Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pharmacognosy wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Discovery and development of neuraminidase inhibitors wikipedia , lookup
Neuropharmacology wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Discovery and development of proton pump inhibitors wikipedia , lookup
Levofloxacin wikipedia , lookup
Ciprofloxacin wikipedia , lookup
Discovery and development of cephalosporins wikipedia , lookup
β-Lactam Antibiotics 1. PENICILLINS 2.Cephalosporins 3.Carbapenems ( Imipenems ) 4. Monobactams ( Aztreonam) Penicillins Classification Narrow spectrum penicillins Antistaphylococcal penicillins Broad spectrum penicillins Extended –spectrum penicillins ( antipseudomonal penicillins). Mechanism of action Like all β-lactam antibiotics , inhibit the synthesis of bacterial cell wall . Through inhibition transpeptidase enzyme They are bactericidal on the actively growing bacteria. Pharmacokinetics Absorption Depending on acid stability Absorption of most oral penicillins is impaired by food except amoxicillin . Metabolism & Excretion Not metabolised Excreted unchanged in urine Probenecid blocks their secretion Nafcillin is mainly cleared by biliary route Oxacillin by both kidney & biliary route. Distribution Relatively insoluble in lipid Poor penetration into cells and BBB Inflammation permits entrance into CSF. Proteins binding vary from 20%-90% Narrow spectrum penicillins Penicillin G Short duration Acid unstable Penicillinase sensitive Used in enterococcal endocarditis usually with aminoglycosides To prevent gonorrheal opthalmia in new born . Procaine penicillin Long acting (every 12 h ) . Acid unstable Penicillinase sensitive Used to prevent subacute bacterial endocarditis due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease . Benzathine penicillin Long acting (every 3-4 weeks ) Acid unstable Penicillinase sensitive Treatment of β-hemolytic streptococcal pharyngitis. Used as prophylaxis against reinfection with βhemolytic streptococci so prevent rheumatic fever . Once a week for 1-3 weeks for treatment of syphilis (2.4 milloion units I.M.) Phenoxymethyl penicillin (P. V) Less effective than penicillin G Acid stable Penicillinase sensitive Short acting Used in minor infections Penicillinase resistant to staphylococcal β-lactamase producer Methicillin acid unstable Nafcillin its absorption is erratic Oxacillin, Cloxacillin,Dicloxacillin (acid stable ). Used in minor & severe Stap. infections Broad &Extended spectrum penicillins Aminopenicillins Carboxypenicillins Ureidopenicillins Aminopenicillins(Ampicillin &Amoxicillin) Therapeutic uses 1)H.influenza 2)E.coli 3)Salmonella&Shigella infections only ampicillin 4)Prophylaxis of infective endocarditis 5) Urinary tract infections 6) Effective against penicillin –resistant pneumococci Carboxypenicillins(Ticarcillin)&Ur eidopenicillin(Piperacillin) Effective against pseudomonas aeruginosa & Enterobacter. Penicillinase sensitive Can be given in combination with βlactamase inhibitors as clavulanic acid ,sulbactam, tazobactam. Adverse effects Hypersensitivity reactions High dose in renal failure ---seizure Naficillin (neutropenia) Oxacillin (hepatitis) Methicillin(nephritis) B.S.P.(pseudomembraneous colitis ) Secondary infections Problems relating to use & misuse of penicillins 1- 90% of staphylococcal strains both in hospital or community are β-lactamase producers 2- New generations of microorganisms as H.influenzae , N.gonorrhoeae or pneumococci are resistant to penicillins 3- Broad spectrum penicillins eradicate normal flora causing superinfections Cephalosporins First-Generation Cefazolin, Cephalexin, cephradin. They are very effective against grampositive cocci They are given orally ,except cefazolin given I.V.I ,or I.M. Excretion Mainly through kidney Probenecid block tubular secretion and increase plasma level . They can not cross B.B.B. Clinical uses Urinary tract infections Minor Staph.infections or minor polymicrobial infections as cellulitis or soft tissue abscess. Cefazolin is the drug of choice for surgical prophylaxis,also as alternative to antistaph.penicillin in allergic patients . Second -Generations Cefaclor ,Cefamandole, Cefonicid Less active against gram-positive bacteria than first generation They have extended gram –negative effect No effect on P-aeruginosa or E-cocci. Pharmacokinetics Given orally or parenterally Can not cross B.B.B. Excreted through kidney Cefonicid is highly protein binding Clinical uses H-influenza infections Mixed anaerobic infections as peritonitis . Community acquired pneumonia Third -Generations Cefoperazone,Cefixime,Ceftriaxone They have extended gram- negative spectrum. Have an effect on P-aeruginosa . No effect on E-coli. Pharmacokinetics Main route I.V.I. Cefixime can be given orally Ceftriaxone has a long half- life (7-8h).can be given once every 24h. Cross B.B.B. Excreted through kidney .Ceftriaxone through bile. Clinical uses Serious infections Cefixime ,first line in treatment of gonorrhea. Meningitis P-aeruginosa infections. Fourth -Generations Cefepime More resistant to hydrolysis by βlactamase Active against P-aeruginosa & E-coli Clinical use as third generations. Adverse Effects Allergy Thrombophilibitis Interstitial nephritis and tubular necrosis mainly with cephaloridine. Cephalosporins that contain a methylthiotetrazole group as cefamandole ,cefperazone cause hypoprothrombinemia And bleeding disorders . Vit.K twice weekly can prevent this . Methylthiotetrazole ring causes severe disulfiram-like reaction. Superinfections. Diarrhea. Carbapenems Imipenem Bctericidal, inhibit bacterial cell wall synthesis. Has a wide spectrum of activity Sensetive to metallo-β lactamase . Pharmacokinetics Not absorbed orally,taken by I.V.I. Inactivated by dehydropeptidases in renal tubules, so it is given with an inhibitor of renal dehydropeptidases,cilastatin for clinical use. Penetrates body tissues and fluids including c.s.f. Clinical uses Mixed aerobic and anaerobic infections Carbapenem is the β lactam of choice for treatment of enterobacter infections. Pseudomonal infections Intraabdominal infections Febrile neutropenic patient Septicaemia. Meropenem Similar to imipenem but it is highly active against gram-negative aerobes . Not degraded by renal dehydropeptidase Adverse effects Nausea,vomiting,diarrhea Skin rash and reaction at the site of infusion High dose with imipenem in renal failure cause seizure Patients allergic to penicillin may be allergic to carbapenems . Monobactams Aztronam Active only against gram-negative aerobic bacteria. Given I.V. Similar to β-lactam in mechanism of action and adverse effects. Macrolides(MACROCYCLIC LACTONE RING 14-16 ATOMS) Erythromycin(14 atom lactone ring ) Is effective against Legionella,cornybacteria,gram-positive cocci,chlamydia,helicobacter Less effective on gram-negative organisms. Mechanism of action Inhibit protein synthesis via binding to 50 S ribosomal RNA subunit. Bactericidal at high conc.and bacteriostatic at low conc. Pharmacokinetics Destroyed by stomach acid and must be administered with enteric coating . Food interferes with absorption Half-life 1.5h Excreted mainly through bile,5%only in urine. Cross placenta not B.B.B. Clinical uses Drug of choice of corynebacterial infections Chlamydial infections Community acquired pneumonia Mycoplasma Legionella Penicillin allergic patients. Adverse effects Anorexia,nausea,vomiting,diarrhea. Liver toxicity especially with the estolate coat produce acute cholestatic hepatitis Drug interactions as it is cytochrome p450 inhibitor. Hypersensitivity reactions . Clarithromycin(14 atom lactone ring) Acid stable Mechanism of action as erythromycin Spectrum as erythromycin but more active against Mycobacterium avium complex.m.leprae.Toxoplasma gondii. Half –life 6h. Metabolised in liver (active metabolites ). Partially excreted in urine Drug interactions similar to erythromycin Has a lower frequency of gastric upset And less frequent dosing More tolerable More expensive Azithromycin(15 lactone ring ) Same mechanism of action Similar spectrum as clarithromycin,but more active on H-influenza &chlamydia. Half-life 3 days . Rapidaly absorbed and well tolerated . Free of drug interactions Excreated in bile and urine Clinical uses Upper and lower respiratory tract infections Skin infections Alternative to penicillin in allergic patients Urethritis or cervicitis mainly by chlamydial infections . Adverse effects Gstric upset (less than erythromycin ) Allergic Superinfections Liver affection Tetracyclines Broad spectrum antibiotics Bacteriostatic,inhibits protein synthesis reversibly by binding to 30 S ribosomal subunits . Pharmacokinetics Absorption: Poorly absorbed 30% as chlortetracycline Medialy absorbed 60-70% as tetracycline ,oxytetracycline and demeclocycline Highly absorbed 95-100% as doxycycline and minocycline. Absorption is impaired by food except Doxycycline and minocycline Absorption of all preparations is impaired by divalent cations,milk and its products ,antacids and alkaline pH. Plasma protein binding 40-80%. Minocycline reaches very high conc. In tears and saliva, makes it useful in eradication of meningococcal carrier. They cross placenta barrier . Excreated through bile and urine Doxycycline is eliminated by nonrenal route . According to half-life : Long acting; doxycycline &minocycline (16-18h once daily ). Intermediate (12h) demeclocycline Short acting (68h)oxy,tetracyclines. Clinical uses: Mycoplasma pneumonia Chlamydial infections Rickettsial infections Spirocates Brucellosis Anthrax Clinical uses Cholera Traveller,s diarrhea Helicobacter pylori Acne(minocycline&doxycycline) Bronchitis Protozoal infections Minocycline to eradicate meningococci carrier Not used in: Streptococcal & staphylococcal infections . Gonococcal infections Meningococcal infections Typhoid fever Adverse effects I.M.(pain & inflammation) I.V.(thrombophilbitis) Gastric upset (N.,V.,D.) Enterocolitis Super infections Damage growing bone &teeth. Adverse effects Yellowish brown discolorationof teeth &dental caries. Liver toxicity Kidney toxicity (tubular necrosis). Photosensitization(demeclocycine) Vestibular reaction(vertigo,dizziness,) (Doxycycline &minocycline). Contraindications With milk or its products,or antacids. Pregnancy Children under 8 years. Chloramphenicol Broad spectrum antibiotics Bacteriostatic,inhibits protein synthesis by binding to 50S ribosomal subunits. Rapidly &completely absorbed Rapidly distributed Cross placental barrier &B.B.B. Metabolised in liver Excreted mainly through urine Enzyme inhibitor(p450) Clinical uses Serious rickettsial infections In children whom tetracyclines are contraindicated Meningitis In allergic patients to penicillin Topically in bacterial eye infections except in chlamydial infections. Adverse effects Gastric upset (N.,V.,D.) Super infections Bone marrow depression Gray baby syndrome Hypersensitivity reactions Drug interactions Aminoglycosides Bactericidal antibiotics Inhibits protein synthesis by binding to 30S ribosomal subunits. Active against gram negative aerobic organisms. Poorly absorbed orally Given parenterally (I.M,I.V.) Not freely cross BBB Aminoglycosides Excreted mainly unchanged in urine More active in alkaline medium Have common adverse effects : Ototoxicity Nephrotoxicity Neuromuscular blocking effect CNS (not common ). Clinical uses Streptomycin T.B. in combination with other antituberculous drugs. Enterococcal endocarditis with penicillin. Severe brucellosis with tetracycline Gentamicin Severe infections caused by gram negative organisms as sepsis ,urinary tract infections & pneumonia caused by pseudomonas. Topically for the treatment of infected burns,wounds,skin lesions,ocular, ear infections. Tobramycin More active against pseudomonas than gentamicin. Ineffective against mycobacteria Less nephrotoxic and ototoxic than gentamicin. Used in treatment of bacteremia, osteomyelitis and pneumonia. Amikacin Has the broadest spectrum Used for serious nosocomial infections by gram negative organisms. In T.B. as alternative to streptomycin Atypical mycobacterial infections Neomycin Highly nephrotoxic ,used only orally for gut sterilization before surgery or topically in skin infections,burn or eye infections. Contraindications of aminoglycosides Renal dysfunction Pregnancy Diminished hearing Myasthenia gravis Respiratory problems Precautions with: Loop diuretics Cephalosporins Monitor plasma level is useful. Neostigmine reverses respiratory depression. FLUOROQUINOLONES (Ciprofloxacin,ofloxacin,norfloxaci Mechanism of action: Block bacterial DNA synthesis by inhibiting bacterial topoisomerase11(DNA gyrase ) and topoisomerase 1V. Antibacterial activity : Highly active against gram-negative aerobic bacteria. Active against gram-positive bacteria. Mycoplasma,chlamydia,legionella,mycobacteria. Pharmacokinetics Well absorbed orally. Widely distributed in body fluids & tissues. Half-life(3-10h). Absorption is impaired by antacids. Concentrated mainly in prostate,kidney,neutrophils ,macrophages. Excreted through kidney. Clinical uses U.T.I.caused by multidrug resistance organisms as pseudomonas. Bacterial diarrhea. Soft tissues,bones,joints,intra-abdominal, respiratory infections caused by multidrug resistance organisms. Gonococcal infections. Legionellosis. Chlamydial urethritis or cervicitis T.B & atypical T.B. Adverse effects N.V.D. Headache,dizziness,insomnia Skin rash ,abnormal liver enzymes. QT prolongation Damage growing cartilage causing arthropathy. Tendinitis in adults Drug interactions & contraindications With antacids Elevate serum levels of theophyline increase the risk of seizure. Contraindicated in children ,adolescents ,pregnancy ,lactation ,epileptic patients. Miscellaneous Antibiotics Polymyxins Active against gram-negative including pseudomonas. Polymyxin B is only available. Bactericidal inhibits cell wall synthesis. Used only topically . Highly nephrotoxic. Spectinomycin Bactericidal,inhibits protein synthesis by binding to 30S ribosomal subunits. Given I.M.I.as a single dose in treatment of gonorrhea. Pain at the site of injection. Excreted through kidney . Nephrotoxicity is rare. Clindamycin Active against gram-positive and anaerobic bacteria. Inhibits protein synthesis by binding to 50S ribosomal subunits. Given orally or parenterally Widely distributed Cross placenta not BBB. Metabolised in liver giving active metabolites. Excreted in bile & 10% in urine. Clinical uses: Anaerobic infections minly in bones and joints . Conjunctivitis. In combination with aminoglycosides or cephalosporin is used to treat penetrating wounds of the abdomen & the gut. Female genital tract e.g. septic abortion ,pelvis abscess. Instead of erythromycin for prophylaxis of endocarditis. Adverse effects : Other inhibitors to cell wall synthesis Vancomycin Bactericidal Active only on gram +ve bacteria. Poorly absorbed orally Given by I.v.I Not freely cross BBB Excreted mainly through kidney Clinical uses Endocarditis mainly caused by methicillin – resistant staphylococci. Alternative to penicillin in enterococcal endocarditis( in combination with gentamicin). Meningitis( in combination with ceftriaxone or rifampin in highly resistant pneumococcus strains). Orally in antibiotic associated enterocolitis Adverse effects Irritation at the site of injection Ototoxicity & nephrotoxicity . Red man or red neck syndrome. Gastric upset. Bacitracin Bactericidal No cross resistance between it and other antimicrobial drugs. Active against gram +ve organisms Used only topically in skin ,eye ,nose infections . Highly nephrotoxic producing proteninuria, hematuria Hypersensitivity reactions As ointment in combination with polymyxin or neomycin for mixed bacterial infections. As solution in saline for irrigation of joints, wounds or pleural cavity. Teicoplanin Glycopeptide antibiotic Bactericidal Inhibits bacterial cell wall Active against gram positive organisms Given I.M. or I.V. Has a long half-life(45-70 h). Given once daily. Cycloserine Bactericidal Inhibits bacterial cell wall Broad spectrum antibiotic Effective on gram positive & gram negative organisms as well as M.tuberculosis. Unstable in acid or neutral medium When given orally 70%- 90% of the drug is rapidly absorbed. Widely distributed in body tissues & fluids. Excreted as active form in urine Used in treatment of pulmonary & extrapulmonary tuberculosis Causes serious dose related C.N.S. toxicity ( headaches, tremors, acute psychosis, convulsions) Contraindicated in epileptic & psychotic patients