Download 2011 GEM Drugs Elderly

Pharmacology in the Frail Elderly
Lawrence Jackson, BScPhm
Veterans Centre
Sunnybrook Health Sciences Centre
Sept 20, 2011
Overview
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Process for identifying drug therapy problems
Clinical presentation of ADE
Anticholinergic load
Background on DI Types
Case
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Avoidable drug interactions (DIs)
Range of drug therapy problems
Strategies to minimize DIs in practice
How Pharmacists Think
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What are the current signs and symptoms
What is the urgency
Are S&S drug or disease related
What are the therapeutic options
What are the Drug Therapy Problems (DTP)
What do we hope to achieve
What is the best therapeutic plan
What is the monitoring plan
How Pharmacists Think
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Drug Therapy Problems
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Unnecessary drug therapy (not indicated)
Need for additional drug therapy
Ineffective drug (needs an alternative)
Dose too low
Dose too high
Adverse Drug Reaction (ADR)
Noncompliance/Nonadherence
Clinical presentations of ADR/ADI
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ADRs and ADIs often present as non-specific
clinical syndromes, referred to as „disease simulators‟
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Always include “drugs” in the differential diagnosis
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confusion, delirium
falls
urinary incontinence
decompensation of heart failure
problems can manifest when person is most susceptible
Atypical presentation of disease
Adverse Drug Events
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Adverse drug event – any injury resulting
from drug administration (all inclusive term)
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10-35% ambulatory elderly have ADE
7% of hospitalizations are due to ADE
(Shelton PS et al. Drugs & Aging 2000;16:437-450)
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Adverse drug event incidence in the elderly
who present to ED ( Am J Emerg Med 1996; 14:144-450)
Two Medications
Five Medications
Seven Medications
Risk ADE: 13%
Risk ADE: 58%
Risk ADE: 82%
Polypharmacy
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Definition
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too many drugs
drugs for too long
drugs in exceedingly high doses
Michocki RJ et al. Arch Fam Med1993;2:441-4
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Drugs used to treat side effects of other drugs
(“drug cascade”)
narcotic confusion antipsychotic EPS anti-parkinsonian therapy
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Consequence of multiple physicians
What makes the elderly different?
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The elderly have an increased frequency of
adverse drug reactions
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Decreased physiological reserve
Altered pharmacokinetics
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water, fat, Alb, Phase 1 metabolism (P450)
Altered pharmacodynamics
Compliance issues
More diseases and more drugs
Impact of Anticholinergic Drugs
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Can precipitate or exacerbate existing
cholinergic deficits
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CNS-dementia
Periphery- dry eyes, dry mouth, constipation,
blurred vision
Anticholinergic Load
Anticholinergic Risk Scale (ARS)
 Score of 3 = 2 or more anti-Ch effects in 70%
3points
2 Points
1 Point
Amitriptyline
Amantadine
Sinemet
Atropine
Baclofen
Entacapone
Benztropine
Cetirizine
Haloperidol
Dicyclomine
Loratadine
Ranitidine
Diphenydramine
Tolterodine
Trazodone
Oxybutinin
Prochlorperazine Risperidone
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Arch Intern Med 2008;168 (5):508-13
Drug Interactions
Definition
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Drug-Drug interaction
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Effect of one drug enhanced or diminished by
use of another
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Associated with some evidence of harm
Four Important Characteristics
1.
2.
Innumerable
Common
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3.
Difficult to study in „real‟ patients
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4.
20-50% of older patients presenting to ED
we often rely case reports & volunteer studies
Inherently avoidable
Types of Drug Interactions
Types
Mechanism of
action
• Augmented or
reduced effects
Drug-drug-pk
Drug-drug-pd
Drug-nutritional status
Drug-disease
Drug-alcohol
Drug-herbal
Outcome
• Synergy
• Adverse effects
• Antagonism
• Treatment
failure
Classification
Change in
drug level
Pharmacokinetic
vs.
Pharmacodynamic
No change in
drug level
Examples:
Pharmacodynamic DIs
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Patient with Parkinson‟s disease
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on levodopa / carbidopa
Rx with chlorpromazine for
persistent hiccups
Patient with Hypertension
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on ramipril 5mg daily
Rx celecoxib 200mg bid
}
Antagonistic,
receptor-mediated
}
Antagonistic, not
receptor-mediated
Examples:
Pharmacodynamic DIs
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Patient with chronic pain
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Patient on Ativan 1 mg tid
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on morphine SR 30mg bid
Rx with gabapentin 300mg tid
has 3 glasses of wine
}
Synergistic, not
receptor-mediated
}
Synergistic, not
receptor-mediated
Patient post MI
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on metoprolol 50mg bid
Rx with timolol 0.5% eye drops
for glaucoma
}
Synergistic,
receptor-mediated
Pharmacokinetic DIs
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One drug changes the level of another
or
or
or
absorption
elimination
metabolism
‘Typical’ Pharmacokinetic DI
120
100
}
80
chronic
medication
60
40
20
0
time 
Therapeutic
range
‘Typical’ Pharmacokinetic DI
120
new
medication
100
}
80
chronic
medication
60
40
20
0
time 
Therapeutic
range
‘Typical’ Pharmacokinetic DI
120
new
medication
Toxicity
100
}
80
chronic
medication
60
40
20
0
time 
Therapeutic
range
‘Typical’ Pharmacokinetic DI
120
new
medication
100
}
80
chronic
medication
60
Therapeutic
range
40
Loss of efficacy
20
0
time 
Examples:
Altered absorption
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H2 blockers, PPIs
absorption of ketoconazole, itraconazole
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Ca2+ or Mg2+ or Fe or cholestryramine
absorption of
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tetracyclines
captopril
quinolones
levothyroxine
Altered drug metabolism:
The cytochrome P450 system
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> 60 different enzymes
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Major ones
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CYP 1A2
CYP 2C9*
CYP 2C19*
CYP 2D6*
CYP 2E1
CYP 3A4 / 3A5
* polymorphisms
Substrates
Inhibitors
Inducers
Phase 1 Metabolism
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Metabolize some drugs to inactive products
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diazepam, simvastatin, sertraline, morphine
Metabolize some drugs to active products
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codeine, enalapril, atorvastatin, clopidogrel
Examples:
Pharmacokinetic DIs
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Patient with DM
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}
Glyburide metabolized by 2C9
Septra inhibits 2C9
Patient on simvastatin 20mg daily
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on glyburide 10mg daily
Rx with Septra DS bid
hypoglycemic episode
Diet changed to include grapefruit
muscle aches
}
Patient on warfarin
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Rx with amiodarone 200mg daily
bleeding episode
}
Simvastatin metab
by 3A4
Gjuice inhibits 3A4
Warfarin metabolized
by 2C9
Amiodarone inhibits
2C9
CYP 3A4 Substrates
The importance of bioavailability
Dresser CMAJ 2004
The importance of inhibition of CYP
3A4 on bioavailability of substrates
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Very low (<10%)
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Low (10% to 30%)
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atorvastatin, felodipine
Intermediate (30% to 70%)
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simvastatin, lovastatin, buspirone
3A4 inhibition:
levels
amio, CBZ, CyA, diazepam, diltiazem,
nifedipine, sildenafil, triazolam
High (>70%)
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3A4 inhibition:
levels
alprazolam, amlodipine, dexamethasone, quetiapine
Dresser Can J Clin Pharm 2002
Examples:
DI related to the patient
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Patient with renal failure
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}
Acyclovir is renally
cleared
Patient with low albumin
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Rx with Acyclovir 800mg 5x/d
CNS confusion, sedation
Rx phenytoin 300mg/d
CNS confusion, sedation
}
↑ unbound phenytoin
( ↑ free fraction)
Patient with Parkinson‟s disease
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Rx with metoclopramide 10mg qid
Increased bradykinesia
}
Metoclopramide
blocks action
of Sinemet
at the D2
receptor
What is P-glycoprotein?
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Membrane glycoprotein
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1976: found in cancer cells
Expressed in gut, kidney,
brain…………..
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A “natural defense
mechanism”
P-glycoprotein
Substrates
Inhibitors
Inducers
digoxin
macrolides
rifampin
loperamide
diltiazem
amiodarone
antifungals
dexamethasone
St. John‟s wort
midazolam
protease inhibitors
quinidine
cyclosporine
chemo (various)
cyclosporine
colchicine
verapamil
ritonavir
Examples:
P-glycoprotein DIs
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Patient on digoxin
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Rx with clarithromycin
Digoxin toxicity with 7 days
}
Dig po bioavailability 50-70%
Clarith inhbits p-g
increasing dig bioavailability
Patient on diltiazem CD 240mg/d
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Rx amiodarone
Slow heart rate
}
↑ bioavailability of diltiazem
Case #1
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80 y.o. man with stable CHF
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GP diagnoses acute gout
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Rx Ramipril 5mg od, metoprolol 100 mg BID,
furosemide 40mg od
Rx Ibuprofen 400mg qid
2 days later patient presents with ankle
edema
Diuretic-NSAID Interaction
•PGE2 inhibits NaCl reabsorption
(via the Na, K, Cl co-transporter)
•PGE2 inhibits free water and Na
reabsorption (via the collecting duct)
•Diuretics increase PGs
•Inhibition of PG synthesis by
NSAIDs (ibuprofen, naproxen, sulindac)
can diminish natriuresis
and diuresis induced by
furosemide, HCT,
triamterene, spironolactone
•Effect is potentiated by salt
restriction
Brenner and Rector's The Kidney, 8th ed.
Case #2
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80 y.o. woman with previous TIA
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GP diagnoses osteoarthritis
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Rx ASA 81mg daily
Rx Ibuprofen 400mg qid
2 months later patient presents with stroke
ibuprofen
X
ASA
Arachadonic acid
Case #3
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55 y.o. man with stable angina
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GP diagnoses arrhythmia
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Rx ASA, metoprolol 100 mg BID
Rx Amiodarone 200mg daily
10 days later patient presents to hospital
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HR 42 bpm BP 90/50
Case #3 What happened?
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Metoprolol is metabolized by 2D6
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Amiodarone inhibits 2D6
Beta blockade is enhanced
Case #4
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Patient receiving Tylenol #3 1 tab tid for
back pain
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GP diagnoses depression
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Rx Paroxetine 20mg daily
2 days later pain is worse
Case #4 What happened?
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Codeine is a prodrug
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converted to morphine by CYP 2D6
Paroxetine inhibits CYP 2D6
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abolishes analgesic effect of codeine
CYP 2D6
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Involved in metabolism of 15-20% of drugs
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Not inducible
7-10% of Caucasians
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no functional CYP 2D6
“poor metabolizers”
Interactions involving CYP 2D6
Drugs metabolized
by CYP 2D6
CYP 2D6
inhibitors
codeine
amiodarone
carvedilol, metoprolol
SSRIs
haloperidol, risperidone
haloperidol
Case #5
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Patient with epilepsy
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well controlled on carbamazepine CR 400 BID
Begins taking St. John‟s wort for depressed
mood
3 weeks later
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GTC seizure; [CBZ] 11 mol/L
Case #5 What happened?
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CBZ is metabolized by CYP 3A4
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St. John‟s wort induces 3A4
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Enhanced metabolism of CBZ
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 lower level; treatment failure
How could it have been avoided?
CYP 3A4 substrates
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Cardiac drugs
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Benzodiazepines (some)
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triazolam, diazepam, alprazolam, midazolam
“Statins”
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verapamil, nifedipine, diltiazem, amlodipine,
nifedipine, amiodarone
atorvastatin, lovastatin, simvastatin
Miscellaneous
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carbamazepine, cyclosporine, antiretrovirals,
Interactions involving CYP 2D6
CYP 2D6
inducers
Anti-epileptic drugs
carbamazepine
phenobarbital
phenytoin
St. John‟s Wort, rifampin
Dexamethasone
CYP 2D6
inhibitors
erythro, clarithro
(not azithromycin)
grapefruit juice, amiodarone
indinavir, nelfinavir,
saquinavir…
itraconazole, ketoconazole
Case #6
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Patient with constipation
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Poorly managed with docusate 100mg BID
Begins taking mineral oil 30 mL daily
3 weeks later
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Anal leakage of mineral oil and puritis ani
Case #6 What happened?
Mineral oil
Prevents reabsorption of fecal water
Poorly absorbed
Combination with docusate will inc absorption
If absorbed, not metabolized→ fatty liver
Aspiration lipoid pneumonia
Reduces absorption of fat-soluble vitamins
Anal leakage → itching (pruritis ani)
Rectal enema OK for fecal impaction
Strategies to Minimize Drug
Interactions in Practice
Optimizing Drug Therapy
Rational Prescribing
Benefits of drugs
Avoid under treatment
ADR risk increases
with the number of drugs used
Approaches
Explicit criteria
(Beers list….)
Implicit criteria
(complete assessment)
Drug utilization tools
Explicit
 Criterion-based
 Expert opinion,
consensus
 Fail to take into
account all health
indicators or patient
preferences or burden
of co-morbid diseases
Implicit
 Clinician uses patientspecific information
and published
evidence to form
judgments about
appropriateness
 Dependent on user‟s
knowledge & attitudes
Explicit criteria
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Beers list- drugs to avoid
Arch Intern Med 2003;163(22):2716-2724.
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IPET (improving prescribing in the elderly tool)
Can J Clin Pharmacol 2000;7(2):103-107
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STOPP (screening tool of older person‟s potentially
inappropriate prescriptions) Age Ageing 2008;37(6):673-79.
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START (screening tool to alert doctors to right treatment)
Int J Clin Pharmacol Ther 2008;46(2):72-83
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MAI (medication appropriateness index)
J Clin Epidemiol 1992;45(10):1045-51.
Minimizing Drug Interactions
Entertain DDI with any new drug
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esp. when a low therapeutic index drug
onboard
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warfarin, digoxin, glyburide, statins, theophylline
Or other high alert drugs
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benzodiazepines, diphenydramine, antipsychotics,
anticonvulsants
Use a Safer Alternative
Drug class
Safest Options
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SSRIs
citalopram, sertraline
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Antibiotics
penicillins
cephalosporins
azithromycin
newer quinolones
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Statins
pravastatin
Traps to avoid
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Overestimating renal function
Starting with too high dose
Failure to attribute S&S to drugs
Use of anticholinergic drugs
Altered ability to tolerate drugs when ill
Resources
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ePocrates
www.epocrates.com
LexiDrugs
www.skyscape.com
Medical Letter ADR
www.medicalletter.com
iFacts (Drug interactions)
www.factsandcomparisons.com
Drug-Interactions
http://medicine.iupui.edu/clinpharm/DDIs/
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Rx Files
www.rxfiles.ca
Global rph
www.globalrph.com
POGOe
http://www.pogoe.org/front2
Hansten and Horn Textbook of Drug Interactions
Micromedex
Recap
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How pharmacists address DTP‟s
Clinical presentation of ADR/ ADI
Anticholinergic load
Various types of drug interactions with examples
Cases to illustrate medication complexity in the
elderly
Strategies to avoid DIs and promote safe
prescribing in the elderly
Drug Interaction Game
Digoxin Donepezil
Oxybutinin
Major,
↑ dig
Ibuprofen
Glyburide
Diltiazem
Septra
Mod,
absorp
Mod,
absorp
Levothyroxine
Metoprolol
Ramipril
Mod, cog
Cipro
Amoidarone
Iron
Mod, HR
Mod,↑ AV
node block
Major,
Mod, BP
effect of ACEI lowering effect
Mod, ↑AV
node block
Major,
BG