Transcript Geriatric Drug-Drug Interactions

Drug-Drug
Interactions
Robert Kelly, MD
Assistant Professor of Psychiatry
Weill Cornell Medical College
White Plains, New York
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 911
Believes 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 medications
simvastatin 20 mg QHS
amlodipine 5 mg QAM
ibuprofen 400 mg TID
chlorpromazine 50 mg, prn for sleep
Case II
Syncope in 70yo woman with Dementia
Admitted 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 Alike
Benzos for Anxiety
Anticholinergic Medications
Medication for Behavioral Disturbances
Results
Falls
Cognitive Impairment
Vicious cycle
Confusion
Delirium
Importance of Drug-Drug Interactions
Increased Number of Medications
Greater likelihood of interactions
Aging Effects
Pharmacokinetics
Pharmacodynamics
ADRs per 10,000 Population
Adverse Drug Reactions (ADRs) as a
Function of Increasing Age
60
50
40
30
20
10
0
1
(infancy)
20-29
Ghose K. Drugs Aging. 1991;1:2-5.
40-49
Age (y)
60-69
80+
Incidence of Bleeding During Anticoagulant
Therapy
 75 years
100
65-74 years
80
< 65 years
60
Major
Bleeding (%)
40
20
0
Years
0
1
2
3
4
N = 660
231
189
114
64
Beyth RJ, Schorr RI. Drugs Aging. 1999;14:231-239.
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. Am J Med. 2000;109:87-94.
Patients (%)
Relationship Between Prescribing Rate and
Prevalence of Potential Drug Interactions
% of Patients With
Interacting Combinations
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
No. of Drugs Prescribed per Patient
Nolan L, O’Malley K. Age Ageing. 1989;18:52-56.
10
11
12
Clinical Dilemma
• Number of possible drug
interactions too large to memorize
• Difficult to determine which
interactions are important
Aging
Primary
Intrinsic, pre-programmed limit
Linked to
Maximum cell divisions
Cell damage accumulation
Interspecies variability
Physiology
Secondary
Accumulated effects of
Environmental insult
Disease
Trauma
Intraspecies variability
Pathology
Physiology
Pharmacokinetics
Absorption
Distribution
Elimination
Metabolism
Excretion
Pharmacodynamics
Tissue response to drug
Distribution
Compartments
Water
Decreases
Hydrophilic meds
Fat
Increases
Lipophilic meds
Plasma Protein
Decreased (albumin), or increased
Barriers
Blood-brain
Intestinal
Elimination
Excretion
Bodily fluids
Urine (Kidneys)
Sweat
Others
Vapors (Lungs)
Feces (Intestines)
Tissues (Skin)
Metabolism
Liver
Intestinal
Cellular
Liver
Aging Effects
Few Generalizations Possible
Reduction in Enzyme Activity
Reduction in Blood Flow, 45% from 25-65
Reduction in Size, One-third
Metabolism
Phase I (P450 enzyme system
Actions include oxidation, reduction, hydrolysis
Often active metabolites
Generally reduced with age
Phase II
Actions include acetylation, conjugation
Usually inactive metabolites
Water-soluble, eliminated by kidneys
Relatively spared with age
Kidneys
Anatomy
Loss of renal mass
Loss of glomeruli
Basement membrane thickenin
Intimal thickening of arteries
Physiology
Reduced GFR (approx. 50%)
Reduced renal plasma flow
Brain
Cognitive Changes
Processing Speed
Memory
Susceptible to delirium
Atrophy
Variable
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
Commonly prescribed in the elderly at
levels that can impair cognition:
•
•
•
•
•
Codeine
Digoxin
Dipyridamole
Isosorbide
Nifedipine
•
•
•
•
Prednisolone
Ranitidine
Theophylline
Warfarin
Tune L, et al. Am J Psychiatry. 1992;149:1393-1394.
SSRIs
Hyponatremia
Exacerbated with HCTZ and others
Bleeding
Inhibits platelet aggregation
Possible Synergism
Warfarin
Aspirin
Ginko Biloba
Lithium
Narrow therapeutic window
Reduced in elderly
Signs of toxicity
Tremor
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 Toxicity
Usually mild
Sedation
Anticholinergic effects
Elevated LFTs
Platelet production inhibition
Elevated serum ammonia levels
Carbamazapine
Enzyme Inducer
Need to increase dose after 6 weeks
Signs of Toxicity
Sedation
Confusion
Ataxia
Sialorrhea
MAOIs
Reversible
Not available in US
Selective
Selegiline patch, low dose
Nonselective
Risk of hypertensive crisis
Medications--Demerol
Food restrictions
Cytochrome P-450 Enzyme Subtypes
CYP1A2
CYP2E1
CYP2C
CYP3A4
CYP2D6
CYP isoform Representative substrates
1A2
Caffeine, theophylline, tacrine
2B6
Propofol, bupropion
2C9
Phenytoin, S-warfarin, tolbutamide,
NSAIDs
2C19
2D6
Omeprazole (partial contributor to
many)
2E1
Some CNS and cardiac drugs
3A
Fluranes, chlorzoxane
(many)
CYP3A
• High abundance
• Present in G.I Tract
• No polymorphism, but high individual
variability
CYP3A Substrates
Complete
Partial
Benzodiazepines (short t1/2) Zolpidem
Buspirone
Amitriptyline
Trazodone
Imipramine
Nefazodone
Sertraline
Cyclosporine
Citalopram
Statins
Diazepam
Calcium antagonists
Clozapine
Quinidine
Protease Inhibitors
Sildenafil
CY3A Inhibitors
High Risk
Moderate Risk
Ketoconazole
Fluconazole
Itraconazole
Fluvoxamine
Nefazodone
Fluoxetine
Ritonavir (acute)
Grapefruit juice
Erythromycin
Other HIV PIs
Clarithromycin
Delavirdine
Calcium Antagonists
Cimetidine
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. Lancet. 2000;355(9203):548-549.
Piscitelli SC, et al. Lancet. 2000;355(9203):547-548.
Cytochrome P-450:
Enzymes and Selected Substrates
1A2
2C
2D6
3A4
Theophylline
Phenytoin
Codeine
Antihistamines
Warfarin
Warfarin
Venlafaxine
Calcium channel
blockers
Antipsychotics
Amitriptyline
Trazodone
Carbamazepine
Benzodiazepines
Clomipramine
Risperidone
Cisapride
Fluvoxamine
Omeprazole
Haloperidol
Corticosteroids
Tramadol
Cyclosporine
-Blockers
Fentanyl
Protease inhibitors
Statins
Triazolobenzodiazepines
Michalets EL. Pharmacotherapy. 1998;18:84 -112.
Cupp MJ, Tracy TS. Am Fam Physician. 1998;57:107-116.
Inhibition of Human Cytochrome P-450
Isoenzymes by Newer Antidepressants
Cytochrome P-450 Isoenzyme
Antidepressant
Fluoxetine
Norfluoxetine
Sertraline
Desmethylsertraline
Paroxetine
Fluvoxamine
Citalopram
R-Desmethylcitalopram
Escitalopram
S-Desmethylcitalopram
Nefazodone
Triazoledione
Hydroxynefazodone
Venlafaxine
O-Desmethylvenlafaxine
Mirtazapine
0
+
++
+++
—
1A2
+
+
+
+
+
+++
+
0
0
0
0
0
0
0
0
0
2C9
++
++
+
+
+
++
0
0
0
0
0
0
0
0
0
—
= minimal or zero inhibition.
= mild inhibition.
= moderate inhibition.
= strong inhibition.
= no data available.
Greenblatt DJ, et al. J Clin Psychiatry. 1998;59(suppl 15):19-27.
von Moltke LL, et al. Drug Metab Disposition. 2001;29:1102-1108.
2C19
+ to ++
+ to ++
+ to ++
+ to ++
+
+++
0
0
0
0
0
0
0
0
0
—
2D6
+++
+++
+
+
+++
+
0
+
0
0
0
0
0
0
0
+
2E1
—
—
—
—
—
—
0
0
0
0
—
—
—
—
—
—
3A
+
++
+
+
+
++
0
0
0
0
+++
+
+++
0
0
0
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 improveduration 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