Beta lactams, protein sythesis inhibitors, other antibiotics 1-suman nizam.iiuc .pharmacy.b.pharm
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- 1.BETA LACTAM ANTIBIOTICS AND OTHER CELL WALL SYNTHESIS INHIBITORS Ma. Shiela Cano-Guiking, M.D.
2. PENICILLINS I. CLASSIFICATION A. PenicillinaseResistant ( Antistaphylococcal Penicillins) 1. Methicillin ( Staphcillin) 2. Nafcillin (Unipen, Nafcil, Nallpen) 3. Isoxazolyl penicillins a. Oxacillin b. Cloxacillin c. Dicloxacillin d. Flucloxacillin 3. B. Penicillinase-Susceptible 1. Narrow-Spectrum a. Benzylpenicillin Penicillin G b. Phenoxymethyl penicillin Penicillin V 2. Extended Spectrum A. Aminopenicillins a.1 Ampicillin a.2 Esters a.2.1. Bacampicillin a.2.2. Pivampicillin a.2.3. Talampicillin a.3. Amoxicillin 4. B. Carboxypenicillins a.1 Carbenicillin a.1.1. Indanyl carbenicillin e.g Geopen a.1.2. Disodium carbenicillin e.g. Pyopen a.2. Ticarcillin a.3. Temocillin C. Ureido-penicillins c.1. Mezlocillin c.2. Azlocillin c.3. Piperacillin c.4. Apalcillin 5. II. GENERAL PROPERTIES A. Chemical Properties Penicillins are derivatives of benzylpenicillin, from which the methyl benzene radical is split off by amidase producing 6-aminopenicillanic acid, the parent compound of all semisynthetic penicillins 6. The compound consists of 2 basic structures: 1 Thiazolidine Ring (A) 2.Beta-Lactam Ring (B) - Site of action of Beta-lactamase - Site of action of Amidase - Site of attachment of side chain , which determines many of the antibacterial and pharmacologic characteristics of a derivative ( spectrum and penicillin-resistance) 7. Mechanisms of Action: Specific: inhibit the last step in the peptidoglycan synthesis of the cell wall Underlying: 1. inhibition of transpeptidase enzymes 2. activation of penicillin binding proteins (PBPs) 3. activation of autolysins (murein hydrolases) 8. C. Mechanisms of Resistance 1. inactivation of antibiotic by Beta lactamases 2. modification of PBPs 3. impaired penetration of drug to target PBPs 4. presence of an efflux pump Kinetics: - absorption vary with the preparation depending on their acid stability and protein binding - absorption of most oral penicillins (except amoxicillin) impaired by food and drugs should be given 1-2 hours before or after meal; parenteral complete and rapid 9. - cannot penetrate the blood-brain barrier; but 50% of the plasma concentration can pass through in the presence of inflammation: Probenecid and certain organic acids can inhibit transfer from cerebrospinal fluid (CSF) to blood stream; may lead to increase CSF level. - Metabolized by the liver to penicillanic/penicillenic acid; penicillamine, penicilloic acid and other penicilloyl derivatives (allergenic metabolites) - Excreted primarily by the kidneys (90% tubular secretion, 10% glomerular filtration) small amount through bile and feces, sputum and milk; renal excretion inhibited by probenecid 10. E. Adverse Effects: 1. Hypersensitivity reactions most common adverse effects - cause the highest incidence of antibiotic allergy a. major antigenic determinant- penicilloyl metabolite skin testing( penicilloyl polylysine (PPL) ) b. Signs and symptoms: - varied skin rashes and purpuric reactions - angioedema and anyaphylactic reactions - fever - eosinophilia - interstitial nephritis 11. 2.Gastrointestinal disturbances after oral administration 3.Convulsions following rapid IV administration 4. Accidental injection into the sciatic nerve severe pain and nerve dysfunction persisting for weeks 5. Chronic use may cause: hepatitis overgrowth of minor/atypical organisms following use of broad spectrum preparations 12. 6. Specific toxicities: a. Procaine Penicillin G after accidental IV injection: pulmonary embolism acute psychotic reactions b. Oxacillin and Nafcillin hepatitis granulocytopenia, bone marrow depression c. Disodium Carbenicillin and high dose Penicillin G Na -hypernatermia d. Penicillin G Potassium hyperkalemia with high doses 13. e. Penicillin G Sodium Jarisch_herxheimer reaction with high doses in secondary syphilis f. Carbenicillin and Ticarcillin bleeding diathesis g. Methicillin interstitial nephritis h. Ampicillin associated with pseudomembranous colitis 14. III. INDIVIDUAL AGENTS A. Penicillin G 1. Antimicrobial Spectrum - Streptococci, meningococci, enterococci, pen. susceptible pneumococci, non-B lactamase producing staph, Treponema, spirochetes, B. anthracis, Clostridium, Actinomyces, G(+) rods and non B lactamase producing G (-)anaerobic organisms 2.Kinetics - 1/3 of oral dose absorbed from intestinal tract rapidly; food impair absorption - maximal concentration: 30-60 min. 15. - intravenous a. Aqueous Penicillin G - peak in 15-30 min -T - 0.5-2 hrs. - intramuscular B. Procaine Penicillin G peak in 1-3 hrs. T1/2 12 hrs. C. Benzathine Penicillin G mean duration of antimicrobial activity - 26 days - 60% albumin bound - widely distributed to the tissues and body fluids - does not readily enter the cerebrospinal fluid when meninges are not inflamed - probenecid and uremia inhibits active transport secretion into the blood stream 16. Preparations: International Units measure of strength Oral Preparations: Penicillin G Sodium Penicillin G Potassium Parenteral Preparations 1.short acting a. aqueous Penicillin G Potassium 1.7 meq K/1M u b. aqueous Penicillin G Sodium 2.4. meq Na/1M u 2. long acting a. Procaine Penicillin G 300,000 600,000 u 120 mg procaine/vial b. Benzathine Penicillin G 600,000 u 1.2 M u/vial 17. 4. Doses and Therapeutic Uses a. Aqueous Penicillin G Child: mild infections 50,000 u 100,000 u/kg/day in equally divided Doses every 4-6 hrs. for 7 days Severe infections 200,000 u 600,000 u/kg/day in equally divided Doses every 2-6 hrs. for 14 days. 18. a. Procaine Penicillin G 300,000 600,000 u IM OD or BID for 7 days for Adults b. Benzathine Penicillin G 1.2 million 2.4 u IM monthly Syphilis less than 1 year duration 2.4 M u IM + Probenicid 1 gm/day for 10 days or 2.4 M u Benzathine Penicillin G IM single dose late latent, complicated 20 M u aqueous Penicillin G/day for 10 days congenital syphilis 50,000 u/kg/day aqueous Penicillin G for 10 days 19. Staphylococcal infections Gram (+) anaerobes Meningococcal infections Gonococcal infections Carrier state diphtheria Other unusual infections actinomycosis, Anthrax, rat bite fever, listeria, pasteurella, lyme disease, erysipeloid Prophylaxis recurrences of streptococcal, rheumatic fever, gonorrhea, syphilis, bacterial endocarditis 20. D . Penicillin V Oral form indicated only in minor infections Relative poor bioavailability; need for dosing 4x a day Gram (+) aerobic activities similar to Penicillin G 5-10x less active against gram(-) microbes, esp. Neisseria and certain anaerobes better absorbed from the gastrointestinal 21. D. Ampicillin 1. Microbial Spectrum Somewhat less active than Penicillin G against gram (+) cocci Enterococcal grp. D and viridans grp. Of streptococci - Listeria monocytogenes - H. influenza Effective for Shigellosis Should not be used for uncomplicated salmonella gastroenteritis may prolong the carrier state 22. 2. Kinetics: Gastric acid stable and well absorbed from the gastrointestinal tract Orally absorbed drug peaks in 2 hrs. Intramuscular administered drug peaks in 1 hour Mainly excreted by the kidneys; also thru the bile and feces Undergoes enterohepatic circulation Other kinetic properties similar to Penicillin G Sodium 23. 3. Adverse Effects: Ampicillin skin rash occurs in 7-8% others similar to Pen G 4. Preparations a. Oral Capsules 250-500 mg Suspension 125 mg, 250 mg/5 ml Drops 100 mg/ml b. parenteral 250 mg; 500 mg/ml vial 24. 5. Doses a. mild infections Newborn 25-50 mg every 12 hrs. Child 50-100 mg/kg/d in 4-6 divided doses Adult 1-4 gm/day b. severe infections Child 200-600 mg/kg/day Adult 6-12 gm/day E. Esters of Ampicillin No inherent antimicrobial activity as esters, but pharmacologically active following hydrolysis to Ampicillin 50% higher blood concentration than Ampicillin and Amoxicillin 25. F. Amoxicillin Closely related to Ampicillin in chemical and pharmacologic properties More rapidly and completely absorbed from gastrointestinal tract Attains higher serum levels than ampicillin 26. G. CARBOXYPENICILLINS AND UREIDOPENICILLINS 1. Antimicrobial Spectrum Gram (-) aerobes Pseudomonas aeroginosa Bacteroides fragilis; but in higher amount/dose Carboxypenicillins certain indole (-) Proteus Ureidopenicillins Klebsiella Azlocillin 10x more active than carbenicillin against Pseudomonas 27. 2.Preparations a. Carbenicillin Disodium salt contains approximately 5 meq sodium/gm for parenteral administration Indanyl esters 500 mg tablets b.Ureidopenicillins Parenteral preparations 28. H. Penicillinase-Resistant 1. Methicillin -15-80x more active against penicillinase producing microbes than Penicillin G; only parenterally available; currently many resistant strains of Staph. Aureus have emerged, no longer used because of nephrotoxicity 2. Nafcillin slightly more active than Cloxacillin against penicillinase producing Staph. Aureus, available in oral and parenteral preparations: GIT absorption is erratic 3. Isoxazolyl Penicillins Stable in gastric acid and adequately absorbed after oral administration Dicloxacillin is most active against penicillinase 29. CEPHALOSPORINS I. CLASSIFICATION A. First Generation 1. Cephaloridine-Loridine, Ceporan 2. Cephalothin-Keflin 3. Cephalexin-Keflex, Ceporex 4. Cefazolin-Cefacidal 5. Cephradine-Velosef 6. Cepharpirin-Cefadyl 7. Cephadroxil-Doricef, Cefamox 30. B. Second Generation 1. Cefaclor-Ceclor 2. Cefoxitin Mefoxin 3. Cefuroxime Zinacef, Zinnat 4. Cefonicid Monocid 5. Cefotetan - Cefotan 6. Cefamdandole Mandol 7. Cefprozil Cefzil 8. Loracarbef Lorabid 9. Cefmetazole Zefazone 10. Ceforanide 31. C. Third Generation 1. Cefotaxime Claforan 2. Cefoperazone Cefobid 3. Moxolactam Moxam 4. Ceftizoxime Cefizox 5. Ceftriaxon