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PHAR2210 Foundations of Pharmacology Lecture 18 Antibacterial drugs Dr Ricky Chen Chapters 51 & 52, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to describe penicillins and cephalosporin...

PHAR2210 Foundations of Pharmacology Lecture 18 Antibacterial drugs Dr Ricky Chen Chapters 51 & 52, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to describe penicillins and cephalosporins in terms of pharmacokinetics, mechanism of action, adverse effects, and mechanisms of drug resistance explain the use of Augmentin to overcome penicillin resistance describe four classes of bacterial protein synthesis inhibitors in terms of pharmacokinetics, mechanism of action, adverse effects, and mechanisms of drug resistance Core concepts of pharmacology pharmacodynamics pharmacokinetics Drug-target Drug target Steady-state Drug absorption Drug bioavailability interaction concentration Mechanism of Structure-activity Drug distribution Volume of distribution drug action relationship Zero- and first- order kinetics Drug metabolism Drug clearance Affinity Drug selectivity Drug elimination Drug elimination half-life Potency Efficacy DRUG Dose/concentration- Drug tolerance response relationship Therapeutic index Adverse drug reaction Individual variation Adapted from Guilding et al. (2023) Defining and Drug interaction in drug response unpacking the core concepts of pharmacology: A global initiative. British Journal of Pharmacology, 1-18. Patient outcomes https://doi.org/10.1111/bph.16222  Mechanisms of action of antibacterial drugs inhibit cell wall synthesis o penicillins* o cephalosporins*​ inhibit protein synthesis o aminoglycosides* drug class o tetracyclines* o amphenicols* o macrolides​* inhibit DNA replication​ inhibit metabolism Lewis (2013) Bacterial cell wall and Gram staining Pseudomonas aeruginosa Rod-shaped Bacillus anthracis Brown et al. (2015)  Bacterial cell wall 3-dimensional lattice comprising peptidoglycan glycan (aminosugar) chains cross-linked by peptide linker chains o peptidase activity of penicillin binding proteins linear strands of two alternating aminosugars o N-acetyl-muramic acid (NAMA) o N-acetyl-glucosamine (NAG) Rang and Dale’s Pharmacology (2024) Cell wall synthesis inhibitors - β-lactams the b-lactam ring (highlighted in orange) is essential for antibacterial activity Interactions between β-lactam drugs and various penicillin binding proteins (PBPs) in bacteria explain differences in antibacterial specificity  β-lactams (I) - penicillins Drug​ Natural (N) / semisynthetic (S) Spectrum of action b-lactamase resistant? penicillin G N narrow no amoxicillin​* S​ broad​ no​ dicloxacillin​ S​ narrow​ yes​ clavulanic acid*​ S​ - β-lactamase inhibitor​ Pharmacokinetics stability in acid varies lipid insoluble o do not enter mammalian cells o cross the blood–brain barrier only if the meninges are inflamed most penicillins are eliminated via the renal route (90% by tubular secretion) rapidly  Penicillin resistance Produce alterations in PBPs → decreased drug binding and subsequent ↓ antibacterial activity Prevent β-lactams from accessing and traversing pore channels and reaching PBPs in the cell membrane of gram-negative bacteria Produce β-lactamase to inactivate β-lactams Augmentin* (amoxicillin + clavulanic acid) amoxicillin: R = β-lactamase producing bacteria clavulanic acid  Penicillin-related adverse drug reaction opening of b-lactam ring → benzylpenicilloyl (major determinant, 95%) hypersensitivity reactions o Type I - symptoms appear (~ an hour) in the skin, e.g., itch, urticaria; anaphylaxis in up to 0.04% of patients o Type IV - T-cell mediated superinfection such as candidiasis occurs due to prolonged use NH2 carrier protein β-lactams (II) - cephalosporins generation of cephalosporins spectrum of action​ 1​ Gram+​ 2​ less Gram+ (compared to 1), and some Gram- 3​ Gram+, and greater Gram- 4​ Gram+, and even greater Gram- Expanded Gram+, including MRSA (methicillin-resistant 5​ Staphylococcus aureus); common Gram- MRSA binding with very low affinity binding with high affinity b-lactams PBP2A ceftaroline (5th gen.) cell wall synthesis  β-lactams (II) - cephalosporins Pharmacokinetics acid stable most are administered parenterally; a few can be administered orally distribution - extracellular fluid ; some can cross blood-brain barrier to treat meningitis excretion is mostly by renal tubular secretion Cephalosporin-related adverse drug reaction similar to penicillins cross-reactivity between penicillins and cephalosporins o opening of b-lactam ring → cephalosporoyl, but is unrelated to adverse drug reaction o similarity of side chain between penicillins and cephalosporins (1st and 2nd gen.)  Bacterial ribosome 70S bacterial ribosome consists of two subunits [S: the Svedberg unit for sedimentation coefficient] 50S subunit 30S subunit 5’ 3’ fMet - N-formylmethionine mRNA Bacterial protein synthesis - key steps  Bacterial protein synthesis inhibitors (PSIs) inhibit one of the four key steps in bacterial protein synthesis most are bacteriostatic (aminoglycosides are bactericidal) Step of protein synthesis​ Drug class Mechanism(s) of action of this drug class [30S] inhibit codon-anticodon interaction;​ initiation​ aminoglycosides* cause mRNA misreading​ tRNA binding​ tetracyclines* [30S] inhibit aa-tRNA binding to the A site​ transpeptidation​ amphenicols* [50S] inhibit peptide bond formation​ elongation and/or [50S] prevent transfer of tRNA with the antibacterial macrolides* translocation growing peptide from A site to P site  Bacterial PSIs (I) - aminoglycosides inhibit codon-anticodon interaction, causing mRNA misreading spectrum of action - Gram- bacteria and some Gram+ bacteria bactericidal​​ time- and concentration-dependent - AUC:MIC Pharmacokinetics administered intramuscularly or intravenously (not absorbed from the GI tract) elimination by glomerular filtration ototoxicity hearing loss and impaired vestibular functions nephrotoxicity accumulation in proximal tubular epithelial cells  Bacterial PSIs (II) - tetracyclines inhibit aa-tRNA binding to the A site broad spectrum of action - Gram- and Gram+ bacteria bacteriostatic tetracyclines Pharmacokinetics administered generally orally but can also be administered parenterally Gastrointestinal disturbance direct irritation and modification of gut flora following prolonged use​ Calcium chelation tetracycline accumulation in teeth and growing bones o staining and bone deformities - avoid in children and pregnant women (category D)​  Bacterial PSIs (III) - amphenicols inhibit peptide bond formation broad spectrum of action - Gram- and Gram+ bacteria bacteriostatic Pharmacokinetics chloramphenicol* o rapid absorption following oral administration o hepatically cleared (UGT2B7; 10% excreted unchanged in the urine) Bone marrow suppression idiosyncratic; pancytopenia - ↓ in all blood cell elements Grey baby syndrome insufficient hepatic glucuronidation and excretion in newborns chloramphenicol  Bacterial PSIs (IV) - antibacterial macrolides prevent transfer of tRNA with the growing peptide from A site to P site similar spectrum of action to penicillins - useful alternatives concentrated within phagocytes - enhance intracellular killing of bacteria macrolides Pharmacokinetics oral (common) or IV administration substrates for and inhibitors of CYP3A4 - drug-drug interactions Gastrointestinal disturbance Mechanisms of resistance to bacterial PSIs drug class mechanism of resistance aminoglycosides (g) drug modification​ tetracyclines (b) active efflux of the drug from the cell; (g) drug modification​ chloramphenicol (d) target modification (ribosomal RNA or proteins) macrolides (d) target modification (ribosomal RNA or proteins); (h) drug degradation (by esterases) Wilson (2014)