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Antibiotics: Inhibitors of Protein Synthesis


Notes on Tetracycline, Chloramphenicol, Aminoglycosides, Macrolides & Clindamycin


“Antimicrobial” is a general term that refers to a group of drugs that includes antibiotics, antifungals, antiprotozoals, and antivirals. An antibiotic is a drug used to treat infections caused by bacteria and other microorganisms. Originally, an antibiotic was a substance produced by one microorganism that selectively inhibits the growth of another.

Understanding  biosynthesis of proteins (translation process):

http://tube.medchrome.com/2010/10/biosynthesis-of-protein-translation.html

Different steps in protein synthesis are susceptible to inhibition by antibiotics of different groups.

Antimicrobials mechanism of action Antibiotics: Inhibitors of Protein Synthesis

TETRACYCLINES

Broad spectrum and Bacteriostatic Antimicrobial Agents (AMAs)

FeaturesTetracyclineOxytetracyclineDemelocyclineDoxycyclineMinocycline
PotencyLowIntermediateHigh
Intestinal absorptionModerateModerateComplete (no food interference)
Plasma half lifeRelatively lowHigher than tetracycline and oxytetracyclineHighest
Alteration of intestinal floraMarkedModerateLeast
DiarrheaHighIntermediateLow
PhototoxicityLowHighestHigh
Specific toxicityLess tooth decolorationMore phototoxic, diabetes insipidusLow renal and vestibula toxicities

Mechanism of Action (MOA):

Tetracycline – - binds – -> 30s ribisomes – -X – -> attachment of aminoacyl-t-RNA to mRNA-ribosome complex – - -> inhibition of peptide synthesis

Pharmacokinetics:

  1. Concentrated in liver, spleen, bone and teeth
  2. Secreted in milk
  3. Oral capsule: should be taken ½ hour before or 2 hours after the food

Adverse Effects:

  • Gastrointestinal upset : gastric pain, nausea, vomiting diarrhea due to
    • Direct mucosal irritant action of substance
    • Damage to natural gut flora (common A/E of broad spectrum antibiotics) and superinfection by pathogenic organisms including candida
  • Accumulation in teeth and bone (chelation of Calcium):
    • irreversible yellow-brownish discoloration of teeth
    • reversible suppression of bone growth
    • teratogenecity
  • Phototoxicity
  • Hepatic damage: fatty infiltration and jaundice
  • Renal damage: Renal failure, Fancony syndrome
  • Esophageal ulceration and thrombophlebitis
  • Vestibular toxicity: ataxia, vertigo and nystagmus
  • Hypersensitivity
  • Diabetes insipidus: with Demelocycline

Uses or Indications:

  • Empirical therapy in serious and mixed infections
  • 1st choice drugs in:
    • Veneral diseases: urethritis, granuloma inguinale
    • Atypical pneumonia due to Mycoplasma pneumonia
    • Cholera
    • Brucellosis
    • Plague: both bubonic and pneumonic plague
    • Relpasing fever
    • Rickettsial infections: typhus, Q fever
  • 2nd choice drugs in:
    • Tetanus, anthrax, actinomycosis, gonorrhea, syphilis, leptospirosis, pneumonia due to Chlamydia pneumonia, chancroid, tularemia
  • Others:
    • UTI
    • Amoebiasis
    • Falciparum malaria
    • Acne vulgaris
    • Chronic obstructive lung disease

Point to Remember:

Concurrent ingestion of antacids and milk would be inappropriate because tetracycline form insoluble complexes with plurivalent cations (eg. Ca2+, Mg2+, Al3+,etc.) resulting in their inactication. i.e. absorbability, antibacterial activity and local irritant action are abolished.

AMINOGLYCOSIDES

  • Bactericidal Antimicrobial Agents (AMA)
  • Spectrum: Mainly gram negative organisms
  • Mycins designates origin from Streptomyces species and Micin from Micromonospra species

Classification:

Systemic:

  1. Streptomycin
  2. Gentamycin
  3. Kanamycin
  4. Tobramycin
  5. Amikacin

Topical:

  1. Neomycin
  2. Framycetin

Mechanism of Action (MOA):

  1. Bind to several sites at 30S and 50S subunits as well as 30S-50S interface à Freeze initiation, interfere with polysome formation
  2. Induce binding of wrong t-RNA-AA complexes resulting in false proteins

Shared toxicity:

A. Ototoxicity (in part irreversible):

  1. Cochlear damage (Organ of corti): tinnitus and hearing loss
  2. Vestibular damage (hair cells) : headache, nausea, vomiting, dizziness, nystagmus, vertigo, ataxia

B. Nephrotoxicity (mostly reversible):

In the kidney, they enter the cells of the proximal tubules via an uptake system for oligopeptides. Tubular cells are susceptible to damage

  1. Loss of urinary concentrating power
  2. Decreased gfr, nitrogen retention, albuminuria
  3. Decreased clearance of antibiotic à increased blood levels à increased ototoxicity

C. Neuromusuclar blockade:

  1. Reduction in Acetylcholine (Ach) release from motor nerve endings
  2. Antagonizes Calcium
  3. Increases myasthenic weakness

Systemic Aminoglycosides:

Streptomycin vs Gentamycin:

FeaturesStreptomycinGentamycin
PotencyRelatively lessRelatively more
SpectrumNarrowBroader
NephrotoxicityLowest among aminoglycosidesRelatively more
Action against M.tuberculosis, S.Pyrogens, S. pneumoniaePresentAbsent
UsesTB, SABE (Subacute Bacterial Endocarditis), Plague, TularemiaRTI (Respiratory Tract Infection), gram negative meningitis, SABE, UTI, pneumonia, septicemia

Topical Aminoglycosides:

Neomycin

  • Wide-spectrum aminoglycosides
  • Pseudomonsa and Streptococcus pyogens are insensitive

Uses or Indications:
Topically:

  • infected wound
  • ulcers
  • burn
  • external ear infection
  • conjunctivitis

Orally:

  • Preparation of bowel before surgery
  • Hepatic coma

Adverse Effects (A/E):

  1. Rashes
  2. Malabsorption syndrome with diarrhea and steatorrhoea
  3. Superinfection by candida
  4. Nephrotoxicity and Ototoxicity
  5. Neuromuscular blockade à apnoea

CHLORAMPHENICOL

  • Broad spectrum and Bacteriostatic Antibiotic
  • Crosses placenta, Blood brain barrier and is secreted in bile and milk

Mechanism of Action (MOA):

  1. Attaches to 50S ribosome
  2. Inhibits peptide synthetase or peptidyl transferase (enzyme that links the AAs of two t-RNA-AA complexes)

Adverse Effects:

  1. Bone marrow depression: leading to aplastic anemia, agranulocytosis, thrombocytopenia
  2. Hypersensitivity
  3. Nausea, vomiting, diarrhea, pain on injection
  4. Superinfections :  < than tetracyclines
  5. Gray baby syndrome:
    1. Occurs due to inability of the newborn to adequately metabolize and excrete chloramphenicol
    2. Effects: Stop feeding, vomiting, hypotonia, hypothermia, irregular respiration, gray cyanosis, CV collapse, death

Uses or Indications:

  1. Typhoid
  2. Pyogenic meningitis
  3. Anaerobic infections
  4. Intraocular infections
  5. Brucellosis and reickettsial infection
  6. Whooping cough
  7. UTI

Point to Remember:

Chloramphenicol despite of crossing diffusion barriers readily, it is rarely indicated (e.g., in CNS infections) because of the danger of bone marrow supression. 2 types of bone marrow depression can occur:

  1. Dose-dependent, toxic, reversible form manifested during therapy
  2. Frequently fatal form that may occur after a latency of weeks and is not dose dependent.

MACROLIDES (Romycins)

Classification:

  1. Erythromycin
  2. Newer Macrolides:
    1. Roxithromycin
    2. Clarithromycin
    3. Azithromycin
    4. Sipramycin

Erythromycin:

Bacteriostatic (mainly directed towards gram positive organisms) but cidal at higher concentration

Mechanism of Action (MOA):

Combines with 50s ribosome and interferes with translocation process – - -> premature termination of peptide chain

Pharmacokinetics:

  1. Acid labile
  2. Incomplete absorption, food interference

Adverse Effects:

  1. Epigastric pain, diarrhea
  2. Reversible hearing impairment
  3. Hypersensitivity: Rashes, fever, hepatitis with cholestatic jaundice

Uses or Indications:

Alternative to penicillin (in case of penicillin allergy or resistance)

  • DPT
    • Diptheria
    • Whooping Cough (Pertusis)
    • Tetanus
  • STDs:
    • Syphilis
    • Chancroid
  • SABE
  • Rheumatic fever
  • Chlamyda trachomatis

Newer Macrolides: overcomes –

  1. Narrow spectrum
  2. Gastric intolerance, gastric lability
  3. Low oral bioavailability
  4. Poor tissue penetration
  5. Short plasma half life

e.g. Roxithromycin, Clarithromycin, Azithromycin

LINCOSAMIDES

Clindamycin is a semisynthetic derivative of Lincomycin.

Clindamycin:

  • Inhibits most gram positive cocci
  • Mechanism of action (MOA):  similar to that of erythromycin

Adverse effects:

  1. Rashes, urticaria, abdominal pain
  2. Diarrhea
  3. Pseudomembranous enterocolitis due to C.difficile superinfection

Uses or Indications:

  1. Bone and joint infection: due to anaerobic Streptococcus and Clostridium perfringes
  2. Prophylaxis of endocarditis in Penicillin allergic patients
  3. Toxoplasmosis and Pneumocystis Jiroveci

Birds eye view:

Antimicrobials Antibiotics: Inhibitors of Protein Synthesis

Tags: aminoglycoside, Antibiotics, antimicrobials, chloramphenicol, clindamycin, macrolides, Pharmacology, tetracycline


Last updated: June 5, 2013



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