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