Protein Synthesis Inhibitors

Protein Synthesis Inhibitors

Aminoglycosides Tetracyclines Cloramphinicol Erythromycin Spectinomycin Clindamycin Fusidic acid

Aminoglycosides
MOA Bacteicidal Bind to 30S subunit of the ribosomes Inhibiting the intiation complex of peptide formation incorrect AA sequence into peptide chain resulting in non functional or toxic protein which is fatal to the bacteria

Phrmacokinetics
Water soluble, do not easily cross cell membranes Poorly absorbed from GIT IV,IM Distrbuted to ECF mainly Poor transfer to CSF ,even in inflammed meninges Eliminated unchanged in the urine ,mainly by GF, may acumulate at renal cortex, dose reduction in renal impairment TDM is indicated for good therapeutic control

Antibacterial spectrum
AG are active against: * Aerobic mos * Gram ve bacilli : P.aerogenosa, V.chotera PEcK ** Streptomycin is used in TB, plague and Taularemia

 1. Gram ve bacillary infections specially septicemia and pelvic abdominal sepsis Caused by PEcK &P.aeroginosa Gentamicin + Beta lactam and or metronidazole 2. Bacterial endocarditis: Gentamicin+ benzyl penicillin Strept.& enterococci and Gentamicin + cloxacillin Staph 3. Other infections as TB, tularemia, plague and brucellosis-Streptomycin 4. Topical use Neomycin, too toxic for systemic use, as eye& ear drops or orally to sterelize bowel

Therapeutic Uses

Side Effects of AG
1.Ototoxicity on VIII, auditory & vestibular, tinitus is a warning sign+ headache, diziness and nausea. Irreversible and even with topical use. 2. Nephrotoxicity, dose related, reversible. Hypotension, loop diuretics and old age are risk factors 3. Neurotoxicity, in high doses, curare like effect. 4. Others : skin rash, drug fever, eosinophilia, BM depression and hemolysis

Spectinomycin
Structurally related to AGs Given IM as alternative to penicillin in allergic pts for treatment of gonorrhea As a single dose S/Es pain at site of injection, fever ,nausea and rare nephrotoxicity

Tetracyclines
Broad spectrum antibiotics Bacteriostatic MOA: They enter into the susceptible mos passively and actively through bacterial cell memb. Then they interfere with ptn synthesis by binding with bacterial ribosomes 30 S subunits Resistance is due to: *Decrease activity of transport system *Active extrusion of tetracyclines out of the bacterial cells.

Pharmacokinetics
Partially absorbed from GIT. Unabsorbed amount may change bacterial flora pseudomembranous colitis Dairy products,antiacids and iron reduce absorption by chelation(?) Distributed through the body and can cross the placenta, CSF(minocycline) Most TCs are reabsorbed from the bile, metabolized to glucuronides and excreted in urine

Therapeutic uses
Effective against nearly all gram +ve & -ve bacteria DOC in: 1. Chlamydia infection-psticosis,trachoma and lymph granuloma venerium 2. Mycoplasma pneumonia 3. Rickettsia (Q fever and typus) 4. V.Cholera and brucella 5. Borrelia (relapsing fever) 6. Acne, for monthes 7. Anerobs (chlosterdia), and democycline in: 8. TT of hyponatremia due to inapropriate secretion of ADH

Adverse Effects
1. Gastric irritationnoncomplience ,reduced by food other than dairy products 2. Diarrhea- change in bacterial flora 3. Superinfections 4. Effects on calcified tissues: deposition in bone and teeth in growing children, leading to discoloration and hypoplasia of teeth and stunting of growth. Avoid TCs from pregnancy12Ys. 5. Staining of nails at any age

Adverse Effects (cont.)

6. Fatal hepatotoxicity high doses,pregnat woman with pyelonephritis 7. Photosesitivity 8. Vestibular effects minocycline, endolymph dizziness, N&V 9. Renal toxicity, renal tubular acidosis and elevated blood urea out dated TCs

Photosensitivity

Cloramphenicol
Bacteriostatic, may be cidal in H.influenza, N.meningitidis and bacteriods. MOA: Interferes with ptn synthesis by the ribosomes through binding to 50S subunit. Antibacterial spectrum: Broad spectrum antibiotic, affecting bacteria and rickettsiae P.aerogenosa and Chlamydiae are not affected. It has exelent activity against anaerobs.

Resistance & Pharmacokinetics

Resistance is due to: Enzymatic inactivation of the drug or inability of the drug to penetrate the organism. Pharmacokinetics: Oral, IM& IV, widely distributed, passes to the CSF. Metabolized by conjugation with glucuronic acid in the liver , it is microsomal enz. Inhibitor Excreted by kidneys, it is also secreted by Breast milk Drug interactions (?)

Therapeutic Uses
Bacterial meningitis + benzyl penicillin Brain abscess + penicillin Typhoid , paratyphoid and salmonella septicemia. Ciprofluxcin is preferred. Ocular infection (topical and systemic)

Adverse Effects
Chloramphenicol use is limited for life threatening infections. (?) serious AEs 1. GITupset 2. Optic and peripheral neuritis ch. Use 3. Rare but serious BM damage of 2 types: a. Dose dependent,reversible,earlyin TT b. Idiosynchrytic,non dose dependent, usually fatal aplastic anemia, during or weeks after TT, even with topical preparations.

Adverse Effects (cont.)

4. Hemolytic anemia in pts with G6PD deficiency . 5. Grey baby syndrome , in neonates, deu to failure of conjugation and renal excretion of the drug, so SDC is elevated, leading to shock ,depressed breathingand cyanotic grey skin.

Macrolides
They are group of antibiotics with macrocyclic lactone ring (14-16 C atoms) To which deoxy sugars are attached. Erythromycin 1st one, DOC and alternative in penicillin allergic pts. Clarthromycin- methylated erythromycin Azithromycin larger lactone ring Telethromycin- semisynthetic

Macrolides
MOA: Bind to 50 S subunits of ribosomes and interfere with ptn synthesis. Bacteriostatics Antibacterial spectrum: Erythromycin: as penicillin G, therefore, it is used in pts who are allergic to penicillins. Clarthromycin:as erythromycin+ H.influenzae,and more effective than erthromycin in: chlamydia and H pylori.

Antibacterial Spectrum(cont.)
Azthromycin: less active against strept and Staph than erythromycin. More active against H.influenzae and Chlamydia. Active against Mycobacterium avium in AIDS pts Telithromycin: as azthromycin but with less incidence of resistance.

Phrmacokinetics
Erythromycin: very well absorbed orally specially the estolate salt, even in presence of food. Distributed readily to most tissues and eliminated entirely by the bile. Microsomal enzyme inhibitor (DI ?) Clarthromycin ,more absorbable than erythromycin,longer half life, 2x/d,MESI Azthromycin,once daily, do not affact MES

Adverse Effects
1. Epigastric distress poor complience 2. Cholestatic jaundice Erthromycin estolate, allergic and reversible. 3. Ototoxicity transient deafness with high doses of erythromycin. Diarrhoea < tetracyclines Patients with hepatic dysfunction should be treated cautiously. Telithromycin ,hepatotoxic, prolongs QT and may aggravate mysthenia gravis

Clindamycin
Binds to 50S subunits of bacterial ribosomes then inhibits protein synthesis Has similar spectrum as erythromycin+ B.fragilis and anaerobs in GIT associated sepsis. Used in :1. Bone and joint infection 2. Intra abdominal sepsis 3. Anaerobic infection Adverse reaction: Pseudomembranous colitis, deu to C.difficile, TT: metronidazole or vancomycin. STOP IT IF ANY DIARRHEA OCCURS