrow) , agranulocytosis (severe reduction in granulocytes), thrombocytopenia or pancytopenia.
2. Hypersensitivity reactions
Rashes, fever, glossitis, angioedema are infrequent
3. Irritative effects
Nausea, vomiting, diarrhoea, pain on injection.
4. Superinfections
These are similar to tetracyclines, but less common.

12. 5. GRAY BABY SYNDROME
Occurred when high doses (-100 mg/kg) were given to neonates, especially premature.
It should be avoided in neonates, and even if given, dose should be – 25 mg/kg/day.

13. Why Gray baby syndrome occurs in neonates ?
Inability of neonate to metabolise & excrete chloramphenicol due to deficiency of glucuronosyl transferase
At higher concentration it inhibits electron transport in liver, heart, skeletal muscle

14. Gray baby syndrome Stops feeding Vomiting Hypotonic Hypothermic
Distended abdomen
Irregular respiration
Ashen gray cyanosis
Cardiovascular collapse
Death

15. Avoided by dose reduction
Gray baby syndrome
Avoided by dose reduction
< 50 mg/kg/day ( full term infants )
< 25 mg/kg/day ( pre term infants )

16. INTERACTIONS Chloramphenicol inhibits metabolism of
Tolbutamide, chlorpropamide, warfarin, cyclophosphamide and phenytoin.
Toxicity can occur if dose adjustments are not done.
Phenobarbitone, phenytoin, rifampin enhance chloramphenicol metabolism reduce its concentration failure of therapy may occur.
Being bacteriostatic, chloramphenicol can antagonize the cidal action of β-lactams/ aminoglycosides on certain bacteria.

17. PRECAUTIONS Because of serious bone marrow toxicity:
(a) Never use chloramphenicol for minor infections or those of undefined etiology.
(b) Do not use chloramphenicol for infections treatable by other safer antimicrobials.
(c) Avoid repeated courses.
(d) Regular blood counts may detect dose-related bone marrow toxicity.
(e) Combined formulation of chloramphenicol with any drug meant for internal use is banned in India.

18. USES 1. Enteric fever 2. Pyogenic meningitis 3. Anaerobic infections
4. Intraocular infections
5. As second choice drug
To tetracyclines
For brucellosis and rickettsial infections
Especially in young children and pregnant women in whom tetracyclines are contraindicated.
(b) To erythromycin
For whooping cough.
6. Urinary tract infections
7. Topically In conjunctivitis, external ear infection

19. THANK YOU -PHARMA STREET