Penicillins
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Pharmacology of Penicllins (Beta lactam antibiotics), description of their mechanism of action, mechanism of resistance, classification, indications and adverse effects
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Penicillins
- 1. Beta Lactam antibiotics-1 (Penicillins) Dr Naser Ashraf Tadvi Associate Professor Department of Pharmacology Ayaan Institute of Medical Sciences
- 2. Beta Lactum antibiotics • Penicillins • Cephalosporins • Monobactum: – Aztreonam • Carbapenems: – Imipenem, merpenem, ertapenem, doripenem
- 3. History of penicillins • 1928 - Alexander Fleming – Bread mold (Penicillium notatum) growing on petri dish • 1939 - Florey, Chain, and Associates – Began work on isolating and synthesizing large amounts of Penicillin. • 1944 - Used in WWII to treat infections • Late 1940’s - available for general use in US
- 4. Site of penicillinase action. Breakage of the lactam ring. STRUCTURE OF PENICILLIN C NH CH CH C O O C N CH CH3 CH3 COOH S AB
- 9. Mechanism of action Penicillins Bind & inactivate PBP on cell wall of susceptible bacteria Inhibit transpeptidase Autolysis & cell death Prevent peptidoglycan synthesis Cell wall deficient forms
- 10. Mechanism of bacterial resistance • Beta lactamases hydrolyse & inactivate β-lactum ring • Altered PBP • ↓ penetration of drug to its site of action • Activation of efflux mechanisms
- 11. Classification Narrow spectrum penicillins Extended spectrum penicillins β- Lactamase sensitive β- Lactamase resistant All are sensitive to β- Lactamase
- 12. Narrow spectrum penicillins β- Lactamase sensitive β- Lactamase resistant Oral • Cloxacillin • Dicloxacillin • Flucloxacillin Parenteral •Methicillin • Nafcillin •Penicillin G •Procaine penicillin G •Benzathine penicillin G •Penicillin V (Oral)
- 13. Extended spectrum penicillins Oral Parenteral Carboxy penicillins •Carbenicillin •Ticarcillin Ureidopenicillins •Mezlocillin •Azlocillin •Piperacillin Amino penicillins • Ampicillin •Bacampicillin •Talampicillin • Amoxycillin
- 14. Benzyl penicillin G • Antibacterial activity: – Gm(+) Cocci: Streptococci – Gm(-) Cocci : Gonococci, meningococci – Gm(+) Bacilli: Corynebacterium diptheriae , clostridium, bacteroides , listeria – Spirochaetes, treponema pallidum – Actinomyces • No significant activity against Gm negative rods
- 15. Why Gm(+) mainly
- 16. Pharmacokinetics • Acid labile hence given IM/IV • Duration of action:4-6 hrs, Elimination t½ = 30 min • Excreted 80 -85% tubular secretion & 10-15% glomerular filtration • Always prepare fresh solution • Renal failure prolongs half life of penicillins • Nafcillin,cloxacillin, dicloxacillin excreted by biliary route
- 17. Repository preparations of Penicillin G • Procaine penicillin G: – DOA = 12-24 hrs – Moderate plasma concentration – Used in mild to moderate infections – Less painful injection • Benzathine penicillin G: – DOA= 3-4 weeks – Slow onset but longest DOA – Used in syphilis , rheumatic fever prophylaxis
- 18. Therapeutic uses of Penicillin G • Streptococcal infections – Pharyngitis, sinusitis, otitis, rheumatic fever – Procaine penicillin G : 6 lac units IM OD • Pneumococcal infections – Pneumococcal pneumonia, meningitis • Meningococcal meningitis: – IV penicillin G, Not for prophylaxis
- 19. Therapeutic uses of Penicillin G • Gonococcal infections: Unreliable now • Syphilis • Leptospirosis • Diptheria • Clostridial infections: Tetanus & gas gangrene • Anthrax: Benzyl penicillin DOC 8-10 days • listeria, trench mouth • Actinomycosis:
- 20. Prophylactic uses • Rheumatic fever – Benzathine penicillin 1.2 million units IM every 4 weeks • Bacterial endocarditis – Valvular lesion patients before surgery – Should be given 1 hr before the surgery
- 21. Adverse effects of Penicillins • Local irritation and direct toxicity – IV penicillin G : thrombophlebitis – Procaine penicillin G: anxiety seizures – Intrathecal penicillin G: arachidonitis, convulsions • Hypersensitivity reactions • Jarisch herxheimer reaction
- 22. Precautions with penicillin • Always take history of allergies & drug therapy • Perform skin sensitivity test before administering penicillin G & its preparations – 0.02 ml of penicillin G – Drop of 10000 units on skin – 0.05 ml penicilloyl polylysine • Keep adrenaline ready in emergency tray
- 23. Semisynthetic penicillins Penicillin Use Penicillin V: Mild streptococcal & pneumococcal infections Oxacillin Cloxacillin Staph aureus, staph epidermidis Ampicillin Amoxicillin Spectrum extended to Gm(-) bacilli Carbenicillin UTI by pseudomonas Mezlocillin piperacillin Pseudomonas , klebsiella infections
- 24. Penicillin V • Acid stable, oral absorption is better • Used only for mild to moderate infections – Streptococcal pharyngitis, sinusitis, otitis media – Prophylaxis of rheumatic fever – Less serious pneumococcal infections, trench mouth • Dose: 250 to 500 mg 6 hrly
- 25. Penicillinase resistant penicillins • Resistant to staphylococcal penicillinase • Their only indication is infections caused by penicillinase producing staphylococci (DOC) • These drugs are not resistant to Gm (-) β-lactamases • Methicillin: not used now – Hematuria, albuminuria, reversible interstitial nephritis • These drugs are not effective in MRSA infection
- 26. Cloxacillin • Highly penicillinase as well as acid resistant • Incomplete but dependable absorption from oral route • > 90% protein bound • Eliminated by kidneys also partly by liver • Dose: 250 – 500 mg QID , in severe infections can be given IM /IV
- 27. Aminopenicillins • Extended spectrum penicillins • Spectrum of action: – Like penicillin G in addition some Gm(-) bacilli like H.influenzae, E.coli, Shigella, salmonella, proteus – More active for streptococcus viridans & enterococci
- 28. Ampicillin & Amoxycillin Ampicillin Amoxycillin Incompletely absorbed from GIT Completely absorbed Diarrhoea more common Less common Food ↓ absorption No effect Enterohepatic circulation No Effective against shigella and H. Influenza Less effective Dose = 250-500 mg QID 250 -500 mg TDS
- 29. Uses of aminopenicillins • Upper respiratory tract infections: • Urinary tract infections: • Meningococcal Meningitis • Shigellosis: Ampicillin • Subacute bacterial endocarditis: • Ampicillin 2 gm IV 6 Hrly in place of penicillin G • Typhoid fever • Cholecystitis: Ampicillin
- 30. Antipseudomonal penicillins • Carbenicillin: – Higher doses can cause fluid retention, CCF & can interfere with platelet function • Piperacillin – 8 times more active than carbenicillin – Good activity against klebsiella – Uses: • Neutropenic, immunocompromised patients having serious Gm(-) infections and burns, septicemia
- 31. Reverse spectrum penicillins • Mecillinam , pivmecillinam • More stable to β-lactamases degeneration than ampicillin • Acid stable but poorly absorbed • Act by inhibiting PBP-2, prevent cell elongation causing spherical forms • Reverse spectrum? – Mainly effective against Gm(-) bacilli- E.coli. Enterobacter, salmonella, klebsiella
- 32. β-lactamase inhibitors • Clavulanic Acid • Sulbactum • Tazobactum Also called as suicide inhibitors
- 33. Clavulinic acid • Isolated from Streptomyces clavuligerus • Inhibits β lactamases produced by variety of Gm(+) & Gm(-) bacteria • Rapid oral absorption, 60 % bioavailable • Elimination half life & tissue distribution matches with amoxycillin • Use: infections caused by β lactamase producing strains of S.aureus, E.coli, H.influenzae, proteus
- 35. Sulbactum • Semisynthetic β-lactamase inhibitor • 2-3 times less potent than clavulanic acid • Oral absorption inconsistent • Uses: – PPNG gonorrhoea – Mixed aerobic-anaerobic infections • Combined with ampicillin for IV/IM administration
- 36. Tazobactum • More potent than sulbactum • Pharmacokinetics matches with piperacillin • Available in combination with piperacillin • Uses: – Severe infection like peritonitis, , pelvic, urinary, respiratory infections caused by β-lactamase producing bacteria
Notes de l'éditeur
- Chemotherapeutic agents - are chemical substances used for therapeutic purposes. •Implies chemical synthesized or modified by chemists. •Antibiotics – are metabolic products of a microorganism. •Antibiotic = Greek -- “against life”.
- Beta lactum antibiotics are group of antibiotics having beta lactum ring in their structure , they share common structure and mechanism of action.
- 1928 – St Mary hospital, studying staphylococcus variants , sir alexander fleming observed that in a culture plate contaminted with a fungus penicillium , the growth of bacteria was inhibited The first marketable penicillin cost several dollars per lac units , now costs few cents Previously was obtained from penicillium notatum now a days obtained from penicillium chrysogenum The name Penicillium comes from penicillus = brush, and this is based on the brush-like appearance of the fruiting structures
- Sulfur containing thiazolidine ring A fused with Beta lactum ring to which side chains are attached through amide linkage penicillin G is original penicillin having benzyl side chain The side chain of natural penicillins can be split off by amidase to produce 6 amino penicillanic acid (Active moeity) , otherside chains can then be attached to this to produce different semisynthetic penicillins with different antibacterial properties and pharmokinetic profile The Beta lactum ring of penicillins is susceptible to beta lactamases – penicillinase produced by invading bacteria like (Staphylococcus, E coli) to form inactive penicilloic acid . This penicilloic acid can combine with host protein and act as antigenic determinant of penicillin induced hypersensitivity.
- Bacteria have no mechanism of their own to regulate the osmolarity so they rely on supportive srtucture around cell wall to withstand the osmotic changes Majority of bacteria have thick cell wall which confers stability and rigidity to their cell structure The cell wall is composed peptidoglycan chain: the later is composed of parallel glycan chain crossed linked by peptide chains hence named peptidoglycan – NAMA & NAG Cross linked by peptide chains, this peptidoglycan layer envelopes the cell and doesn’t allow it to swell
- Penicillins they are bactericidal drugs: agents that show time dependent killing with shirter Post antibiotic effect Their conc should be kept above MIC or MBC for as long as possible during dose intervals (Agents that show conc dependent killing with long PAE= Aminoglycosides, fliroquinolones, metronidaxzole, rifampicin, these agents kill bacteria more rapidly if their serum conc are kept appreciably above the MIC , hence wider dosage intervals can be chosen from this group of drugs Agents showing time dependent killing with longer PAE = Azithromycin, clarithromycin, vancomycin, tetracycline) The glycan chain consists of the repeating units of two amino amino sugars – N-acetyl muraminic acid & N acetyl glucosamine , the penta peptide chain is linked to N acetyl muraminic acid, these peptide chains are cross linked to other peptide chains with help of penta glycine bridge which extends from L- lysine residue of one peptide chain to D alanine residue of other peptide chain. This cross bridging between the peptide chains of peptidoglycan is essential for to provide necessary strength to bacterial cell wall. The process of cross bridging is called transpeptidation reaction it is catalyzed by penicillin binding proteins Penicillin binding proteins: are transmembrane surface enzymes present in the bacteria Three types of penicillin binding proteins are found in cytoplasmic membrane of all bacterial species Transpeptidase: PBP-1: cleaves the Terminal d-ala and joins it to l lysine adjacent PBP 2: is carboxypeptidase: it hydrolyses the terminal D-ala residue present on the pentapeptide chain to promote further cross linking at that site , its inhibition leads to formation of spherical cells rather than rod shaped bacilli PBP-3: is an endopeptidase: it splits cross linking invoved in septum formation during cell division. Its inhibition results in filamentation wherein the cells cannot separate from one another during cell division
- The stereochemical configuration of Penicillin is similar to D-Alaninyl D alanine portion of pentapeptide strand, so penicillins compete for penicillin binding proteins and inhibit penicillin binding protein mediated transpeptidation reaction. Formation of incomplete cell wall formation of incomplete cell wall leads to an osmotic drive of fluid from outside of the environment to inside of bacteria which then swells and bursts to die. The death of bacteria is not solely due to osmotic drive but also results from activation of autolysing enzymes called murein hydrolases or autolysins. penicillins are lethal in multiplying phase rather than dormant phase.
- Penicillin G & its esters Penicillin G, procaine penicillin G, benzathine penicillin G Penicillins (Eg, Penicillin G) These have greatest activity against gram-positive organisms, gram-negative cocci, and non– -lactamase producing anaerobes. However, they have little activity against gram-negative rods, and they are susceptible to hydrolysis by lactamases. Acid Resistant penicillins Phenoxyethyl penicillin Phenoxy methyl penicillin Penicillinase resistant penicillins Acid stable: Cloxacillin, dicloxacillin, flucloxacillin Acid labile: Methicillin, nafcillin
- All are sensitive to beta lactamase
- Streptococci except group D, viridans or enterococci.
- Penicillin G is acid labile destroyed by gastric juice as such less than 1/3 of active oral dose is absorbed Probenecid blocks the tubular secretion of penicillins and prolongs the half life and increases the concentration of penicillin G as Well as other penicillins Probenecid when administered orally in dose of 2 gm /day in divided doses along with penicillin it increases the plasma levels 2-4 fold Probenecid is capable of producing allergic reactions not recommended in children
- Most strains of pneumococci are susceptible to penicillins and hence it continues to be drug of choice for these infections Pneumococcal pneumonia: therapeutic response to penicillin becomes apparent witin 48 to 72 hrs, in milder cases and in patients known to be allergic to penicillins oral macrolide like erythromycin or azithrromycin may be used , 15 -30 % resistance developed S.pneumoniae so in hospitalized pt who are seriously ill cefotaxime or ceftriaxone drug of choice Pneumococcal empyema and pericarditis; Benzyl penicillin G 2 mega units IV every 2 hrly (24 mega units per day ) in addition half to 1 mega unit of benzyl penicillin benzyl penicillin in 50 to hundred ml of isotonic saline should be infused intrapeluerally for several days if pleural fluid is very thick you can give proteolytic enzymes like streptokinase & streptodornase
- Amoxycillin 2 gm in adults , 50 mg/kg In children 1.2 mega units of benzathine penicillin Rheumatic fever: low conc of penicillins prevent the colonization by streptococci responsible for rheumatic fever.
- Local irritancy or direct toxicity : pain at IM site ,
- Peak blood level reached in 1 hr t1/2 = 30-60 min
- Except MRSA
- But not against MRS, Oxacillin, dicloxacillin, flucloxacillin are not marketed in India Nafcillin: parenteral penicillinase resistant penicillin
- Bacampicillin: prodrug of ampicillin , nearly completely absorbed from GIT , largely hydrolysed during absorption Thus higher plasma levels are achieved Tissue penetration is better Doesn’t disturb intestinal ecology: less diarrhoea Dose: 400-800 mg BD
- Ticarcillin is more potent than carbenicillin against pseudomonas, other properties are similar Mezlocillin: Given parenterally primarily for infections caused by enreric bacilli
- Clavulinic acid has a beta lactum ring but no activity of its own Progressive inhibitor : binding withbeta lactamase is reversible initially but later becomes covalent (Inhibition increases with time) Half life = 1 hr Eliminated mainly by glomerular filtration and its excretion is not affected by probenecid , largely hydrolysed and decarboxylated before excretion. Amoxicillin is primarily excreted unchanged by tubular secretion SHE, PROTEUS, KLEBSIELLA, SHIGELLA, SALMONELLA , BACTEROIDES FRAGILIS USES: skin, soft tissue, intraabdominal infections , gynaae sepsis, urinary , biliary & respiratory tract infections , emperic therapy for hospital acquired infections Gonorrhoea 3 +0.5 + 1 gm probenecid Amoxycillin 250 mg + 125 CL acid / 500 amox + 125 Clav , inj 1g + 0.2 cl acid TDS
- Pain at site of injection, thrombophlebitis most common adverse events