pharmacology

• Anti-microbial drugs


  • Anti-bacterial drugs

  
• Classes of anti-bacterial drugs


  • Class I: glucose or carbon source for generation of ATP (not used)
  • Class II: utilisation of precursors of factors needed by cell for survival and growth (folate synthesis inhibition (sulphonamides), folate utilisation inhibition (trimethoprim and pyrimethamine))
  • Class III: assembly of small molecules into macromolecules (peptidoglycan synthesis (b-lactam antibiotics), prevent binding of tRNA (tetracyclines), promote misreading of mRNA (aminoglycosides), inhibit transpeptidation (chloramphenicol), inhibit translocation of tRNA (erythromycin), altering base pairing of DNA (vidarabine), inhibiting DNA polymerase (acyclovir), inhibiting DNA gyrase (ciprofloxacin))

  
• Bacteriostatic


  Prevents growth of bacteria
• Bactericidal


  Kills bacteria
• Sulphonamides and trimethoprim


  • Sulfonamides (sulfamethoxazole)
  • Trimethoprim (TMP)
• Sulfonamides (sulfamethoxazole)


  Acts on bacterial folate synthesis, compete with PABA for the enzyme dihydropteroate synthetase. Bacteriostatic- inhibit synthesis of DNA and RNA in bacteria.
• Indications/uses of sulfonamides


  • UTIs, pneumocystis carinii, toxoplasmosis and nocardiosis
  • Combined with pyrimethamine for drug-resistant malaria
• Side effects of sulfonamides


  • Mild-moderate: nausea, vomiting, headache, depression, haemolysis in G6PD deficient patients
  • Serious (need to stop therapy): hepatitis, hypersensitivity reactions (stevens-johnson syndrome, toxic necrolysis, fever, anaphalxis), bone marrow depression
  • Acute renal failure (acetylated metabolites in urine → interstitial nephritis or crystalluria)
• Contraindications of sulfonamides


  • Allergy to sulphonamides or porphyria
  • Near term or breastfeeding mothers, patients <2mths old (except for congenital toxoplasmosis)
  • Possibility of kernicterus in foetus or neonate
• Sulfonamides are used in combination with trimethoprim (co-trimoxazole)
• Trimethoprim (TMP)


  Inhibits dihdrofolate reductase (folate X→ tetrahydrofolate). Bacteriostatic.
• Indications/uses of trimethoprim


  • Urinary, pulmonary and other infections
  • Fungal pneumonia, toxoplasmosis, pneumocystis (MRSA strains), nocardiasis

  
• Side effects of trimethoprim


  • Nausea, vomiting, megaloblastic anaemia (due to folate deficiency)
  • Hyperkalaemia, leukopenia (treats marrow poorly)
• Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole)
• Benzylpenicillin (penicillin G, IV or IM form) and Phenoxymethylpenicillin (penicillin V, oral form)


  Cell wall synthesis inhibitors. Attach to penicillin-binding proteins to inhibit transpeptidation enzyme that crosslinks the peptide chains attached to the backbone of peptidoglycan. Bactericidal- inactivation of an inhibitor of autolytic enzymes in cell wall → lysis.

  
• Indications/uses of benzylpenicillin


  • Bacterial meningitis, skin and soft tissue infections, endocarditis
  • Procaine benzylpenicillin: syphilis
• Indications/uses of phenoxymethylpenicillin


  • Pharyngitis
• Side effects of penicillins


  • Hypersensitivity reactions: rash, fever, serum sickness, acute anaphylactic shock
  • Oral: alter bacterial flora in the gut (GI disturbances and suprainfection → pseudo-membranous colitis
• Contraindications of penicillins


  • Allergy
  • Severe renal insufficiency (drug induced interstitial nephritis)
• Probenecid inhibits tubular secretion of many penicillins
• Penicillins


  • Widely distributed in body fluids (joints, pleural and pericardial cavities, bile, saliva, milk, placenta)
  • Only cross BBB if meninges are inflamed
  • Elimination is rapid and mainly renal (90% tubular secretion)
• Mechanism of resistance to penicillins


  • Naturally occurring
  • Large, water soluble molecules
  • Poor absorption in GI, susceptible to bacterial beta-lactamases
  • B-lactamases cleave B-lactam ring of penicillins and cephalosporins
  • Genes coding for enzymes are on plasmids that can be transferred by transduction (in staphylococci, the enzyme is inducible and antibiotics de-repress the gene increasing expression) → enzyme passes through bacterial envelope and inactivates antibiotic
• Types of penicillins


  • B-lactamase resistant penicillins (methicillin, flucloxacillin, temocillin)
  • Broad spectrum penicillins (ampicillin, amoxicillin)
  • Extended spectrum penicillins (ticarcillin, piperacillin)
  • Carbapenems (imipenem, meropenem, ertapenem)
  • Monobactams (aztreonam)
  • Glycopeptides (vancomycin)
• Indications/uses of penicillins


  • Flucloxacillin: bone and joint infections, skin and soft tissue infections
  • Amoxicillin: otitis media, pneumonia, bronchitis, UTIs
  • Co-amoxiclav: animal bites
  • Serious pseudomonas aeruginosa infections

  
• Carbapenems


  Affect peptidoglycan cross-linking. Broad spectrum, resistant to b-lactamase.
• Monobactams


  Affect peptidoglycan cross linking. Resistant to b-lactamase. Gram – rods only.
• Glycopeptides (vancomycin)


  Inhibit wall peptidoglycan formation. Resistant to b-lactamase.
• Indications/uses of glycopeptides


  • Parenteral for systemic infection, oral for pseudomembranous colitis
  • Gram +
  • Serious resistant organisms

  
• Side effects of glycopeptides


  • Normally well tolerated
  • Nephrotoxicity, ototoxicity, hypersensitivity reactions (red man syndrome) (prevented by slow infusion rate and anti-histamines)
• Glycopeptides are used for MRSA and Clostridium difficile
• Generations of cephalosporins


  • 1st generation: cefazolin, cephalexin
  • 2nd generation: cefaclor, cefoxitin, cefuroxime
  • 3rd generation: ceftriaxone, cefotaxime, ceftazidime
  • 4th generation: cefepime
  • 5th generation: ceftaroline
• 3rd generation cephalosporins are most commonly used, 4th/5th generation are reserved for more serious or resistant infections
• Mechanism of resistance to cephalosporins


  Plasmid encoded or chromosomal b-lactamase or alterations to outer membrane proteins/ binding site proteins
• Indications/uses of cephalosporins


  • Gonorrhoea, septicaemia, pneumonia, meningitis, biliary tract infection, UTIs, sinusitis

  
• Side effects of cephalosporins


  • Hypersensitivity reactions, cross-reactivity with penicillin, nephrotoxicity (drug-induced alcohol intolerance), diarrhoea
• Cefuroxime, cefotaxime and ceftriaxone cross the blood-brain barrier and are excreted by the kidney
• Cephalosporins should be avoided in severe penicillin allergy
• Tetracyclines, amphenicols and aminoglycosides


  • Tetracyclines (tetracycline, doxycycline, oxytetracycline, demeclocycline, lymecycline, minocycline)
  • Amphenicols (chloramphenicol)
  • Aminoglycosides (gentamicin, streptomycin, amikacin, tobramycin, neomycin)
• Tetracyclines


  Affect 30S subunit of bacterial protein synthesis. Uptake by active transport → inhibit protein synthesis. Bacteriostatic.
• Indications/uses of tetracyclines


  • Broad spectrum for gram + and gram – bacteria, spirochaetes and some protozoa
  • Rickettsial and chlamydial infections, brucellosis, anthrax, Lyme disease
  • Acne (doxycycline, minocycline), second choice for pts with allergies, respiratory tract infections
  • SIADH or malignant lung tumours: demeclocycline