Protein Synthesis Inhibitors (Pharmacology) PDF

Macrolides: Erythromycin, clarithromycin, azithromycin, Roxithromycin, Olendamycin, Spiramycin Ervthromvcin: Jr e natural. Pharmacokinetics: Absorbed orally but is destroyed by gastric acidity(acid-sensitive) and is given"enteric coated". It may be given IV. Poor penetration or BBB....

Macrolides: Erythromycin, clarithromycin, azithromycin, Roxithromycin, Olendamycin, Spiramycin Ervthromvcin: Jr e natural. Pharmacokinetics: Absorbed orally but is destroyed by gastric acidity(acid-sensitive) and is given"enteric coated". It may be given IV. Poor penetration or BBB. Passes placental barrier and is safe in pregnancy. Melabolized intheliver Excreted inurine and bile. Pharmacodynamics: I. Mechanism ofaction: Macrolides bind reversibly to 50S ribosomal subunits and inhibil lranslocation of amino acids, thus inhibiting protein synthesis. They aremore active in alkaline medium. II. Artion on hacteria Macrolidesare bacteriosiatic or bactericidal according totheir concentration. Spectrum: Gram positive bacteria; both cocci and bacilli. Gramnegalive cocci and someGramnegalive bacilli as H.influenzaand 3S Legionella. Mycoplasma pneumoniae, Chlamydia, and Spirochaetes. Indications: 1 - Treatmenl of Respiralory lract infeclions 2- Treatmenl ofChlamydia infeclions 3- Treatment of sexually transmitted diseases:gonorrheaandsyphilis. 4- Allernative to penicillin in penicillin-allergic patienls 5- Topically intreatment ofAcnevulgaris. 6- Erythromycin acts as”prokinetic" incases ofdiabetic gastroparesis by stimulating "motilin" receptors in GIT. Adverse effects: l- GITdisturbances 2- Cholestatic hepatitis (jaundice). 3- Allergic reactions: fever, rash, and eosinophilia. 4- Druginteractions:Erythromycin(andClarithromycin) but not Azithromycin) inhibit CYP4503A4anddecreases clearance of lheophylline and warfarinand may cause toxicity by these drugs. 36  Clarithromycin: As eryihromycin but More active against atypical bacteria. Belter oral absorption Less gutupsel. Used inpeptic ulcer to eradicate H.pylori. HME inhibitor (aserythromycin). Azithromycin (Zithroinax‘): As erythromycin but More active on mycobacteria and Chlamydia and less active on Siaph. and Strept. HightissueconcentrationexceptCSFlhenslowly released fromtheiissues leading tolongi 1/2andlong duraiionofaction Given once daily. Not HME inhibitor. Ketolides:Telithromvcin Semi-synthetic macrolide. Given orally once daily due to high tissue concentration. Active against Gram positive, Gram negative, and Chlamydia. HME inhibitor(inhibits CYP450 3A4aseryihromycin and clarithromycin). Useful incases of bacterial resistance to macrolides. 37  Incocamines Clindamycin and Lincomycin Pharmacokinetics: Absorbed orally and can be given IV. Highly bound toplasma proteins. Poor penetration into CSF but highly concentrated inteeth and bone. Melabolized by theliver and excreted in urine and bile. Mechanism ofaction:as macrolides. Spectrum: asmacrolides bu1 moreactive againslanaerobesexceplClostridium difficile. Indications: 1) Treatmenl of anaerobic infections as dental infections. 2) Prophylaxis against endocaditis. 3) Tretment ofintra-abdominal and female genital infeclions in combination with aminoglycosides orcephalosporins. 4) Combined wilh primaquine (anti-malarial) in lrealment of Pneumocystis carinii pneumonia asalternative to Co-trimoxazole (drug or choice). Adverse effects: 1) Superinfection by Clostridium difficile leading to seriousand maybe fatal pseudomembranouscolitis treated by oral vancomycin and metronidazole. 2) GIT disturbances. 3) Impaired liverfunctions. 4) Allergy: skin rash. 5) Neutropenia. 3B  Broad Spectrum Antibiotics: 1 Chloramphenicol: Jr natural. Pharmacoltiqetics: Well absorbed orally, and may be p iven by injection and topically. Passes BBB. Metabolized by theliver by conjugalion wilh glucrironic acid. Excreted inurine mainly asmetabolite. Pharinacodvnamics: Bacleriostatic. Mechanism ofaction: Binds lo50S ribosomal subunit and inhibils peplidyl transterase leading to inhibition of’ proteinsynlhesis. Spectrum: Gram positive, Gram nep a1ive, Ricketlsia, and anaerobes. Indications: 1 - Respiratory tracl inf'ections. 2- Typhoid f'ever(in acute slage and not in carriers}, Meningitis (especially H.influenza) and Rickettsial inf'ections asTyphus. 3- Anaerobic inf'ections. 4- Topically in eye and ear inf'ections. Adver.se effects: l - Bone marrow' depression(blood dyscrasias): usually in lhe form ot’ ap ranu1ocytosis, and is eilher: 39 1. Toxic = Dose-Dependent It is usually reversible atler sloppage ot'the drrig. 2. Idiosyncralic = Dose-Independent: is irreversible and may be f'ata1. 2- Gray Baby Syndrome: occursinnewborn andespecially if’ premature due to failure lo conjugate chloramphenicol. It is characterized by ash color of the skin. vomiting, hypothermia, hypotension, collapse and shock (lreated by HME indiicers as phenobarbitone). 3- Diarrhea, superinfeclion, and vitaminK deficiency. 4- HME inhibilion and decreases clearance of theophylline. wartarin, phenytoin, and oral hypoglycemic drugs as tolbutamide. 40  Tetracyclines: Jr e natural andsemisyntheiic. Pharmacokinetics' Absorption: 1. Telracycline-Chlortetracycline-Oxyietracycline are incomplelely absorbed orally especially in the presence or food. 2. Doxycycline is completely absorbed orally and not affected by food. 3. All tetracyclines are "chelated" with Ca"(in milk and other dairy products and in some antacids), Al”(in most antacids), Mg'*(in most antacids), and iron(in oral iron preparations used intreatment of iron deficiency anemia). This decreasesabsorptionand oral bioavailabilityof tetracyclines(andiron). Distribution: Poorpenetration of BB B except Minocycline which may reach an adequate CSF concentration and was used ineradication of meningococci inmeningococcal carriers (Rifampicin isbetter). Pass placental barrier and are teratogenic. Tetracyclines are concenlraled bone and teeth, and in calcified tumors, where they are precipitaled wilh Can*.Tetracyclines are also concentrated inliver and kidney. Fate: All tetracyclines are excreted mainly unchanged inurine (useful in treatment of UTIs butthedose should be adjusted inrenal impairmenl) except Doxycycline which is 41 eliminated inbile and can be used inrenalimpairmeni without dose adjustment. Doxycyclineundergoesentero-hepaticcirculationandisgiven once daily. All telracyclines are excreled inbreast milk and areaccordingly contraindicaled during lactation. Pharmacodynamics: Bacieriostatic. Mechanism ofaction: Bind to 30S ribosomal subunit and inhibit protein synlhesis Spectrum: Telracyclines have thebroadest speclrum bularenotcommonlyused because of serious toxic effects. GramposiiiveandGramnegaiivebacteria(veryactiveagainstvibrio cholera).Chlamydia, Mycoplasma, and Ricketisia.Spirochaetes (Treponemapallidum).Amoeba (luminal amoebicidal). Indications: 1. Respiratory tractinfeclions: especially ifcausedby Chlamydiaand Mycoplasma (Atypical Pneumonia) butare contraindicaledin newborn andpregnant females II. Urinary tract infections (except doxycyline). III. GIT infections as Cholera and eradication ofH.pylori inpeptic ulcer and amoebic dysentery. lV. Minocycline was usedineradicalionofmeningococci inmeningococcal carriers but is now replaced by rifampicin. V. Demiclocyclinedecreases renal action ofADHandis used in patients with excessive ADH release known asSyndrome of Inappropriate ADH (SIADH). 42 Toxicity: 1. GIT dislurbances: anorexia, nausea, vomiting, hyperacidity, esophagilis, esophageal ulcerations and bleeding. 2. Diarrhea, superinfeclion(by candida, Staph. or Clostridium difficile), and vitaminK andB deficiency especially with poorly absorbrd tetracyclines. 3. Teratogenicity. 4. Chelation with Ca'*in bone and teelh leading todefective growth (enamel hypoplasia), yellow-brown discoloration, and denial caries. 5. Allergy: rash andphotosensiiiviiy. 6. Hepatoioxicity and pancreatic toxicity is more common inpregnant 7. Fanconisvndrome:1heuseofoutda1ed(expired)tetracyclines causes nephrotoxicity(glucosuria,aminoaciduria,polyuria, proteinuria). 8. Minocycline causes CNS disturbances as dizziness and vertigo. Demiclocycline causes nephrogenic diabeles insipidus. 10.Thrombophlebitis. 43