Cell Wall Synthesis Inhibitors Part 1 PDF

Cell wall synthesis inhibitors Part 1 Pharmacology 3 Dr. Rawan Abudalo Department of Clinical Pharmacy and Pharmacy Practice Faculty of Pharmaceutical Sciences Hashemite University Inhibitors of Cell Wall Synthesis Inhibitio...

Cell wall synthesis inhibitors Part 1 Pharmacology 3 Dr. Rawan Abudalo Department of Clinical Pharmacy and Pharmacy Practice Faculty of Pharmaceutical Sciences Hashemite University Inhibitors of Cell Wall Synthesis Inhibition of Cell Wall Synthesis β-Lactam Drugs  The main group of AB that act on bacterial cell wall is the ‘beta lactams’; so called due to presence of a β-lactam ring.  Irreversibly inhibit enzymes involved in the final steps of cell wall synthesis  β-lactam drugs include:  Penicillins  Cephalosporins  Carbapenems  Monobactams β-lactam antibiotics Basic structures of four groups of β-lactam antibiotics and clavulanic acid. The structures illustrate the β-lactam ring (marked B) and the sites of action of bacterial enzymes that inactivate these antibiotics (A, thiazolidine ring). Bacterial lactamse: Enzyme that hydrolyzes B-Lactam ring and causes loss of activity (acid does that too)  Bacterial cell wall The cell wall is a rigid outer layer that completely surrounds the cytoplasmic membrane, maintains cell shape and integrity, and prevents cell lysis from high osmotic pressure. The cell wall is composed of a complex, cross- linked polymer of polysaccharides and polypeptides, peptidoglycan. Mechanism of action of β-lactam antibiotics All β-lactam antibiotics interfere with the last step of bacterial cell wall synthesis, which is the cross-linking of adjacent peptidoglycan strands by a process known as transpeptidation. They compete for and inhibit enzymes called transpeptidases (Penicillin Binding Proteins (PBP)). Mechanism of action of β-lactam antibiotics β-Lactam antibiotics, structural analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active site of PBPs They interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross- linkage) The result is the formation of a weakened cell wall and ultimately cell death (or this reason, they are regarded as bactericidal). Mechanism of action of β-lactam antibiotics 11 Penicillins  The most widely effective and the least toxic drugs known.(interfere with a site or function unique to the growth of m.o)  Safe drugs (if we exclude the allergy rxn)  Mainly excreted by the kidneys.  Suffix : cillin Chemically penicillins consist of a 6-amino penicillanic acid nucleus with attached side chain (R). Members of penicillin family differ from each other by side chain (R) attached to 6-amino penicillanic acid. The nature of this side chain affects the: 1.antimicrobial spectrum 2.stability to stomach acid 3.cross-hypersensitivity, 4.susceptibility to bacterial degradative enzymes (β-lactamases).  Classification of penicillin 1- Natural Penicillins 3- Anti-pseudomonal Penicillins Penicillin G( parenteral) Penicillin V( oral) Piperacillin 2- The extended Spectrum Penicillins 4- Penicillinase Resistant Penicillins (anti-staphylococcal) Aminopenicillins : Ampicillin Cloxacillin. Amoxicillin  1. Natural Penicillins They are susceptible to inactivation by B-lactamases (penicillinases) Narrow -spectrum  (Benzylpenicillin) (Phenoxymethylpenicillin) Penicillin G Penicilin V -also called Crystalline penicillin. Penicillin V is more acid-stable than penicillin G. -it is powder form. Given orally (every 4h). -can be given IV (bolus or infusion) or IM. Oral penicillin. - Has short duration (1-2 h). It is indicated in the treatment of: Destroyed by gastric juice if it is given Tonsillitis. orally so, NOT given orally. Pharyngitis - It is indicated in the treatment of:  Syphilis.  acute Tonsillitis.  tetanus  Derivatives of penicillin G Long-acting forms:- insoluble salt of penicillin G thus slow abs with long duration. 1- Procaine penicillin G (12 h). 2- benzathine penicillin G (4 weeks). Effective in treatment in syphilis. Prophylactic in rheumatic fever patients. Both are administered IM and serve as depot forms. they are suspension formulation that is never given by IV route.  2. Extended-spectrum Penicillins or Aminopenicillin: Ampicillin and amoxicillin They are susceptible to inactivation by B- lactamases (penicillinases) Ampicillin Amoxicillin Orallly is given every 8h (3x1). (IV, Oral) is given every 6h (4x1).  better absorbed orally than ampicillin with less diarrhea. It is used in Bacillary Dysentery. 1g for 5 days + fluids.  Is employed prophylactically by dentists for patients with abnormal heart valves who are to Indicated in listeriosis. undergo extensive oral surgery.  used in treatment of peptic ulcer  Diarrhea is common side effect to eradicates H.Pylori. WHY????  Otitis media.  urinary tract infections. Some bacteria produce β-lactamase enzyme that breaks the critical β-lactam ring  B-lactamase inhibitors Substance don’t have antibacterial activity but they have the ability to inhibit the B- lactamase enzyme…. Ex. Clavulanic acid clavulanic acid binds to beta-lactamase and competitively protects amoxicillin *They potentiating amoxicillin against beta- lactamase producing bacteria. * It is called “suicide inhibitor” Formulation with a β-lactamase inhibitor, such as : amoxicillin +clavulanic acid ampicillin +sulbactam. protects from enzymatic hydrolysis  extends their antimicrobial spectra. without the β-lactamase inhibitor, MSSA is resistant to ampicillin and amoxicillin.  3- Anti staphylococcal penicillins Also called anti-staph or penicillinase resistance penicillins. Ex. Methicillin, Flucloxacillin, Cloxacillin, Dicloxacillin, Nafcillin. Given IV & orally. (every 4-6 hr) They are restricted to the treatment of infections caused by penicillinase-producing staphylococci (narrow-spectrum). Because of nephrotoxicity caused by methicillin, nowadays this drug is not used clinically. Strains of staphylcoccus resistant to these drug called : methicillin- resistant staphylococcus aureus (MRSA). MRSA is a serious source of nosocomial (hospital-acquired) infections. (MRSA commonly respond to vancomycin.) 4- Anti pseudomonal Penicillins: Ex. Piperacillin, Ticarcillin Ps.aeruoginosa: G-ve bact lacks porins  Making these organism resistant to many antimicrobial agents. Ps.aeruginose very difficult to deal with & produce resistance easily. Given parentally not orally. piperacillin with tazobactam, extends the antimicrobial spectrum to include penicillinase-producing organisms.  Pharmacokinetics of Penicillins  Absorption:  Penicillins vary in their resistance to gastric acid and therefore vary in their oral bioavailability.  Examples of compounds relatively stable to gastric acid and suitable for oral administration are penicillin V, dicloxacillin, and amoxicillin.  Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food (administered at least 1–2 hours before or after a meal).  Distribution:  Most penicillins cross the blood-brain barrier only when the meninges are inflamed.  Pharmacokinetics of Penicillins  Metabolism and excretion:  Penicillins are polar compounds usually excreted unchanged in the urine (inhibited by probenecid).  Patients with impaired renal function must have dosage regimens adjusted.  Because nafcillin and oxacillin are primarily metabolized in the liver, they do not require dose adjustment for renal insufficiency.  Adverse reactions of penicillins 1-Hypersensitivity reaction : 5% of population Allergic reactions range from a variety of skin rashes to anaphylactic shock (very rare—0.05% of recipients).  Cross sensitivity with other β-lactam as cephalosporins.  Should be avoided if history is positive. 2-Diarrhea (most common): it is a common problem mainly with (Ampicillin). Pseudomembranous colitis may occur. 3. Nephritis: Penicillins, particularly methicillin, have the potential to cause acute interstitial nephritis. [Note: Methicillin is therefore no longer used clinically.] Piperacillin-tazobactam, when combined with vancomycin, has been associated with greater incidence of acute kidney injury compared to alternate β-lactam agents. 4. Neurotoxicity: The penicillins can provoke seizures if injected intrathecally or if very high blood levels are reached.  Resistance to penicillins and other B-lactams Resistance to penicillins and other β-lactams is due to one of four general mechanisms: 1.Inactivation of antibiotic by B-lactamase (the most common mechanism) 1.Decreased permeability to the drug  is a greater concern in G- (impermeable outer cell wall ) A. Absence or down-regulation of porins. B. Presence of an efflux pump, which transport B-lactam antibiotics from the periplasm back across the outer membrane. 3. Modification of target PBPs. low affinity for binding B-lactam antibiotics basis of methicillin resistance in staphylococci (MRSA). 32 Thank you