Drug 10

• adverse drug event 


  harm caused by appropriate or inappropriate use of drug (can be equipment)
• adverse drug reaction


  subset of events, harm caused by drug under appropriate use (normal dose)
• 3 groups at increased risk of ADRs

  elderly patients, pregnant women, paediatric patients
• Type A ADR


  linked to pharmacological effects of a drug, show a dose-response relationship
• Type A ADR example

  respiratory depression with opioids such as morphine
• respiratory depression symptoms 


  miosis (pupil constriction), euphoria, sedation, nausea
• opioids and mediation by receptor 


  u opioid receptor mediates both therapeutic and adverse effects, when receptor activated get signal transduction associated with both effects
• Type C ADR


  chronic, cumulative dose and time related
• Type D ADR


  delayed, after use of drug
• Type D ADR example

  teratogenesis from teratogens, the toxic response is in offspring
• Type E ADR


  unwanted effects following withdrawal of a drug
• Type F ADR


  unexpected failure of drug to produce therapeutic effects
• Type F ADR example

  antibiotic resistance
• Type B ADR


  hypersensitivity reactions, strange, no link to pharmacological mechanism of action so unpredictable
• Type B ADR example

  anaphylaxis to penicillin (drug induced sensitivity)
• how can some type B ADR be predicted

  linked to genetic predisposition (polymorphism) affecting PK/PD
• what makes paediatric patients at increased ADR risk

  are developing DME's, receptors and transporters so don't have metabolising or clearance capacity, dosing based on adult formula may be inappropriate
• Pregnant women - drug absorption

  increased gastric pH ionisation of drugs, decreased absorption of weak acids
• Pregnant women - drug distribution

  increased Vd for lipophilic and hydrophilic drugs
• Pregnant women - drug metabolism and excretion

  increased CO, increased hepatic and renal metabolism
• Pregnant women - protein binding

  decrease drug binding, more free drug for action
• elderly patients drug distribution

  increased Vd for lipophilic drugs, decreased for hydrophilic drugs
• elderly patients drug metabolism

  impaired CYP mediated metabolism (important if drug hepaticaly cleared)
• elderly patients drug excretion

  deceased GFR (reduced renal size and nephron function), consider for renally cleared drugs
• elderly patients drug protein binding

  decrease plasma albumin level, less drug binding and more free drug for action
• Type 1 B ADRs

  IgE mediated hypersensitivity, immediate reaction
• Type 4 B ADR

  T cell mediated hypersensitivity, delayed
• T cell mediated hypersensitivity theories

  pi concept, hapten theory, altered peptide repertoire model, altered TCR repertoire model
• hapten theroy (T cell hypersensitivity)

  drugs of low molecules weight bind carrier protein, phagocytose by APCs, antigen presentation to T cells
• p-i concept 


  drugs or metabolites interact directly with HLA or TCR get get T cell response (not APC processing)
• altered TCR repertoire model 


  drug binds TCR and changes HLA recognition
• altered peptide repertoire model


  self to non self recognition, drug binds and changes shape of TCR/HLA so don't recognise correct peptides
• type 1 (Type B ADR) reaction


  skin, itch, maybe anaphylaxis (is immediate)
• type 4 (type B ADR) reaction

  delayed, on second exposure after sensitisation is inflammation and tissue damage often targeting skin