Inhibitors of Protein synthesis - Pharmacology Review of Lipincott, kadzung And Past Papers.

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Bacterial ribosome 70s (50s+30s) Mammalian ribosome 80s (60s+40s)

Tetracycline, pharmaPhila , pharmacology, lipincott review and kadzung Linezolid, clindamycin


Tetracyclines (Bacteriostatic /Bacteriocidal) 

Group of fused 4 rings 

MOA

enter into susceptible organisms by Passive diffusion & by an energy dependent mechanism to cell memb

bind reversibly to 3OS subunit of ribosome 

blocking access of acyl-tRNA into mRNA

ϴ protein synthesis Anti-bacterial synthesis= Gram +Ve Bacilli ( Bacillus anthracis), Gram –Ve  Rod(Brucella, Vibrio, Yersinia pestis) anaerobe,Spirochete, Mycoplasma, Chlamydia 

Resistance:

due to alteration in R factor, Mg dependent efflux, TetA protein, 

T.E:

 Doxycycline used in Cholera (Vibrio cholera), Lyme disease (Borrelia burgdoferi), Chlamydial infection (Chlamydia trachomatis, Chlamydia psittaci), Mycoplasma pneumonia, Tetracycline in Rocky Mountain spotted fever (Ricketssia rickettsii),

P.K

 form non-absorbable chelate with Ca in dairy products … bind to tissue undergo Calcification (teeth, bone, Gastric carcinoma)… only Minocycline enter CSF completely…

Doxycycline & Minocycline completely absorbed orally

S.E:

 Epigastric distress, Calcifiication & Hypoplasia of teeth, Fatal hepatotoxicity,Phototoxicity Pseudotumor cerebri (Benign intrarannial hypertension i.e blurred vision, headache, ) superinfection(overgrowth of Candida or Pseudomembranous colitis with C.difficile)

Minocycline conc. In Endolymph of ear

Contraindicated in Renal impair except Doxycycline, in Pregnancy, Lactation Child<8 …. In Azotemia (↑urea or Nitrogen containing compound in blood)

Glycylcycline (Bacteriostatic)

1. Tigecycline derivative of Minocycline….bind to 30S ...inhibit Translation

2. Treat Bacteremia… side effect same to tetracycline…ϴWarfarin met...Digoxin Cmax↑

Aminoglycoside (Bactericidal)

Mainstay for Gram –Ve Bacilli…Streptomyces derived suffix “Mycin”…Microspora derived suffix “Micin”…2 Amino sugar joined by Glycosidic linkage to central Hexose (Aminocyclitol)

MOA

  • enter into Susceptible organism by Porin Channel …
  • Oxygen –dependent mechanism… 
  • Bind to 30S ribosome…
  • Interfere with Assembly of Ribosomal Apparatus misread the Genetic code…
  • Polysome disaggregation.

Anti-baterial spectrum

1. Gram –Ve rod, Gram+Ve cocci, Anaerobic, Spirochete,

2. Mycoplasma, Chlamydia, others

T.E

 👉 Gentamicin in Tularemia (Francisella tularencis, through rabbit infection),

👉 Gentamicin/Streptomycin plus Vancomycin or Ampicillin used in Enterococci infection,

👉 Tobramycin alone or with Ticarcillin/Piperacillin used in P.aeroginosa infection

Resistance

 1)due to Acyltransferase, Nucleotidyltransferase, Phosphotransferase enzyme 

2)↓ uptake of drug when oxygen-dependent transport sys absent

P.K

  • parenterally administer…
  • effect conc. & times dependent… 
  • have post-antibiotic effect… 
  • administer in divided doses in Pregnancy, 
  • Neonatal infection, Bacterial Endocarditis every 8hr….
  • dose calculated based on Lean Body mass b/c drug not distribute into fat
  • Narrow-therapeutic index…
  • Peak & trough level measured..
  • Peak level with 30min-1hr
  • trough level obtained immediately before the next dose.

S.E

ototoxicity, Nephrotoxicity, Neuro-muscular paralysis (Pt. With Myasthenia gravis at risk), contact dermatitis

Macrolides (Bacteriostatic/Bactericidal)

Macrocyclic lactone with one or more Deoxy sugar...

Clarithromycin methylated forms of Erythromycin…..

Azithromycine have Larger Lactone ring…. Telithromycin Semi-synthetic derivative of rythromycin first Ketolide agent

MOA

 bind to 50S ribosome…

 ϴ translocation step... interfere with Transpeptidation

Anti-bacterial spectrum

 Aziithromycin more active in Respiratory infection due to H.influennza, Moraxella catarrhalis, Chlamydia trachomatis

have activity against M.avium-intracellular complex

Clarithromycin have activity against H.pylori > than Erythromycin

Resistance

due to Erythromycin esterase, 

↓affinity to 50S ribosome

P.K

 Erythromycin destroyed by Gastric acid, i.v administration cause Thrombophlebitis,enter into Prostatic fluid, accumulate into Macrophage….

Foods interfere with abs…

Azithromycin have longest Vd & t1/2….

S.E:

Epigatric distress & cholestatic jaundice by Erythromycin , Ototoxicity

Contraindicated in Hepatic dysfunction …

Telithromycin ↑ QT-interval & contraindicated in Myasthenia gravis

Chloramphhenicol (Bacteriostatic/ Bactericidal)

Bind to 50S ribosome...

ϴ protein synthesis at Peptidyl transferase reaction… 

also inhibit human ribosome at high dose produce Bone marrow toxicity

Resistance:

by R factor code for Acetyl Co-enzyme A transferase

S.E

Hemolytic Anemia in Pt. with ↓Glucose-6-phosphate, Aplastic Anemia independent of dose & occur when therapy ceased…

Gray-Baby syndrome: poor feeding, depressed breath, CVS collapse, Cyanosis

Clidamycin (Bactericidal)

Same to Erythromycin… 

used in treatment of B.fragilis…

C.diificile resistant & cause

Pseudomembranous colitis.

Quinupristin /Dalfopristin (Bactericidal)

Mixture of Streptogramins with 30-70 ratio….bind to 50S ..

long post-antibiotic effect

Resistance:

enzyme methylates 23S ribosome interfere Quinupristin binding….

Plasmid Acetyltransferase inactivate Dalfopristin

Antibacterial spectrum

active against VRE, E.faecium…E.faecalis resistant

S.E

venous irritation, Arthralgia, Myalgia, Hyperbilirubinemia.

Linezolid (Bacteriostatic)

ϴ 70S initiation complex… bind to  50S

Antibacterial spectrum=active agaist MRSA, VRE, E.faecium,

E.faecalis…bacteriostatic but bactericidal against Streptococci & C.perferingen….used in Bactermia by VRE 

S.E

Thrombocytopenia, neuropathy, optic neuritis, not in Pt. consume Tyramine food, precipitate Serotonin syndrome.

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