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Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College

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.

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Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College

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

  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 60 50 40 ADRs per 10,000 Population 30 20 10 0 1(infancy) 20-29 40-49 60-69 80+ Age (y) Ghose K. Drugs Aging. 1991;1:2-5.

  8. Incidence of Bleeding During Anticoagulant Therapy  75 years 65-74 years < 65 years 100 80 60 MajorBleeding (%) 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.

  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 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

  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. Codeine Digoxin Dipyridamole Isosorbide Nifedipine Prednisolone Ranitidine Theophylline Warfarin Anticholinergic Medications Commonly Prescribed in the Elderly Commonly prescribed in the elderly at levels that can impair cognition: Tune L, et al. Am J Psychiatry. 1992;149:1393-1394.

  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 CYP2E1 CYP1A2 CYP2C CYP3A4 CYP2D6

  28. CYP isoform Representative substrates

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

  30. CYP3A Substrates

  31. CY3A Inhibitors

  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):548-549. Piscitelli SC, et al. Lancet. 2000;355(9203):547-548.

  34. 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 Triazolo- benzodiazepines Michalets EL. Pharmacotherapy. 1998;18:84 -112.Cupp MJ, Tracy TS. Am Fam Physician. 1998;57:107-116.

  35. Inhibition of Human Cytochrome P-450 Isoenzymes by Newer Antidepressants Cytochrome P-450 Isoenzyme Antidepressant 1A2 2C9 2C19 2D6 2E1 3A Fluoxetine + ++ + to ++ +++ — +Norfluoxetine + ++ + to ++ +++ — ++ Sertraline + + + to ++ + — +Desmethylsertraline + + + to ++ + — + Paroxetine + + + +++ — + Fluvoxamine +++ ++ +++ + — ++ Citalopram + 0 0 0 0 0R-Desmethylcitalopram 0 0 0 + 0 0 Escitalopram 0 0 0 0 0 0S-Desmethylcitalopram 0 0 0 0 0 0 Nefazodone 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 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.

  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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