Pharmacology PPT

1. Glycopeptide,Oxazolidinone,
Lipopeptides,Polypeptides
Dr. Chintan M Doshi

2. Glycopeptide
Vancomycin
 M/A-acts by inhibiting bacterial cell wall synthesis
• It binds to the terminal dipeptide “D-ala-D-ala”
sequence of peptidoglycan units
• Prevents its release from bactoprenol lipid carrier
• Assembly of the units at the cell membrane and their
cross linking to form cell wall do not take place

3. Contd.
 Mechanism of resistance
• Enterococcal resistance due to plasmid mediated
alteration of the dipeptide target site ,reducing its
affinity for vancomycin
• Staph. Aureus may express reduced or intermediate
susceptibility vancomycin due to abnormally thick wall
and false targets for vancomycin

4. Antimicrobial activity
Exclusively effective against aerobic and anaerobic gm
(+) species like
• Strepto and staphylococci(including
MRSA),enterococci,peptostreptococci,corynebacterium
diptheriae, listeria, C.tatany,C perfringens,bacillus
anthracis
• Gm(-) baciili –non responsive as –because of their
larger molecular size they unable to penetrate the
outer membrane

5. P/K
Absorption
• Poorly absorbed orally
• Given i.v
• i.m it causes muscle damage
Distribution
• PPB-30%
• Peak after 1 hr after i.v 1gm dose
• Appears in CSF and pleural,pericardial,synovial
ascitic fluids
Elimination
• 90% excreted through glomerular filtration
• T1/2-6 hrs

6. Uses and doses
• Orally 125-600 mg 6 hrly is the second choice
drug to metronidazole for antibiotic associated
pseudomembranous enterocolitis caused by
C.difficile
• Systemically 500mg 6 hrly or 1gm 12 hrly infused
i.v over 1 hr for serious MRSA infection
• And as a penicillin substitute for enterococcal
endocarditis with gentamycin

7. Untoward effects
Hyper sensitivity reactions
• Skin rashes,anaphylaxis,eosinophilia
On i.v injection
• Flushing,tachycardia,hypotension,chills, fever,
• The extreme flushing that can occur is sometimes
called "red-neck" or "red-man" syndrome.
• This is not an allergic reaction but a direct toxic
effect of vancomycin on mast cells, causing them
to release histamine.

9. Contd.
Auditory impairment
• Due to high concentration-permanent
Nephrotoxicity, formerly very problematic due to
the impurities in earlier formulations of
vancomycin
 less common with modern formulations at
standard dosages.

10. Teicoplanin
• Very similar to vancomycin in chemical
structure,mechanism of action,spectrum of
activity,route of elimination and uses

11. spectrum
• Active against gm(+) bacteria only
• More active against enterococci than vancomycin,equally
active against MRSA
• Some VRE but not VRSA are susceptible to teicoplanin
• Listeria monocytogenes, Corynebacterium spp.,
Clostridium spp., and anaerobic gram-positive cocci
inhibited

12. P/K
• i.m or i.v
• Largely excreted unchanged in urine
• T1/2-100 hrs
Untoward effects
• Less than vancomycin
• Rashes,granulocytopenia,fever occasionally
hearing loss
• Histamine release are rare

13. Use
• Entrococcal enocarditis
• MRSA
• Penicillin resistant streptococcal infection
• Osteomylitis
• As an alternative to vancomycin in surgical
prophylaxis

14. Linezolid
 Approved in 2000
 Spectrum
Oxazolidinone
VRSA,VRE,Penicillin resistant Strep.pyogens,
Strep.viridans, Strep.
Pneumoniae,Cornebacterium,Listeria, Clostridia,
Bact.fragilis, M.tuberculosis

15. Mechanism of action
 Linezolid inhibits protein synthesis:
 by binding to the 23S fraction of the 50S ribosome
preventing formation of ternary N- formylmethionine-
tRNA(fMet-tRNA)-70S ribosomal initiation complex
that initiates protein synthesis.
 Its unique binding site, located on 23S fraction of the
50S ribosome, results in no cross-resistance with other
drug classes.

16. Contd.
 Resistance is caused by mutation of the
linezolid binding site on 23S ribosomal RNA.
Pharmacokinetics
 100% bioavailability orally
 30% protein-bound
 Volume of distribution :0.6-0.7 L/kg
 t1/2: 4-6 hrs

17. USES
• Serious hospital acquired pneumonia
• Febrile neutropenia
• Wound infections and others cause by gram
+ve bacteria such as:
– VRSA
– VRE
– Resistant S. Pneumoniae
• Being bacteriostatic :not useful for
enterococcal endocarditis

18. Contd.
• Used for uncomplicated and complicated skin and soft
tissue infections,
• Community acquired pneumonias
• Bacteremias and other drug resistant gram positive
infections.
• XDR tuberculosis

19. Contd.
• Also approved in diabetic foot and pediatric patients
in 2005
• Dose:100 mg BD oral or i.v.

20. Adverse effects
• Hematological Toxicity
• Myelosuppression, including anemia, leucopenia,
pancytopenia, and thrombocytopenia
• Thrombocytopenia in 2.4% in patients receiving
courses of therapy lasting beyond 2 weeks
• Cause: drug binds to mitochondrial 70s ribosome

21. Contd.
 Other Toxic and Irritative Effects
• GI complaints, headache, rash
 Long-term (e.g., >8 weeks) treatment:
o peripheral neuropathy
o optic neuritis
o lactic acidosis

22. Interactions
• Reversible inhibitor of MAO-A and leads to
cheese reaction with food containing tyramine
• Precipitate “serotonin syndrome” if used with
SSRI
• Linezolid is neither a substrate nor an inhibitor of
CYPs.

23. Tedizolid
• Approved by the FDA on June 20, 2014
• Structural analogue of linezolid
• 4-6 time more active than linezolid for staphylococci
and enterococci infections
• Low thrombocytopenia rates
• Lower potential for monoamine oxidase interaction

24. Lipopeptides
Daptomycin
 is a novel cyclic lipopeptide fermentation
product of Streptomyces roseosporus
 It was discovered 3 decades (1980) ago at
for the treatment of infections caused by
Gram-positive bacteria.

25. Mechanism

26. Antibacterial activity.
• Bactericidal against all clinically relevant Gram-
positive bacteria including multiple-drug resistant
pathogens:
MRSA and vancomycin-resistant S. aureus (VRSA),
vancomycin-resistant strains of enterococci (VRE)

27. Phramacokinetics
• Poorly absorbed orally and should only be administered
intravenously
• Direct toxicity to muscle precludes intramuscular injection
• Protein binding is 92%.
• Serum half-life is 8 to 9 hours
• Approximately 80% of the administered dose is recovered in
urine; a small amount is excreted in feces.

28. Uses
• Complicated skin and soft-tissue infections.
• Pulmonary surfactant antagonizes daptomycin, and it
should not be used to treat pneumonia.
• Staphylococcus aureus bloodstream infections
(bacteremia)

29. Untoward Effects
• Damage to the musculoskeletal system
• In humans, elevations of creatine kinase may
occur
• Rhabdomyolysis has been reported to occur
rarely.

30. •Polypeptide
antibiotics

31. • Low molecular weight cationic polypeptide
antibiotics
• Powerful bactericidal agent
• Not used systematically because high chance
of toxicity
• All are produced by bacteria

32. Drugs
• Polymixin B
• Colistin
• Bacitracin

33. Polymixin B and colistin
• Active against gram -ve bacteria
• Proteus ,serratia and Neisseria are not
inhibited
• Colistin is more potent against pseudomonas,
salmonella and shigella

34. Mechanism of action
• Detergent like action on cell membrane
• High affinity for phospholipids
• Peptide molecule orient between phospholipid
and proteins
• Causes membrane distortion
• Amino acids and ions leak out

35. Adverse effects
• Orally: nausea, vomiting and diarrhea
Systemic:
• Flushing, paresthesias
• Kidney damage
• Neurological disturbances
• Neuromuscular blockade

36. Uses
Topically
• Skin infections
• Burns
• Otitis externa
• Conjunctivitis
• Corneal ulcer

37. Contd.
Orally:
• Gram-ve bacillary diarrheas mainly in infants
and children
• Pseudomonas superinfection enteritis

38. Bacitracin
• Active against gram+ ve bacteria
• Inhibit bacterial cell wall synthesis
• Bactericidal
 Uses:
 Topically: infected wounds, ulcers, eye infections
generally combination with neomycin and polymixin
B
 Not penetrate intact skin
 No value in boils, carbuncles and furunculosis

39. Contd.
Boil carbuncle

40. •Urinary antiseptics

41. • Some orally antimicrobials attain antibacterial
concentration only in urine with no systemic
antibacterial effect
• They are concentrated in kidney tubules and
useful in lower urinary tract infections
• This are called urinary antiseptics

42. Nitrofurantonin
• Primary bacteriostatic
• Bactericidal at higher concentration and in acidic
urine
• Gram –ve bacteria are susceptible
• M/o: bacteria enzymatically reduce
nitrofurantonin to generate reactive intermediates
which damages DNA

43. Contd.
Pharmacokinetics:
 Well absorbed orally
 T1/2:30-60 min
 Metabolized in liver
 Excreted unchanged in urine

44. Contd.
Adverse effect
 Nausea, epigastric pain, and diarrhoea
 Acute reaction: Fever, chills and leucopenia
 Hemolytic anemia with G6PD deficiency
 Peripheral neuritis on chronic use
 Liver damage and pulmonary fibrosis are rare
 Urine turns dark brown on exposure to air

45. Use
• Uncomplicated lower UTI not associated with
prostatitis
• Acute infection with E.coli: treated by 50-100mg
TDS for 5-10 days
• 100 mg bed time given prophylaxis of UTI
following catheterization and women with
recurrent cystitis

46. Methenamine
• Hexamethylene -tetramine
• Decompose slowly in acidic urine to release
formaldehyde which inhibits all bacteria
• Acidic urine is essential for its action
• Administered enteric coated tablets to
prevent gastritis
• Dose:1 g TDS with fluid restriction

47. Use
 Chronic resistant type of UTI
Adverse effect
 Gastritis due to release of formaldehyde in
stomach
 Chemical cystitis and hematuria on high doses
 CNS symptoms occasionally

48. Urinary analgesic
Phenylzopyridine
 Orange dye which exerts analgesic action in
urinary tract and afford symptomatic relief in
burning sensation, dysuria and urgency
 Not have antibacterial property
 Side effects: nausea and epigastric pain

49. THANK YOU