Protein Synthesis Inhibitors PDF

Protein Synthesis Inhibitors Professor Dr. S. Mohsin Turab Head, Department of Pharmacology Hamdard College of Medicine & Dentistry Hamdard University, Karachi. Email: [email protected] Cell #: 03332115515  Protein Synthesis Inhibitors A...

Protein Synthesis Inhibitors Professor Dr. S. Mohsin Turab Head, Department of Pharmacology Hamdard College of Medicine & Dentistry Hamdard University, Karachi. Email: [email protected] Cell #: 03332115515  Protein Synthesis Inhibitors ACTING ON 30s RIBOSOME TETRACYCLINES (30s) AMIMOGLYCOSIDES (30s) CLINDAMYCIN (30s) ACTING ON 50s RIBOSOME MACROLIDES (50s) CHLORAMPHENICOL (50s) STREPTOGRAMINS (50s) OXAZOLIDINONES GENERAL MECHANISM OF ACTION OF PROTEIN SYNTHESIS INHIBITORS TETRACYCLINE  Tetracycline SHORT ACTING Chlortetracycline (SA) Oxytetracycline (SA) Tetracycline (SA) INTERMEDIATE ACTING Demeclocycline (IA) Methacycline (IA) LONG ACTIONG Doxycycline (LA) (VIBRAMYCIN) Minocycline (LA) (MINOCIN)  Spectrum & Mechanism of Action Highly effective against rickettsiae, gm + and – bacteria, chlamydia Inhibit protein synthesis by reversibly binding to 30S subunit of bacterial ribosome, preventing binding of aminoacyl tRNA to mRNA ribosomal complex Bacteriostatic GENERAL MECHANISM OF ACTION OF PROTEIN SYNTHESIS INHIBITORS  Kinetics Absorption: Incomplete GI absorption: tetracycline (60-80%), doxycycline (95%), minocycline (100%) Dairy foods decrease absorption by forming nonabsorbable chelates with calcium ions; also Mg, Fe, Al (antacids) (Continue)  Distribution: Widely distributed in body  Bind in tissues undergoing calcification (teeth, bones) or tumors with high calcium content (gastric carcinoma)  All cross placenta and concentrate in fetal bones and teeth  Excretion:  Doxycycline and minocycline largely excreted in feces  Use in renal insufficiency  Resistance Efflux pump Enzymatic inactivation Prevention of binding to ribosomes  General Therapeutic Uses Lyme disease Mycoplasma pneumonia Rocky mountain spotted fever Acne Chlamydia Cholera  Adverse Effects GI discomfort Anorexia, epigastric pain, abdominal distention, nausea, vomiting, diarrhea, sore mouth, perianal irritation Hepatotoxicity Nephrotoxicity (Continue)  Adverse Effects Teeth damage Discoloration enamel and hypoplasia of teeth Depression of bone growth Deposition in fetal and growing bones, stunted growth Photosensitization Severe sunburn ; doxy/demeclocycline Superinfections Candida or GI staphylococcus  Contraindications Pregnancy Children Renal insufficiency Can use doxycycline AMINOGLYCOSIDES  AMINOGLYCOSIDES Streptomycin Gentamycin (Genticin, Gentamycin) Tobramycin Amikacin Kenamycin Netilmicin Neomycin (Cicatrin powder, Polyfax ointment)  Mechanism of Action Binds to 30S ribosomal subunit there by interfering with assembly of functional ribosomal apparatus or misreading of genetic code Effective against Aerobic gram negative bacteria Bactericidal or static GENERAL MECHANISM OF ACTION OF PROTEIN SYNTHESIS INHIBITORS  Kinetics Absorption: Inadequate absorption when oral ALL PARENTERAL, except neomycin Neomycin Only topical use to reduce intestinal bacteria  Resistance Decreased uptake Altered receptor Enzymatic modification  General Therapeutic Uses Bacterial endocarditis (+ Pen) Tuberculosis (Streptomycin combination) Tularemia- hunters skinning infected animals Urinary tract infections (E coli, enterobacter) Pneumonia (pseudomonas, E coli, kleb) Meningitis Peritonitis Serious infections with enterobacteriaceae and other aerobic gram negative bacilli  Adverse Effects Ototoxicity Nephrotoxicity Neuromuscular paralysis Contact dermatitis- neomycin topical Monitor peak and trough plasma levels CHLORAMPHENICOL  Mechanism of Action Binds to 50S ribosomal subunit Inhibits Peptidal transferase step of protein synthesis Bacteriostatic Broad spectrum GENERAL MECHANISM OF ACTION OF PROTEIN SYNTHESIS INHIBITORS  Kinetics Excretion depends on conversion in liver to glucuronide, then secretion in kidney  Therapeutic Uses Severe odontogenic infections threatening orbital contents or brain Typhoid fever- salmonella Refractory meningitis by H.influenza, S.pneumonia, N.meningitidis, rickettsia, brucella, bacteroides  Adverse Effects Anemias Hemolytic, reversible/mild, aplastic Gray baby syndrome Neonates if doses not adjusted Low capacity to glucoronidate antibiotic and underdeveloped renal function Decreased excretion ability Poor feeding then cyanosis then death MACROLIDES  Mechanism of Action Bind to 50S subunit of bacterial ribosome, inhibiting translocation step of protein synthesis Bacteriostatic activity Better intracellular concentration with gram + bacteria Clarithro and Azithro are more effective against anaerobic GENERAL MECHANISM OF ACTION OF PROTEIN SYNTHESIS INHIBITORS  Macrolides Erythromycin Azithromycin Clarithromycin Dirithromycin Troleandomycin Telithromycin  Metabolism: Inhibits oxidation of other drugs through interaction with cytochrome P-450 system  Resistance Inability of organism to take up antibiotic Decreased affinity of binding site for antibiotic Efflux pump  General Therapeutic Uses Mycoplasma pneumonia Syphilis- in penicillin allergic Chlamydia- alternative to tetracycline; during pregnancy Legionellosis pneumonia Corynebacterium diptheriae- carriers Ureaplasma- urethritis (Continue)  General Therapeutic Uses Alternative to penicillin in allergic patients Clarithromycin (Klaricid) and Azythromycin (Azomax) COPD, pneumonia Pharyngitis, tonsillitis Acute maxillary sinusitis Lower respiratory tract infections  Adverse Effects Epigastric distress Nausea, vomiting, pain, diarrhea Cholestatic jaundice Ototoxicity High doses CLINDAMYCIN  Mechanism of Action Binds to 50S subunit of bacterial ribosomes to inhibit protein synthesis Bacteriostatic activity, but bactericidal action against susceptible organisms in vivo  Spectrum Similar to erythromycin Increased activity against gram +ve and –ve anaerobes, staph aureus  Therapeutic Uses Strep, Staph, pneumococci, anaerobic infections Purulent osteitis or other bone infection caused by anaerobes  Adverse Effects GI distress Diarrhea Pseudomembranous colitis caused by clostridium difficile Superinfections STREPTOGRAMINS  STREPTOGRAMINS QUINUPRISTIN-DALFOPRISTIN Spectrum includes Gram +ve cocci. Rapidly bactericidal for most organisms except Enterococcus faecium Toxicities includes Arthralgia and myalgia syndrome. OXAZOLIDINONES  LINEZOLID Active against gram-positive organisms Bacteriostatic Binds to 23S ribosomal RNA of the 50S ribosomal subunit and Inhibits protein synthesis by preventing formation of 70S initiation complex Life threatening adverse effects includes thrombocytopenia, anemia and neutropenia.