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Drug-Drug Interactions Robert Kelly, MD
Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York Lecture available at
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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 We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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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
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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
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Common Mistakes Treat Young and Old Adults Alike Results
Benzos for Anxiety Anticholinergic Medications Medication for Behavioral Disturbances Results Falls Cognitive Impairment Vicious cycle Confusion Delirium We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Importance of Drug-Drug Interactions
Increased Number of Medications Greater likelihood of interactions Aging Effects Pharmacokinetics Pharmacodynamics We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Adverse Drug Reactions (ADRs) as a Function of Increasing Age
N5-067 Dem Con Template 4/6/2017 3:28 PM Adverse Drug Reactions (ADRs) as a Function of Increasing Age 60 50 40 ADRs per 10,000 Population 30 20 10 1 (infancy) 20-29 40-49 60-69 80+ Age (y) Ghose K. Drugs Aging. 1991;1:2-5.
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Incidence of Bleeding During Anticoagulant Therapy
N5-067 Dem Con Template 4/6/2017 3:28 PM Incidence of Bleeding During Anticoagulant Therapy 100 75 years 65-74 years < 65 years 80 Major Bleeding (%) 60 40 20 The cumulative incidence of major bleeding during anticoagulant therapy in 660 patients according to 3 age categories. The “N” refers to the number of patients at each corresponding time point. Major bleeding was more common in patients aged 75 years (p= by the log-rank test). Years 1 2 3 4 N = 660 231 189 114 64 Beyth RJ, Schorr RI. Drugs Aging. 1999;14:
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Adverse Drug Reactions in the Nursing Home
N5-067 Dem Con Template 4/6/2017 3:28 PM 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.
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N5-067 Dem Con Template 4/6/2017 3:28 PM Relationship Between Prescribing Rate and Prevalence of Potential Drug Interactions Nolan L, O’Malley K. Age Ageing. 1989;18:52-56.
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N5-067 Dem Con Template 4/6/2017 3:28 PM Clinical Dilemma Number of possible drug interactions too large to memorize Difficult to determine which interactions are important
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Aging Primary Secondary 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 We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Physiology Pharmacokinetics Pharmacodynamics Absorption Distribution
Elimination Metabolism Excretion Pharmacodynamics Tissue response to drug We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Distribution Compartments Barriers Water Fat Plasma Protein
Decreases Hydrophilic meds Fat Increases Lipophilic meds Plasma Protein Decreased (albumin), or increased Barriers Blood-brain Intestinal We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Elimination Excretion Metabolism Bodily fluids Vapors (Lungs)
Urine (Kidneys) Sweat Others Vapors (Lungs) Feces (Intestines) Tissues (Skin) Metabolism Liver Intestinal Cellular We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Liver Aging Effects Metabolism Phase I (P450 enzyme system Phase II
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 We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Kidneys Anatomy Physiology Loss of renal mass Loss of glomeruli
Basement membrane thickenin Intimal thickening of arteries Physiology Reduced GFR (approx. 50%) Reduced renal plasma flow We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Brain Cognitive Changes Atrophy Processing Speed Memory
Susceptible to delirium Atrophy Variable Substantia Nigra We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Balance CNS Proprioception Central processing Semicircular canals
Vision Lack of exercise Medications for HTN Sedating medications We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Interactions Elimination Increases Decreases Synergism Toxic Effects
We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Anticholinergic Medications Commonly Prescribed in the Elderly
N5-067 Dem Con Template 4/6/2017 3:28 PM 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:
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SSRIs Hyponatremia Bleeding Exacerbated with HCTZ and others
Inhibits platelet aggregation Possible Synergism Warfarin Aspirin Ginko Biloba We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Lithium Narrow therapeutic window Signs of toxicity
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 We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Valproic Acid Liver enzyme inhibitor Signs of Toxicity Usually mild
Sedation Anticholinergic effects Elevated LFTs Platelet production inhibition Elevated serum ammonia levels We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Carbamazapine Enzyme Inducer Signs of Toxicity Sedation Confusion
Need to increase dose after 6 weeks Signs of Toxicity Sedation Confusion Ataxia Sialorrhea We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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MAOIs Reversible Selective Selegiline patch, low dose Nonselective
Not available in US Selective Selegiline patch, low dose Nonselective Risk of hypertensive crisis Medications--Demerol Food restrictions We are thinking of starting with the hypothesis that activity levels correlate with depressive symptom severity in general, such as measured by the Hamilton; and then adding exploratory studies to determine if specific manifestations of depression or executive dysfunction may be related to specific brain abnormalities.
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Cytochrome P-450 Enzyme Subtypes
N5-067 Dem Con Template 4/6/2017 3:28 PM Cytochrome P-450 Enzyme Subtypes CYP2E1 CYP1A2 CYP2C CYP3A4 The cytochrome enzymes are a family of enzymes that metabolism substrates (medications). CYP2D6
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CYP isoform Representative substrates
N5-067 Dem Con Template 4/6/2017 3:28 PM CYP isoform Representative substrates 1A2 2B6 2C9 2C19 2D6 2E1 3A Caffeine, theophylline, tacrine Propofol, bupropion Phenytoin, S-warfarin, tolbutamide, NSAIDs Omeprazole (partial contributor to many) Some CNS and cardiac drugs Fluranes, chlorzoxane (many)
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CYP3A High abundance Present in G.I Tract
N5-067 Dem Con Template 4/6/2017 3:28 PM CYP3A High abundance Present in G.I Tract No polymorphism, but high individual variability
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CYP3A Substrates Complete Partial Benzodiazepines (short t1/2)
N5-067 Dem Con Template 4/6/2017 3:28 PM CYP3A Substrates Complete Partial Benzodiazepines (short t1/2) Buspirone Trazodone Nefazodone Cyclosporine Statins Calcium antagonists Quinidine Protease Inhibitors Sildenafil Zolpidem Amitriptyline Imipramine Sertraline Citalopram Diazepam Clozapine
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CY3A Inhibitors High Risk Moderate Risk Ketoconazole Itraconazole
N5-067 Dem Con Template 4/6/2017 3:28 PM CY3A Inhibitors High Risk Moderate Risk Ketoconazole Itraconazole Nefazodone Ritonavir (acute) Erythromycin Clarithromycin Calcium Antagonists Fluconazole Fluvoxamine Fluoxetine Grapefruit juice Other HIV PIs Delavirdine Cimetidine
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CYP3A Inducers Rifampin Barbiturates Carbamazepine Ritonavir (chronic)
N5-067 Dem Con Template 4/6/2017 3:28 PM CYP3A Inducers Rifampin Barbiturates Carbamazepine Ritonavir (chronic) Nevirapine Hypericum perforatum (St. John’s Wort)
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St. John’s Wort Induces P-glycoprotein Induces CYP3A4 Digoxin by 30%
N5-067 Dem Con Template 4/6/2017 3:28 PM St. John’s Wort Induces P-glycoprotein Digoxin by 30% Induces CYP3A4 Indinavir Cyclosporine Statins Ruschitzka F, et al. Lancet. 2000;355(9203): Piscitelli SC, et al. Lancet. 2000;355(9203):
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Cytochrome P-450: Enzymes and Selected Substrates
N5-067 Dem Con Template 4/6/2017 3:28 PM 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 Triazolo- benzodiazepines Michalets EL. Pharmacotherapy. 1998;18: Cupp MJ, Tracy TS. Am Fam Physician. 1998;57:
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Inhibition of Human Cytochrome P-450 Isoenzymes by Newer Antidepressants
N5-067 Dem Con Template 4/6/2017 3:28 PM Cytochrome P-450 Isoenzyme Antidepressant 1A2 2C9 2C19 2D6 2E1 3A Fluoxetine to — + Norfluoxetine to — ++ Sertraline to ++ + — + Desmethylsertraline to ++ + — + Paroxetine — + Fluvoxamine — ++ Citalopram R-Desmethylcitalopram Escitalopram S-Desmethylcitalopram Nefazodone — +++ Triazoledione — + Hydroxynefazodone — +++ Venlafaxine — 0 O-Desmethylvenlafaxine — 0 Mirtazapine 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:
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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
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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.
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Elderly Are More Difficult to Treat Safely
N5-067 Dem Con Template 4/6/2017 3:28 PM 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
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Coping With Drug Interactions
N5-067 Dem Con Template 4/6/2017 3:28 PM Coping With Drug Interactions Anticipation and prevention Highly potent inducer/inhibitor Narrow therapeutic index of victim Victims dependent on one metabolic enzyme/transport protein
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Coping With Drug Interactions
N5-067 Dem Con Template 4/6/2017 3:28 PM 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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