Protein Synthesis Inhibitor Antibiotics

Protein Synthesis Inhibitor Antibiotics

     Antimicrobials Agents Affecting Bacterial Protein Synthesis
Antimicrobial agents affecting bacterial protein synthesis can be classified into the following classes:
 a/ Antimicrobials that bind to the 30s ribosomal subunit
>Aminoglycosides (bactericidal)
o Streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin and
neomycin (topical)

>Tetracyclines (bacteriostatic)
o Tetracycline, minocycline and doxycycline
o Spectinomycin (bacteriostatic)
•     Antimicrobials that bind to the 50s ribosomal subunit
o Chloramphenicol, lincomycin, clindamycin (bacteriostatic)
o Macrolides (bacteriostatic) - Erythromycin (also azithromycin, clarithromycin)
•      Antimicrobials that interfere with elongation factors
o Fusidic acid (bacteriostatic)
•      Inhibitors of RNA synthesis and function
o Rifampin, rifamycin, rifampicin (bactericidal)
• Inhibitors of DNA synthesis and function
o Quinolones - nalidixic acid, ciprofloxacin, oxolinic acid (bactericidal)
Choice of Suitable Medicines
•   Before selecting an antibacterial the clinician must first consider two factors related to the patient and those related to the causative organism.
•   Factors related to the patient which must be considered include:
o History of allergy
o Renal and hepatic function
o Susceptibility to infection (i.e. whether immunocompromised)
o Ability to tolerate drugs by mouth
o Severity of illness
o Age
o Whether taking other medication
o If female, whether pregnant, breast-feeding or taking an oral contraceptive.
o Duration of therapy, dosage, and route of administration depend on site, type and severity of infection and response.
•    Factors related to the causative organism include:

•    The receptor protein on the 30S ribosome may be deleted or altered as result of mutation

Pharmacokinetic Aspects of Amino Glycosides
•    Poorly absorbed from gastrointestinal tract (GIT)
•    Highly polar
•    All aminoglycosides (except neomycin) must be given parenterally to achieve adequate
serum levels
•    High concentration in renal cortex → nephrotoxicity
•    High concentration in endolymph & perilymph of inner ear → ototoxicity
•   Excreted rapidly by glomerular filtration
•    Distribution:
o Levels achieved in most tissues are low, and penetration into most body fluids is
variable
o Concentrations in cerebro-spinal fluid (CSF) are inadequate even when the meninges are inflamed
o All cross the placental barrier and may accumulate in foetal plasma and amniotic fluid

•   Tetracyclines are broad-spectrum antibiotics - bacteriostatic
•   The group includes tetracycline, oxytetracycline, doxycycline and minocycline.
Clinical Use/Indication of Tetracyclines
•    Broad-spectrum antibiotics
•    The spectrum of antimicrobial activity of the tetracyclines is very wide and includes
Gram-positive and Gram-negative bacteria
Mechanism of Action of Tetracyclines
•   Bacteriostatic
•   Inhibit protein synthesis by binding specifically to the 30S ribosome
•   Prevents the addition of amino acid to the growing peptide chain
Pharmacokinetic Aspects of Tetracyclines
•   All tetracyclines are adequately but incompletely absorbed from the GIT.
•   The percent of an oral dose that is absorbed (when the stomach is empty) is lowest for chlortetracycline (30%) and highest for minocycline (98-100%).
•     Most absorption takes place from the stomach and upper small intestine (greater in a fasting state).
•     Absorption of tetracycline is impaired by food in the stomach, milk products, and aluminium hydroxide - preparations. They should be taken at least half an hour before meal.
•   They have short half lives except doxycycline which can be administered once or twice daily (Tetracycline T ½ = 6hrs, Doxycycline T ½ = 16hrs and Minocycline 15hrs).

•     Doxycycline is virtually completely absorbed even with food.
•      Doxycycline does not accumulate in patients with renal failure so it can be of value in treatment of patient with impaired renal function

Drug Interactions
•   Anti acids, oral iron, divalent and trivalent cations (Mg2+, Ca2+, Al3+) and dairy products reduce the absorption of tetracyclines.
•   Barbiturates, carbamazepine and phenytoin reduce plasma concentration of doxycyclines.
•    Oral tetracyclines reduce the effect of combined oral contraceptives, but to a less extent.
Contraindication
•     It is contraindicated in renal failure, pregnancy and breast feeding women and children less than 12 years.
Dosage
•   The adult oral dose is 250mg increased in severe infection to 500mg every 6-8 hours.

Unwanted Effects
•    The most common unwanted effects are GIT disturbances caused initially by direct irritation and later by modification of the gut flora (e.g. nausea, vomiting and diarrhoea)
•      Because they chelate Ca2+, tetracyclines are deposited in growing bones and teeth, causing staining and sometimes dental hypoplasia and bone deformities. They should not
be given to children under 12 years, pregnant women or nursing mothers.
•    Another hazard to pregnant women is hepatotoxicity.
•   High doses of tetracyclines can decrease protein synthesis in host cells, an anti anabolic
effect that may result in renal damage.
•    Long-term therapy can cause disturbances of the bone marrow.
•    Headache and visual disturbances are signs of intracranial hypertension. Discontinue from using the medication if these occurs.

Other Tetracycline Formulations
•   Tetracycline and oxytetracycline are also available as creams/ointments for treatment bacterial skin infections.
•    Ointments for eye infections are also available but with different concentration as compared to those used for skin.

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