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Module 10 Notes.docx

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Pharmacology 2060A/B
Angela Nissen

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Module 10 Advserse Drug Reactions and Medication Errors 10.1 Advserse Drug Reactions • ADRs: unintended and undesired responses from drugs o Enormous societal health problem o 7.5% of hospital admissions in Canada are attributed to adverse drug reactions   185,000 ppl/yr • includes o Side effects o Drug toxicity o Allergic reaction o Idiosyncratic reaction o Mutagenic effects o Teratogenic effects • Side Effects o Secondary to main therapeutic effect of drug o Occur at normal therapeutic doses o Often unavoidable o Often due to poor specificity or selectivity of drug o Ex.  Antihistamines block H1 histamine receptors to prevent symptoms of allergy  Side effects include drowsiness, dry mouth, urinary retention  Histamine binds histamine receptor in sinuses, causes vasodilation which results in runny  nose and watery eyes  Antihistamines block effect of histamine  Side effects occur when they bind to histamine receptors or other receptors in brain • Produces sedation, dry mouth and urinary retention • • Drug Toxicity o A severe adverse drug event o Often mediated by overdose   Where patients unintentionally or intentionally take too much medication o Often extensions of therapeutic effect o Ex.  A patient who takes too much insulin gets hypoglycaemia (low blood glucose) • • Allergic Reaction o Mediated by immune system o Requires prior sensitization where patient is exposed to allergen (drug) o Upon subsequent exposure, allergic reaction will occur  Mast cells release chemical mediators such as histamine o Allergic reactions can vary from itching and rash, to life threatening anaphylaxis  (bronchospasms, edema, severe hypotension) o Intensity is independent of dosage size  Small doses can produce severe allergy o ~10% of all ADRs are related to drug allergy o very few drugs cause allergic reactions  most common is penicillin   Sulfonamides (antibiotic) and nonsteroidal anti­inflammatory drugs (NSAIDs) also  • • • Idiosyncratic Reaction o Reactions that occur rarely and unpredictably o Recent evidence that genetic polymorphisms account for majority   Occurring in drug metabolizing enzymes and drug transport proteins o Hoped that one day, routine blood tests will be able to determine people at risk for idiosyncratic  rxns due to genetic polymorphisms  This already occurs in some centres for drugs called warfarin and 6­mercaptopurine • Which are metabolized by CYP2C9 and Thiopurine methyltransferase (TPMT)  respectfully o Ex. Of genetic polymorphisms that cause idiosyncratic reactions  CYP2C9 ­ ~15% of Caucasians have a polymorphism that decreases metabolism  CYP2D6 – 10% of Caucasians and African Americans are poor metabolizers • These patients do not experience pain relief to codeine (prodrug metabolized by  this CYP to morphine)  Thiopurine Methyltransferase  (TPMT) ­ ~10% of patients have decreased activity and  0.3% have no activity • treatment with thiopurine drugs in patients with low or absent TPMT can result in  life threatening bone marrow suppression  OATP1B1 – uptake drug transporter in the liver • ~15% of Asian and Caucasian patients have a polymorphism that decreases  function • leads to increase in plasma drug concentrations • implicated in causing myopathy (muscle toxicity) in patients taking statin drugs  Glucose 6­Phosphate Dehydrogenase Deficiency (G6PDH) – enzyme important in  RBC metabolism • Common in African and Middle Eastern descent • Patients with deficiency may have RBC hemolysis following treatment with  certain analgesics (ASPIRIN) or antimalarial drugs • Carcinogenic Effects o Means ability of a drug to cause cancer o Determining whether a drug is carcinogenic is difficult  Takes years after initial dose to appear o Diethylstilbestrol  Used to be prescribed to prevent spontaneous abortion in high risk pregnancies  Determined that female offspring developed vaginal or uterine cancer • Mutagenic Effects o Able to change DNA o Often also carcinogenic or teratogenic  Sometime not though • These drugs may receive approval for use from regulatory agencies if there is  sufficient evidence of safety from preclinical studies o
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