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Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York Drug-Drug Interactions Lecture available at www.robertkelly.us.

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Presentation on theme: "Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York Drug-Drug Interactions Lecture available at www.robertkelly.us."— Presentation transcript:

1 Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York Drug-Drug Interactions Lecture available at

2 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

3 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

4 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

5 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

6 Importance of Drug-Drug Interactions Increased Number of Medications Greater likelihood of interactions Aging Effects Pharmacokinetics Pharmacodynamics

7 Adverse Drug Reactions (ADRs) as a Function of Increasing Age Ghose K. Drugs Aging. 1991;1: Age (y) ADRs per 10,000 Population 1 (infancy)

8 Beyth RJ, Schorr RI. Drugs Aging. 1999;14: Major Bleeding (%) N = Years  75 years years < 65 years Incidence of Bleeding During Anticoagulant Therapy

9 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.

10 Relationship Between Prescribing Rate and Prevalence of Potential Drug Interactions Nolan L, O’Malley K. Age Ageing. 1989;18:52-56.

11 Clinical Dilemma Number of possible drug interactions too large to memorize Difficult to determine which interactions are important

12 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

13 Physiology Pharmacokinetics Absorption Distribution Elimination Metabolism Excretion Pharmacodynamics Tissue response to drug

14 Distribution Compartments Water Decreases Hydrophilic meds Fat Increases Lipophilic meds Plasma Protein Decreased (albumin), or increased Barriers Blood-brain Intestinal

15 Elimination Excretion Bodily fluids Urine (Kidneys) Sweat Others Vapors (Lungs) Feces (Intestines) Tissues (Skin) Metabolism Liver Intestinal Cellular

16 Liver Aging Effects Few Generalizations Possible Reduction in Enzyme Activity Reduction in Blood Flow, 45% from 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 a cetylation, conjugation Usually inactive metabolites Water-soluble, eliminated by kidneys Relatively spared with age

17 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

18 Brain Cognitive Changes Processing Speed Memory Susceptible to delirium Atrophy Variable Substantia Nigra

19 Balance CNS Proprioception Central processing Semicircular canals Vision Lack of exercise Medications for HTN Sedating medications

20 Interactions Elimination Increases Decreases Synergism Toxic Effects

21 Anticholinergic Medications Commonly Prescribed in the Elderly Codeine Digoxin Dipyridamole Isosorbide Nifedipine Prednisolone Ranitidine Theophylline Warfarin Commonly prescribed in the elderly at levels that can impair cognition: Tune L, et al. Am J Psychiatry. 1992;149:

22 SSRIs Hyponatremia Exacerbated with HCTZ and others Bleeding Inhibits platelet aggregation Possible Synergism Warfarin Aspirin Ginko Biloba

23 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

24 Valproic Acid Liver enzyme inhibitor Signs of Toxicity Usually mild Sedation Anticholinergic effects Elevated LFTs Platelet production inhibition Elevated serum ammonia levels

25 Carbamazapine Enzyme Inducer Need to increase dose after 6 weeks Signs of Toxicity Sedation Confusion Ataxia Sialorrhea

26 MAOIs Reversible Not available in US Selective Selegiline patch, low dose Nonselective Risk of hypertensive crisis Medications--Demerol Food restrictions

27 Cytochrome P-450 Enzyme Subtypes CYP1A2 CYP2E1 CYP2C CYP2D6 CYP3A4

28 CYP isoform Representative substrates 1A2 1A2 2B6 2B6 2C9 2C9 2C19 2C19 2D6 2D6 2E1 2E1 3A 3A Caffeine, theophylline, tacrine Propofol, bupropion Phenytoin, S-warfarin, tolbutamide, NSAIDs Omeprazole (partial contributor to many) Some CNS and cardiac drugs Fluranes, chlorzoxane (many)

29 CYP3A High abundance Present in G.I Tract No polymorphism, but high individual variability

30 CYP3A Substrates CompletePartial Benzodiazepines (short t 1/2 ) BuspironeTrazodoneNefazodoneCyclosporineStatins Calcium antagonists Quinidine Protease Inhibitors SildenafilZolpidemAmitriptylineImipramineSertralineCitalopramDiazepamClozapine

31 CY3A Inhibitors High Risk Moderate Risk KetoconazoleItraconazoleNefazodone Ritonavir (acute) ErythromycinClarithromycin Calcium Antagonists FluconazoleFluvoxamineFluoxetine Grapefruit juice Other HIV PIs DelavirdineCimetidine

32 CYP3A Inducers Rifampin Barbiturates Carbamazepine Ritonavir (chronic) Nevirapine Hypericum perforatum (St. John’s Wort)

33 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):

34 Cytochrome P-450: Enzymes and Selected Substrates Michalets EL. Pharmacotherapy. 1998;18: Cupp MJ, Tracy TS. Am Fam Physician. 1998;57: A22C2D63A4 TheophyllinePhenytoinCodeineAntihistamines WarfarinWarfarinVenlafaxineCalcium channel blockers AntipsychoticsAmitriptylineTrazodoneCarbamazepine BenzodiazepinesClomipramineRisperidoneCisapride FluvoxamineOmeprazoleHaloperidolCorticosteroids TramadolCyclosporine  -BlockersFentanyl Protease inhibitors Statins Triazolo- benzodiazepines

35 Inhibition of Human Cytochrome P-450 Isoenzymes by Newer Antidepressants Greenblatt DJ, et al. J Clin Psychiatry. 1998;59(suppl 15): von Moltke LL, et al. Drug Metab Disposition. 2001;29: = minimal or zero inhibition. += mild inhibition. ++= moderate inhibition. +++= strong inhibition. —= no data available. Antidepressant1A22C92C192D62E13A 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 Cytochrome P-450 Isoenzyme

36 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

37 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.

38 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

39 Coping With Drug Interactions Anticipation and prevention –Highly potent inducer/inhibitor –Narrow therapeutic index of victim –Victims dependent on one metabolic enzyme/transport protein

40 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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