Transcript File - Autism Raw Data

Patient Safety and Medical Error
Pharmacogenetics:
Predicting Adverse
Drug Reactions
Heather White
Department of Health Science
June 26, 2016
Introduction
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106,000 fatal adverse drug reactions/year
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Drug therapies are only 25-60% successful
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Polymedication & Iatrogenic Disease
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Multiplying reasons for fatalities
Training Objective
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Identify predisposing genotypes
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Familiarize clinicians to pharmacogenetics
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Familiarize with metabolic diseases
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Importance of cofactors
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Familiarize with Cytochrome P450 (CYP)
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Tailor medications
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Plan for improvement
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Monitor effectiveness
Important Definitions
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Enzymes
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Genome sequencing
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Molecular diagnostic tests
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Pharmacogenetics
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Cofactors
enzyme
Genetic Differences
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Mutations: SNPs, deletions, rearrangements, &
insertions
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Classifications: leaky, null, & silent
❖
Metaboliser Categories: poor metabolisers, intermediate
metabolisers, ultrarapid metaboliser, extensive
metabolisers
Metabolic Defects & Diseases
❖
Errors in transport, processing,
or binding of cofactors
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Mitochondrial disorders
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Galactasemia
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Friedrich Ataxia
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Hurler Syndrome
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Niemann-Prick Disease
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Grouchier Disease
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MTHFR
Human Cell
Methylenetetrahydrofolate Reductase
(MTHFR)
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Create metabolic defects within methylation
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Multiplying endpoints: neurotransmitters, inflammation,
heart disease, birth defects, difficult pregnancies, difficult
detoxification
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Negative responders to synthetic folic acid
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C677T & A1298C
Cofactors & Enzymes
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fine-tune enzymes
❖
600 human enzymes require
vitamin & mineral cofactors
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poor nutrient uptake in GI
disease interferes with essential
metabolic cofactors
Cytochrome P450 (CYP)
Enzyme
❖
Catalyst of 75% of drugs
❖
Located in endoplasmic reticulum of hepatic cells
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57 CYP genes
❖
Mutations cause deficiencies in excretion rates
Psychotropic Agents
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CYP2D6 Duplications =
Ultrarapid Metabolisers (UMs) =
Increased dose for therapeutic
response
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CYP2D6 2 Null alleles = Poor
Metabolisers (PMs) = Increased
risk for toxicity
(Samer et al., 2013)
Drug/therap
eutic class
CYP
Antidepressa
nt
CYP2D6
CYP2D6 & CYP2C19 Mutations
Antidepressants
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❖
❖
Mutations responsible for
metabolizing SSRIs, NSRIs, &
tricyclic agents
Ultrarapid metabolism = therapeutic
resistance
Poor metaboliser = reduced ability to
excrete; reduce prescribed dose +
increased monitoring
CYP2C1
9
Dose recommendation
Clomipromine and Imipramine
Poor Metaboliser (PM): reduce dose 50-70% + plasma
concentration monitoring
Ultrarapid Metaboliser (UM): consider alternative drug or
increase imipramine dose by 70%
Amitriptyline
PM & UM: consider alternative drug or plasma
concentration monitoring
Intermediate Metabolisers (IM): reduce dose 25% + plasma
concentration monitoring or consider alternative drug
Nortriptyline
PM (IM): reduce dose by 60 (40) % + plasma concentration
monitoring
UM: consider alternative drug or increase dose by 60 % +
plasma concentration monitoring
Venlafaxine
PM, IM: insufficient data to calculate dose adjustment, seek
alternative drug or adjust dose to clinical response + plasma
concentration monitoring
UM: titrate dose to maximum of 150% or seek alternative
drug
Doxepine
PM (IM): reduce dose by 60 (20) % + plasma concentration
monitoring
UM: seek alternative drug or increase dose by 100%
Paroxetine
PM, IM: no dose adjustment
UM: select alternative drug
Duloxetine, Mirtazapine
No dose adjustment recommendations
Citalopram, Escitalopram
UM: monitor plasma concentration and titrate dose to a
maximum of 150% in response to efficacy and adverse drug
event or seek alternative drug
PM & IM: none
Sertraline
PM: reduce dose by 50%
IM: insufficient data to calculate dose adjustment, be alert to
adverse drug events (nausea, vomiting, diarrhea)
UM: insufficient data to calculate dose adjustment
Imipramine
PM: reduce dose by 30% + plasma concentration
monitoring or seek alternative drug
IM: insufficient data to calculate dose adjustment, seek
alternative drug
UM: no data
(Samer et al., 2013)
CYP2D6 Mutations
Drug/ther
apeutic
class
CYP
Codeine
CYP2D
6
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Extensive Metabolisers (EMs):
standard starting dose of codeine
Poor Matabolisers (PMs): avoid
codeine, choose alternative drug or be
alert to symptoms of insufficient pain
relief
Opioids
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Dose recommendation
Intermediate Matabolisers (IMs):
monitored closely for less than optimal
response, alternative analgesic if
required. Begin with 15-60 mg every
4h PRN. If no response, consider
alternative analgesics such as
morphine or a non-opioid. Monitor
tramadol use for response
CYP2D6 mutations affect codeine,
tramadol, & oxycodone
Poor metabolizes = reduce or no
analgesic effects
Ultrarapid metabolisers = expedited
analgesic effects
Ultrarapid Metabolisers (UMs): avoid
codeine (toxicity). Alternative
analgesics (morphine or a non-opioid).
Avoid tramadol
Oxycodon
e
CYP2D
6
PM: alternative drug (not tramadol or
codeine) or be alert to symptoms of
insufficient pain relief.
UM: be alert to adverse drug events
Tramadol
CYP2D
6
PM and IM: alternative drug (not
oxycodone or codeine) and/or be extra
alert to insufficient pain relief
UM: dose reduction by 30%, be alert
for adverse drug events, or alternative
drug (not oxycodone or codeine)
(Samer et al., 2013)
CYP2D6 Mutations
Anti arrhythmic
Agents
❖
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Mutations associated with carvedilol,
bufuralol, metoprolol, propranolol, &
timolol
Poor matabolisers = X6 exposure =
increased adverse drug effects
Drug/thera
peutic
class
CYP
Metoprolo
and
Propafenon
e
CYP2D
6
Dose recommendation
Poor Matabolisers (PMs): dose
reduction by 70-75% or alternative drug,
record ECG, monitor plasma
concentration
Intermediate Matabolisers (IMs): dose
reduction by 50% or alternative drug
Ultrarapid Metabolisers (UMs):
alternative drug or titration to a
maximum of 250% of the normal
metoprolol dose; insufficient data to
allow propafenone dose adjustment
calculation but adjust to plasma
concentration, record ECG or select
alternative drug
Flecainide
PM: dose reduction by 50% record ECG,
monitor plasma concentration
IM: dose reduction by 25%, record ECG,
monitor plasma concentration
UM: dose reduction and monitor plasma
concentration or select alternative drug
(e.g. sotalol, disopyramide, quinidine,
amiodarone)
Carvedilol
No recommendation at this time
CYP2C19, CYP450, & CYP3A4
Mutations
Proton Pump
Inhibitors
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Treatment drugs may include acidrelated disorders, reflux, & gastritis
(Samer et al., 2013)
Drug/therape
CYP
Dose recommendation
Esomeprazol
e,
lansoprazole,
omeprazole,
pantoprazole
CYP2C1
9
Ultrarapid Metabolisers (UMs): be extra
alert to insufficient response, dose
increase by 50-400%
Poor Matabolisers (PMs) &
Intermediate Matabolisers (IMs): no
dose recommendation
Rabeprazole
CYP2C1
9
No dose recommendation
utic class
Clinical Practice
❖
Order CYP phenotype tests prior to prescribing
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Predict therapeutic dose, foresee toxicities, & categorize
non responders
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Interpreting experts rely on credible guidelines
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The Great Plains Laboratory
Improved Patient Safety &
Quality
Adverse drug events due to pharmaceuticals contribute to
a significant portion of mortality and morbidity rates in the
United States. Utilizing predicative measures to mediate
adverse drug affects seems prudent in our overprescribed
population.
Case Study
Bipolar I Disorder
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Neurology consult for sedation, ataxia,
vertigo, diplopia, & headache
Questionable lamotrigine adverse
effect
Initial evaluation presentation irritable,
labile, agitated mood, lack of sleep, &
racing thoughts.
Unremarkable CT findings
Case Study: Bipolar I Disorder
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Previous treatment included divalproex sodium (wt gain),
carbamazepine, & oxcarbazepine. All ineffective.
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Previous treatment included risperidone caused profound
sedation.
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1st clinical visit prescription: 900 mg/day, clonazepam 6
mg/day, & aripiprazole 5 mg/day titrated to 15 mg/day
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Report of restlessness & urge to move constantly;
discontinued aripiprazole and symptoms resolved
Case Study: Bipolar I Disorder
CYP450 Genetic
Testing Revealed
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CYP2D6 genotype *3 / *5 with
predicted phenotype of poor
metabolizer
CYP2C19 genotype *1 / *1 with
predicted phenotype of extensive
(normal) metabolizer
Patient stabilized on lithium,
clonazepam, & topiramate
Plans for Improvement & Gauge
Effectiveness
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Coordinate with outsourced laboratories
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Implement pharmacogenetics within general practice
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Invest in training pharmacists in interpretation
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Legislature policy change for insurance coverage
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Monitor effectiveness by the quality control department
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Active surveillance with quarterly comparisons
Summary
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Patient safety and pharmaceutical effectiveness is a
significant issue in the management of health care. As
new tools develop, which can aid in the reducing the
high prevalence rate of drug adverse events,
organizations should implement policies to aid in their
use. Clinicians should remain open-minded and adopt
changes to their practice, which protect the patient
population.
References
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References
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10.1007/s40291-013-0028-5
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