Robert Kelly, MD
Assistant Professor of Psychiatry
Weill Cornell Medical College
White Plains, New York
Drug-DrugInteractions
Lecture available at www.robertkelly.us
Financial Conflicts of Interest
As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation.
I do not have an interest in any commercial products or services—Robert Kelly, MD
Case I
68-year-old female BIB police after calling 911Believes objects stolen from home
Sudden debut of sx in early morning hours
Says she saw numerous animals and people in home
Much anxiety
BP 145/90, HR 100, T 97.6
H/o mild memory impairment, worsening over time
Current medicationssimvastatin 20 mg QHS
amlodipine 5 mg QAM
ibuprofen 400 mg TID
chlorpromazine 50 mg, prn for sleep
Case II
Syncope in 70yo woman with DementiaAdmitted due to behavioral disturbance
Medications upon admission:
metoprolol 50 BID for HTN
Tylenol 650 mg prn for pain
Tx with Haldol 1 mg BID for psychosis
Three days later added Cymbalta 30 mg BID
Three days after that passed out while walking in the lounge area
Common Mistakes
Treat Young and Old Adults AlikeBenzos for Anxiety
Anticholinergic Medications
Medication for Behavioral Disturbances
ResultsFalls
Cognitive ImpairmentVicious cycle
Confusion
Delirium
Importance of Drug-Drug Interactions
Increased Number of MedicationsGreater likelihood of interactions
Aging EffectsPharmacokinetics
Pharmacodynamics
Adverse Drug Reactions (ADRs) as a Function of Increasing Age
Ghose K. Drugs Aging. 1991;1:2-5.Ghose K. Drugs Aging. 1991;1:2-5.
0
10
20
30
40
50
60
20-29 40-49 60-69 80+
Age (y)
AD
Rs
per
10,
000
Po
pu
lati
on
1(infancy)
Beyth RJ, Schorr RI. Beyth RJ, Schorr RI. Drugs AgingDrugs Aging. 1999;14:231-239.. 1999;14:231-239.
0
MajorBleeding (%)
20
40
60
80
100
10 2 3 4
231N = 660 189 114 64Years
75 years75 years
65-74 years65-74 years
< 65 years< 65 years
Incidence of Bleeding During Anticoagulant Therapy
Adverse Drug Reactions in the Nursing Home
• Psychoactive medications (antipsychotics, antidepressants, and sedatives/hypnotics) and anticoagulants were the medications most often associated with preventable ADRs
Gurwitz JH, et al. Gurwitz JH, et al. Am J Med.Am J Med. 2000;109:87-94. 2000;109:87-94.
Relationship Between Prescribing Rate and Prevalence of Potential Drug Interactions
Nolan L, O’Malley K.Nolan L, O’Malley K. Age Ageing. Age Ageing. 1989;18:52-56.1989;18:52-56.
0
1020
3040
50
6070
8090
100
0 1 2 3 4 5 6 7 8 9 10 11 12
No. of Drugs Prescribed per Patient
Pat
ien
ts (
%)
% of Patients With Interacting Combinations
Clinical Dilemma
• Number of possible drug interactions too large to memorize
• Difficult to determine which interactions are important
AgingPrimary
Intrinsic, pre-programmed limit
Linked toMaximum cell divisions
Cell damage accumulation
Interspecies variabilityPhysiology
SecondaryAccumulated effects of
Environmental insult
Disease
Trauma
Intraspecies variabilityPathology
Physiology
PharmacokineticsAbsorption
Distribution
EliminationMetabolism
Excretion
PharmacodynamicsTissue response to drug
Distribution
CompartmentsWater
Decreases
Hydrophilic meds
FatIncreases
Lipophilic meds
Plasma ProteinDecreased (albumin), or increased
BarriersBlood-brain
Intestinal
Elimination
ExcretionBodily fluids
Urine (Kidneys)
Sweat
Others
Vapors (Lungs)
Feces (Intestines)
Tissues (Skin)
MetabolismLiver
Intestinal
Cellular
LiverAging Effects
Few Generalizations Possible
Reduction in Enzyme Activity
Reduction in Blood Flow, 45% from 25-65
Reduction in Size, One-third
MetabolismPhase I (P450 enzyme system
Actions include oxidation, reduction, hydrolysis
Often active metabolites
Generally reduced with age
Phase IIActions include acetylation, conjugation
Usually inactive metabolites
Water-soluble, eliminated by kidneys
Relatively spared with age
Kidneys
AnatomyLoss of renal mass
Loss of glomeruli
Basement membrane thickenin
Intimal thickening of arteries
PhysiologyReduced GFR (approx. 50%)
Reduced renal plasma flow
Brain
Cognitive ChangesProcessing Speed
Memory
Susceptible to delirium
AtrophyVariable
Substantia Nigra
Balance
CNS
Proprioception
Central processing
Semicircular canals
Vision
Lack of exercise
Medications for HTN
Sedating medications
Interactions
Elimination
Increases
Decreases
Synergism
Toxic Effects
Anticholinergic Medications Commonly Prescribed in the Elderly
• Codeine• Digoxin • Dipyridamole• Isosorbide• Nifedipine
• Prednisolone• Ranitidine• Theophylline• Warfarin
Commonly prescribed in the elderly at Commonly prescribed in the elderly at levels that can impair cognition:levels that can impair cognition:
Tune L, et al. Tune L, et al. Am J Psychiatry.Am J Psychiatry. 1992;149:1393-1394 1992;149:1393-1394..
SSRIs
HyponatremiaExacerbated with HCTZ and others
BleedingInhibits platelet aggregation
Possible Synergism
Warfarin
Aspirin
Ginko Biloba
LithiumNarrow therapeutic window
Reduced in elderly
Signs of toxicityTremor
Ataxia
GI upset
Severe polyurea
Cognitive Impairment
Delirium
Blood levels affected by:NSAIDS
Dehydration
Salt intake
Non-adherence
Valproic Acid
Liver enzyme inhibitor
Signs of ToxicityUsually mild
Sedation
Anticholinergic effects
Elevated LFTs
Platelet production inhibition
Elevated serum ammonia levels
Carbamazapine
Enzyme InducerNeed to increase dose after 6 weeks
Signs of Toxicity
Sedation
Confusion
Ataxia
Sialorrhea
MAOIs
ReversibleNot available in US
Selective
Selegiline patch, low dose
NonselectiveRisk of hypertensive crisis
Medications--Demerol
Food restrictions
Cytochrome P-450 Enzyme Subtypes
CYP1A2CYP1A2 CYP2E1CYP2E1
CYP2CCYP2C
CYP2D6CYP2D6
CYP3A4CYP3A4
CYP isoform Representative substrates
1A21A2
2B62B6
2C92C9
2C192C19
2D62D6
2E12E1
3A3A
Caffeine, theophylline, tacrineCaffeine, theophylline, tacrine
Propofol, bupropion Propofol, bupropion
Phenytoin, S-warfarin, Phenytoin, S-warfarin, tolbutamide, NSAIDs tolbutamide, NSAIDs
Omeprazole (partial contributor to Omeprazole (partial contributor to many)many)
Some CNS and cardiac drugsSome CNS and cardiac drugs
Fluranes, chlorzoxane Fluranes, chlorzoxane
(many)(many)
CYP3A
• High abundance
• Present in G.I Tract
• No polymorphism, but high individual variability
CYP3A Substrates
CompleteComplete PartialPartialBenzodiazepines (short Benzodiazepines (short tt1/21/2) )
BuspironeBuspirone
TrazodoneTrazodone
NefazodoneNefazodone
CyclosporineCyclosporine
StatinsStatins
Calcium antagonistsCalcium antagonists
QuinidineQuinidine
Protease InhibitorsProtease Inhibitors
SildenafilSildenafil
ZolpidemZolpidem
AmitriptylineAmitriptyline
ImipramineImipramine
SertralineSertraline
CitalopramCitalopram
DiazepamDiazepam
ClozapineClozapine
CY3A Inhibitors
High Risk High Risk Moderate RiskModerate Risk
KetoconazoleKetoconazole
ItraconazoleItraconazole
NefazodoneNefazodone
Ritonavir (acute)Ritonavir (acute)
ErythromycinErythromycin
ClarithromycinClarithromycin
Calcium AntagonistsCalcium Antagonists
FluconazoleFluconazole
FluvoxamineFluvoxamine
FluoxetineFluoxetine
Grapefruit juiceGrapefruit juice
Other HIV PIsOther HIV PIs
DelavirdineDelavirdine
CimetidineCimetidine
CYP3A Inducers
• Rifampin
• Barbiturates
• Carbamazepine
• Ritonavir (chronic)
• Nevirapine
• Hypericum perforatum
(St. John’s Wort)
St. John’s Wort
• Induces P-glycoprotein Digoxin by 30%
• Induces CYP3A4 Indinavir Cyclosporine– Statins
Ruschitzka F, et al. Ruschitzka F, et al. Lancet.Lancet. 2000;355(9203):548-549. 2000;355(9203):548-549.Piscitelli SC, et al. Piscitelli SC, et al. Lancet.Lancet. 2000;355(9203):547-548. 2000;355(9203):547-548.
Cytochrome P-450:Enzymes and Selected Substrates
Michalets EL. Pharmacotherapy. 1998;18:84 -112.Cupp MJ, Tracy TS. Am Fam Physician. 1998;57:107-116.
1A2 2C 2D6 3A4
Theophylline Phenytoin Codeine Antihistamines
Warfarin Warfarin Venlafaxine Calcium channelblockers
Antipsychotics Amitriptyline Trazodone Carbamazepine
Benzodiazepines Clomipramine Risperidone Cisapride
Fluvoxamine Omeprazole Haloperidol Corticosteroids
Tramadol Cyclosporine
-Blockers Fentanyl
Protease inhibitors
Statins
Triazolo-benzodiazepines
Inhibition of Human Cytochrome P-450 Isoenzymes by Newer Antidepressants
Greenblatt DJ, et al. Greenblatt DJ, et al. J Clin PsychiatryJ Clin Psychiatry. 1998;59(suppl 15):19-27.. 1998;59(suppl 15):19-27.von Moltke LL, et al. von Moltke LL, et al. Drug Metab Disposition.Drug Metab Disposition. 2001;29:1102-1108. 2001;29:1102-1108.
00 = minimal or zero inhibition.= minimal or zero inhibition.++ = mild inhibition.= mild inhibition.
++++ = moderate inhibition.= moderate inhibition.++++++ = strong inhibition.= strong inhibition.
—— = no data available.= no data available.
Antidepressant 1A2 2C9 2C19 2D6 2E1 3AFluoxetine + ++ + to ++ +++ — +
Norfluoxetine + ++ + to ++ +++ — ++Sertraline + + + to ++ + — +
Desmethylsertraline + + + to ++ + — +Paroxetine + + + +++ — +Fluvoxamine +++ ++ +++ + — ++Citalopram + 0 0 0 0 0
R-Desmethylcitalopram 0 0 0 + 0 0Escitalopram 0 0 0 0 0 0
S-Desmethylcitalopram 0 0 0 0 0 0Nefazodone 0 0 0 0 — +++
Triazoledione 0 0 0 0 — +Hydroxynefazodone 0 0 0 0 — +++
Venlafaxine 0 0 0 0 — 0O-Desmethylvenlafaxine 0 0 0 0 — 0
Mirtazapine 0 — — + — 0
Cytochrome P-450 IsoenzymeCytochrome P-450 Isoenzyme
Pharmacokinetic Issues in BP Elders
• Reduced renal clearance of some drugs, e.g lithium;• Decreased volume of distribution for hydrophilic drugs,
e.g. lithium;• Changes in plasma binding proteins, e.g. lower albumin
conc.; proportion of non bound valproate is increased; • Changes in effective drug concentration/dose may have
clinical meaning for benefit/toxicity: lithium- lower doses and longer time to steady state
Pharmacodynamics in Aged
• Older BP patients may be slow to improve- duration of adequate treatment trial not clear;
• Optimal doses/concentrations not defined; • Some patients respond to low
concentrations, e.g. of lithium. • Patients with dementia, and mild cognitive
impairments, may have slower/attenuated benefit and greater neurocognitive side effects.
Elderly Are More Difficult to Treat Safely
• Pharmacokinetic changes result in higher and more variable drug concentrations
• The elderly often take multiple medications
• Greater sensitivity exists to a given drug concentration
• Homeostatic reserve may be impaired
Coping With Drug Interactions
• Anticipation and prevention– Highly potent inducer/inhibitor– Narrow therapeutic index of victim – Victims dependent on one metabolic
enzyme/transport protein
Coping With Drug Interactions
• Recognize interaction potential of “nondrugs” (herbals)
• Keep knowledge base current
• Consider interactions whenever the clinical picture unexpectedly changes
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