Antibiotics act by inhibition of protein synthesis د. شذى هاني Ph.D. candidate (pharmacology )

A number of antibiotics exert their antimicrobial effects by targeting the bacterial ribosomes which has components that differ structurally from those of the mammalian cytoplasmic ribosomes.The mammalian mitochondrial ribosome,however,more closely resemble the bacterial ribosome.

Thus, although drugs that interact with bacterial site usually spare the host cells, high levels of drugs like tetracycline may cause toxic effects as a result of interaction with the mitochondrial ribosomes.

Tetracycline Tetracyclines are a group of closely related compounds that, as the name implies, consist of 4 fused rings with a system of conjugated double bonds.

Mechanism of action : Tetracycline enter microorganism.Once inside the cell, tetracyclin bind reversibly to the 30S subunit of the bacterial ribosome.This prevent addition of amino acids to the growing peptides,thus inhibiting bacterial protein synthesis.

Antimicrobial activity of tetracyclines: Tetracyclin is bacteriostatic, broad spectrum antibiotic for many Gr +ve &Gr –ve bacteria,including anaerobes,rickettsia,chlamydia, mycoplasma, and are active against some protozoa.eg. amoebas.

Classification of Tetracyclin : -short- acting: t 1/2 =6-8 hours includes: Chlortetracycline,tetracycline,oxy tetracycline -intermediate- acting t 1/2=12 hours they include : Demeclocycline, methacycline -long –acting : t 1/2=16-18 hours,they include: Doxycycline,minocycline

Tigecyline (approved in June,2005)the 1st member of anew subgroup of tetracycline named glycyclines,was introduced to treat infections which are resistant to conventional tetracyclines

Resistance : Three mechanisms of resistance have been described ; - ↓ intracellular accumulation due to either impaired influx or ↑ efflux by an active transport protein pump -ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome - enzymatic inactivation of tetracyclines

Pharmacokinetics of tetracycline: Oral &injectable preparation are available(IV.) Absorption: Absorption is impaired by food (except doxycycline &minocycline) by divalent cat ions (Ca+²,Mg+²,Fe+²)or Al+³;by diary product and antacids,this is because of the formation of non-absorbable chelates of tetracycline with calcium ions &with other divalent and trivalent cations.

distribution -it is concentrate in the liver,kidney spleen and bind to tissues undergoing calcification (as teeth, bones) -all enter the CSF but level are insufficient for therapeutic efficacy except for minocycline( that used in eradicating meningococcal carrier state) -tetracycline cross the placental barrier and concentrate in fetal bones and teeth.

Excretion They are metabolized in the liver by conjugation,most of tetracyclines are reabsorbed in the intestine and enter the glomerular filtrate except doxycycline that is excreted via bile into feces. That’s why it can be used in treating infection in renally compromised patients.

Clinical uses: -is the drug of 1st choice in infections with mycoplasma pneumonia, chlamydia, rickettsiae, vibrio cholera and some spirochetes. -chlamydial infections as trachoma,pelvic inflammatory diseases -mycoplasma pneumonia -rickettsial infection (Qfever and relapsing fever) -vibrio cholera -brucellosis(in combination with streptomycin or rifampicin)

-plague (in combination aminoglycosides) -treatment of acne vulgaris. -in combination regimens to treat gastric and duodenal ulcers Caused by Helicobacter pylori. -minocycline can eradicate meningeococcal carrier state

- demeclocycline inhibit the action of ADH in the renal tubules and has been used in the treatment of inappropriate secretion of ADH. -tetracycline sometimes employed in the treatment of protozoal infections e.g. entamoeba histolytica or plasmodium falciparum (malaria).

Side effects of tetracycline: 1- GIT :most common a-heartburn,nausea and vomiting due to gastric irritation are the most common reasons for discontinuing the medication b-modify the normal flora with overgrowth of clostridium difficile(pseudomembranous colitis). c-disorders of epithelial surfaces as sore throat,black hairy tongue,dysphagia.

2-superinfections:over growth of candida and resistant staphylococci. 3-effects on calcified tissues Due to deposition in the bones and teeth in growing children this causes discoloration and hypoplasia of the teeth and a temporary stunting of growth. That’s why tetracycline should be avoided in pregnant or lactating women and in children with developing teeth and growing bones(under 8 years of age).

4-Liver and pancreatic damage esp. in pregnant and patient with renal disease. 5-antianabolic effect because it act by inhibiting bacterial protein synthesis and same thing occur in man. 6-phototoxicity :sensitivity to light esp. with tetracycline and doxycycline.

7-vestibular problems :dizziness,nausea, vomiting esp. noted with minoycycline that conc. In the endolymph of the ear &affect function. 8-kidney toxicity 9-local tissue toxicity e.g. thrombosis with IV. Injection And painful local irritation in IM.injection.

Cholramphenicol: Mechanism of action: This drug bind to the bacterial 50S ribosomal subunit and inhibit protein synthesis at the peptidyl transferase reaction

Antimicrobial spectrum: It is primarily bacteriostatic but may be bacteriocidal against Haemophilus influenza,Nisseria meningitids and Streptococcus pneumoniae. It is active for both aerobic and anaerobic Gr+ve and Gr-ve also active against rickettsiae but not chlamydia.

Pharmacokinetic: -Oral &injectable preparation are available(IV, IM.) - Metabolism by conjugation with glucuronic acid in the liver(in neonate this process is slow → grey baby syndrome. -Excreted by glomerular filtration &in to bile or feces,so dose adjustment is needed in renal &hepatic failure. -good penetration to all tissues including CSF &brain

Clinical uses: 1-rickettsial infections. 2-brain abscess 3- initial treatment of bacterial meningitis plus benzylpencillin 4-salmonella infection (typhoid fever, salmonella septicemia) 5-topical (eye drops& ointment) for bacterial conjunctivitis.

Side effects : 1-GIT upset (mild) 2-optic and peripheral neuritis with prolonged use.

3- grey baby syndrome(as circulatory collapse in which the skin develop a cyanotic grey color due to high plasma conc. Of drug as a result of failure of the liver to conjugate and of the kidney to excrete the drug properly due to limited capacity of both glucorunidation &renal excretion. This condition → poor feeding, vomiting,flaccidity hypothermia shock,cardiovascular collapse,cyanosis(gray color &death. That’s why it should be used with caution in neonates &infants.

4-bonemarrow suppression or damage of either : -Dose dependent -Idiosyncratic 5-anemias(dose-related reduction of red cell production Aplastic anemia hemolytic anemia). Note: chloramphenicol inhibit hepatic microsomal enzymes that metabolize several drugs so t1/2 is prolonged &serum conc. Of drugs ↑.

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