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Lecture

Pharmacology 2060A/B Lecture Notes - Cyp2C9, Hepatotoxicity, Jaundice


Department
Pharmacology
Course Code
PHARM 2060A/B
Professor
Angela Nissen

Page:
of 8
Module 10
Advserse Drug Reactions and Medication Errors
10.1 Advserse Drug Reactions
ADRs: unintended and undesired responses from drugs
oEnormous societal health problem
o7.5% of hospital admissions in Canada are attributed to adverse drug reactions
185,000 ppl/yr
includes
oSide effects
oDrug toxicity
oAllergic reaction
oIdiosyncratic reaction
oMutagenic effects
oTeratogenic effects
Side Effects
oSecondary to main therapeutic effect of drug
oOccur at normal therapeutic doses
oOften unavoidable
oOften due to poor specificity or selectivity of drug
oEx.
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
oA severe adverse drug event
oOften mediated by overdose
Where patients unintentionally or intentionally take too much medication
oOften extensions of therapeutic effect
oEx.
A patient who takes too much insulin gets hypoglycaemia (low blood glucose)
Allergic Reaction
oMediated by immune system
oRequires prior sensitization where patient is exposed to allergen (drug)
oUpon subsequent exposure, allergic reaction will occur
Mast cells release chemical mediators such as histamine
oAllergic reactions can vary from itching and rash, to life threatening anaphylaxis
(bronchospasms, edema, severe hypotension)
oIntensity is independent of dosage size
Small doses can produce severe allergy
o~10% of all ADRs are related to drug allergy
overy few drugs cause allergic reactions
most common is penicillin
Sulfonamides (antibiotic) and nonsteroidal anti-inflammatory drugs (NSAIDs) also
Idiosyncratic Reaction
oReactions that occur rarely and unpredictably
oRecent evidence that genetic polymorphisms account for majority
Occurring in drug metabolizing enzymes and drug transport proteins
oHoped 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 6-mercaptopurine
Which are metabolized by CYP2C9 and Thiopurine methyltransferase (TPMT)
respectfully
oEx. 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 6-Phosphate Dehydrogenase Deficiency (G6PDH) – enzyme important in
RBC metabolism
Common in African and Middle Eastern descent