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PROTEIN SYNTHESIS INHIBITORS. INTRODUCTION. These antibiotics exert their actions by targeting the bacterial ribosomal subunit at various steps in the synthesis of bacterial protein. Bacterial ribosome is smaller 70 s as compared to the mammalian cytoplasmic ribosome - 80 s.
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INTRODUCTION • These antibiotics exert their actions by targeting the bacterial ribosomal subunit at various steps in the synthesis of bacterial protein. • Bacterial ribosome is smaller 70 s as compared to the mammalian cytoplasmic ribosome - 80 s
CLASSES OF DRUGS • AMINOGLYCOSIDES • TETRACYCLINES • GLYCYLCYCLINE • CHLORAMPHENICOL • MACROLIDES • CLINDAMYCIN • LINEZOLID • DALFOQUISTIN/ QUINOPRISTIN
p. 554 Azithromycin (Zithromax) Very broad spectrum. Aerobic gm +/- SE: Toxicity Nephro- Oto-toxic Very broad spectrum. Many gm +, some gm – Pen allergic pt SE: GI distress Gm+/- bacteria Spirochetes, Rickettsiae Resistant organisms SE: GI distress Photosensitivity Impair teeth & bone growth Chloramphenicol: many Gm -/+ bacteria Serious infxn. SE: Bone marrow aplasia Clindamycin: Most Gm +, some Gm – Alternative use. SE: colitis - PMC (C. difficile) Ethionamide: TB SE: GI distress
Aminoglycosides • THEY ARE BACTERICIDAL. • Susceptible organisms allow aminoglycosides to diffuse through their porin channels in their outer membranes. • These organisms have oxygen dependant system that transports the drug across cell membrane.
Aminoglycosides • Streptomycin • Gentamicin • Tobramycin • Amikacin • Neomycin
MOA: They bind to the 30s ribosomal subunit distorting its structure, thus interfering with the assembly of functional ribosomal apparatus(initiation). • They also allow for misreading resulting in mutation or premature chain termination • Synergism: They synergize with beta lactAM ANTIBIOTICS BECAUSE OF THE LATTERS ACTION ON CELL WALL SYNTHESIS, WHICH ENHANCES DIFFUSION OF THE AMINOGLYCOSIDES INTO THE BACTERIUM.
Actions • THAY ARE EFFECTIVE AGAINST AEROBIC GRAM -VE BACILLI and RODS AS ANEROBES LACK THE OXYGEN REQUIRING TRANSPORT SYSTEM. • Synergistic action occur for infections caused by enterococci and pseudomonas
Organisms susceptible to aminoglycosides • Klebsiella • Francisella tularensis • Yersinia pestis • Brucella • STREPTOMYCIN IS USED TO TREAT TB, PLAGUE & TULAREMIA.
Resistance • Decreased uptake of drug due to absence of Porin channels and oxygen dependent uptake system • Altered 30 s subunit • Plasmid associated synthesis of conjugating enzymes such as acetyl transferase that eliminates the drug faster.
Aminoglycosides Route : parenteral • Exception : neomycin –topical and sometimes oral for hepatic coma. • The bacteriocidal effect is conc and time dependent i.e., the greater the conc of drug, the greater the bacteria killing. • Toxicity is dependent on drug concentration and thus once daily dosing is recommended which results in fewer toxicities. • Distribution : low conc. in CSF, • Crosses placenta
Excretion : Glomerular filtration • HIGH CONCENTRATIONS ACCUMULATE IN THE RENAL CORTEX, ENDOLYMPH AND PERILYMPH OF INNER EAR
Aminoglycosides - SE • OTO TOXICITY • DEAFNESS (irreversible), VERTIGO (reversible) may be enhanced by loop diuretics • NEPHRO – TOXICITY: includes acute tubular necrosis which is usually reversible but enhanced by vancomycin, ampho-B, cisplatin • NEURO MUSCULAR PARALYSIS- ↓ release of Ach • RX – mostly calcium gluconate or neostigmine can reverse the situation • CONTACT DERMATITIS –neomycin
Tetracyclines • Doxycycline • Minocycline • demeclocycline
TETRACYCLINES • Consist of 4 fused rings with a system of conjugated double bonds. • Broad spectrum antibiotics • Are bacteriostatic • MOA: THEY BIND TO THE 30S SUBUNIT OF THE BACTERIAL RIBOSOME AND BLOCK ACCESS OF THE AMINO ACYL-TRNA TO THE MRNA-RIBOSOME COMPLEX AT THE ACCEPTOR SITE. THUS THEY INHIBIT BACTERIAL PROTEIN SYNTHESIS.
Actions • Effective against gram +ve & -ve organisms. • Good activity against: chlamydial and mycoplasmal species, H-pylori, Rickettsia, Borrelia burgdoferi, Brucella and Vibrio • Backup to penicillin G in syphilis • Demeclocycline can be used to treat SIADH
TETRA CYCLINES • ROUTE : ORAL ,DECREASED BY • MILK • ANTACIDS • IRON SUPPLEMENTS • DISTRIBUTION :CROSSES BBB but not sufficient for therapeutic efficacy except Minocycline. • All tetracyclines readily crosses placenta. • High levels in calcium tissues- bones, teeth, some tumors • Excretion :renal , exception – doxycycline ( In bile )
Resistance • Production of an efflux pump by bacteria which causes elimination of the drug resulting in decreased conc of drug intracellularly.
TETRA CYCLINES - SE • MC : GIT- epigastric discomfort, • CALCIUM DEPOSITION : GROWTH –STUNTED, TEETH – SMALL,DISCOLORED • PHOTO TOXICITY • HEPATO TOXICITY in pregnant women(high doses) • VERTIGO – MINOCYCLINE • SUPERINFECTION: overgrowth of candida and C.dificile causing pseudomemranous colitis • CI : WOMEN – preg, lactating, children(<8yrs)
GLYCYLCYCLINES • TIGECYCLINE: structurally similar to the tetracyclines • Has a broad-spectrum of activity against: • Gram –ve organisms • Anaerobic organisms • Its bacteriostatic • MOA: Binds to 30s ribosomal subunit preventing the binding of aminoacyl t-RNA to the A-site. • SE: SIMILAR TO TETRACYCLINE
Macrolides • Erythromycin • Telithromycin • Azithromycin • Clarithromycin
Macrolides • Are bacteriostatic • Macrolides bind to 50 s subunit of the bacterial ribosome thus inhibiting the translocation steps of protein synthesis.
Erythromycin • Indication –effective against : • gram +ve cocci (not MRSA) • Legionella pneumophilia, • Campylobacter jejuni • Atypical organism: chlamydia, mycoplasma and ureaplasma species • used in pt. with allergy to penicillins
ACTIONS Clarithromycin • Spectrum : - Haemophilus INFLUENZA, urethritis caused by chlamydia trachromatis Azithromycin • Spectrum: Moraxella & H-influenza related respiratory pneumonias and M. Avium in AIDs pts
Macrolides • Route : • Erythromycin is given orally but are destroyed by acid and so the enteric coated or esterified form is usually given. • Clari and azithromycin: orally and stable to acid • IV – for azithromycin also • Distribution : CSF – poor. • Prostate – good • Excretion : in bile by erythromycin and clarithromycin • Exception – Azithromycin – renal
Erythromycin and clarithromycin: are not safe in pregnancy and inhibit cyt P450 • Azithromycin: safe in pregnancy and does not inhibit cyt P450
Resistance • Ability of the bacteria to methylate a base in the 23s subunit of rRNA. • Presence of a plamid associated erythromycin esterase which inactivates the drug. • Presence of an efflux pump which limits the conc of drug intracellularly
Macrolides - SE • MC : GIT DISTRESS • OTO TOXICITY: which is reversible • CHOLESTATIC JAUNDICE • CI : LIVER FAILURE
chloramphenicol • MOA: BINDS TO THE 50 S RIBOSOMAL SUBUNIT THEREBY INHIBITING THE PEPTIDYL TRANSFERASE REACTION.
Actions • Broad spectrum antibiotic • Active against rickettsiae • Salmonella typhi • Bacteriodes Fragilis • Can be bactericidal (more commonly) or bacteriostatic depending on the organism.
Resistance • RESISTANCE IS BECAUSE OF R FACTOR WHICH CODES FOR ACETYL CO-A transferase that inactivates the drug
CHLORAMPHENICOL • ROUTE : ORAL / IV • DISTRIBUTION : CROSSES BBB • Metabolized by hepatic conjugation to metabolite called glucuronide • EXCRETION : of glucuronide renally • SE: GRAY- BABY SYNDROME- due to poor conjugating capacity and under developed renal function. Accumulation leads to interference with function of mitochondrial ribosomes. • HEMOLYTIC ANEMIA : G 6 PD DEFICIENCY
Clindamycin • MOA and Resistance: same as macrolides • INDICATION: infections caused by anerobes such as BACTERIODES FRAGILIS, osteomyelitis due to gram +ve cocci • ROUTE : ORAL • EXCRETION : RENAL & HEPATIC • SE : MC is PSEUDOMEMBRANOUS COLITIS • Treatment of pseudomembranous colitis: first choice- metronidazole and then vancomycin
QUINOPRISTIN/DALFOPRISTIN • Quinipristin/dalfopristin • Mixture of two streptogramins in a ratio of 30 to 70. • MOA: Each component of this combination binds to a separate site on 50 s bacterial ribosome interfering with the binding of amino acyl tRNA with acceptor site. • Active against VRSA & VRE
LINEZOLID • Effective against gram +ve organism such VRSA & VRE • MOA: binds to the 50s subunit Inhibits formation of 70 s initiation complex and thus inhibits protein synthesis. • It is bacteriostatic • Inhibits MAO, so caution must be exercised by pts taking tyramine containing foods