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Pharmacology in the Frail Elderly Lawrence Jackson, BScPhm Veterans Centre Sunnybrook Health Sciences Centre Sept 20, 2011 Overview Process for identifying drug therapy problems Clinical presentation of ADE Anticholinergic load Background on DI Types Case Avoidable drug interactions (DIs) Range of drug therapy problems Strategies to minimize DIs in practice How Pharmacists Think What are the current signs and symptoms What is the urgency Are S&S drug or disease related What are the therapeutic options What are the Drug Therapy Problems (DTP) What do we hope to achieve What is the best therapeutic plan What is the monitoring plan How Pharmacists Think Drug Therapy Problems Unnecessary drug therapy (not indicated) Need for additional drug therapy Ineffective drug (needs an alternative) Dose too low Dose too high Adverse Drug Reaction (ADR) Noncompliance/Nonadherence Clinical presentations of ADR/ADI ADRs and ADIs often present as non-specific clinical syndromes, referred to as „disease simulators‟ Always include “drugs” in the differential diagnosis confusion, delirium falls urinary incontinence decompensation of heart failure problems can manifest when person is most susceptible Atypical presentation of disease Adverse Drug Events Adverse drug event – any injury resulting from drug administration (all inclusive term) 10-35% ambulatory elderly have ADE 7% of hospitalizations are due to ADE (Shelton PS et al. Drugs & Aging 2000;16:437-450) Adverse drug event incidence in the elderly who present to ED ( Am J Emerg Med 1996; 14:144-450) Two Medications Five Medications Seven Medications Risk ADE: 13% Risk ADE: 58% Risk ADE: 82% Polypharmacy Definition too many drugs drugs for too long drugs in exceedingly high doses Michocki RJ et al. Arch Fam Med1993;2:441-4 Drugs used to treat side effects of other drugs (“drug cascade”) narcotic confusion antipsychotic EPS anti-parkinsonian therapy Consequence of multiple physicians What makes the elderly different? The elderly have an increased frequency of adverse drug reactions Decreased physiological reserve Altered pharmacokinetics water, fat, Alb, Phase 1 metabolism (P450) Altered pharmacodynamics Compliance issues More diseases and more drugs Impact of Anticholinergic Drugs Can precipitate or exacerbate existing cholinergic deficits CNS-dementia Periphery- dry eyes, dry mouth, constipation, blurred vision Anticholinergic Load Anticholinergic Risk Scale (ARS) Score of 3 = 2 or more anti-Ch effects in 70% 3points 2 Points 1 Point Amitriptyline Amantadine Sinemet Atropine Baclofen Entacapone Benztropine Cetirizine Haloperidol Dicyclomine Loratadine Ranitidine Diphenydramine Tolterodine Trazodone Oxybutinin Prochlorperazine Risperidone Arch Intern Med 2008;168 (5):508-13 Drug Interactions Definition Drug-Drug interaction Effect of one drug enhanced or diminished by use of another Associated with some evidence of harm Four Important Characteristics 1. 2. Innumerable Common 3. Difficult to study in „real‟ patients 4. 20-50% of older patients presenting to ED we often rely case reports & volunteer studies Inherently avoidable Types of Drug Interactions Types Mechanism of action • Augmented or reduced effects Drug-drug-pk Drug-drug-pd Drug-nutritional status Drug-disease Drug-alcohol Drug-herbal Outcome • Synergy • Adverse effects • Antagonism • Treatment failure Classification Change in drug level Pharmacokinetic vs. Pharmacodynamic No change in drug level Examples: Pharmacodynamic DIs Patient with Parkinson‟s disease on levodopa / carbidopa Rx with chlorpromazine for persistent hiccups Patient with Hypertension on ramipril 5mg daily Rx celecoxib 200mg bid } Antagonistic, receptor-mediated } Antagonistic, not receptor-mediated Examples: Pharmacodynamic DIs Patient with chronic pain Patient on Ativan 1 mg tid on morphine SR 30mg bid Rx with gabapentin 300mg tid has 3 glasses of wine } Synergistic, not receptor-mediated } Synergistic, not receptor-mediated Patient post MI on metoprolol 50mg bid Rx with timolol 0.5% eye drops for glaucoma } Synergistic, receptor-mediated Pharmacokinetic DIs One drug changes the level of another or or or absorption elimination metabolism ‘Typical’ Pharmacokinetic DI 120 100 } 80 chronic medication 60 40 20 0 time Therapeutic range ‘Typical’ Pharmacokinetic DI 120 new medication 100 } 80 chronic medication 60 40 20 0 time Therapeutic range ‘Typical’ Pharmacokinetic DI 120 new medication Toxicity 100 } 80 chronic medication 60 40 20 0 time Therapeutic range ‘Typical’ Pharmacokinetic DI 120 new medication 100 } 80 chronic medication 60 Therapeutic range 40 Loss of efficacy 20 0 time Examples: Altered absorption H2 blockers, PPIs absorption of ketoconazole, itraconazole Ca2+ or Mg2+ or Fe or cholestryramine absorption of tetracyclines captopril quinolones levothyroxine Altered drug metabolism: The cytochrome P450 system > 60 different enzymes Major ones CYP 1A2 CYP 2C9* CYP 2C19* CYP 2D6* CYP 2E1 CYP 3A4 / 3A5 * polymorphisms Substrates Inhibitors Inducers Phase 1 Metabolism Metabolize some drugs to inactive products diazepam, simvastatin, sertraline, morphine Metabolize some drugs to active products codeine, enalapril, atorvastatin, clopidogrel Examples: Pharmacokinetic DIs Patient with DM } Glyburide metabolized by 2C9 Septra inhibits 2C9 Patient on simvastatin 20mg daily on glyburide 10mg daily Rx with Septra DS bid hypoglycemic episode Diet changed to include grapefruit muscle aches } Patient on warfarin Rx with amiodarone 200mg daily bleeding episode } Simvastatin metab by 3A4 Gjuice inhibits 3A4 Warfarin metabolized by 2C9 Amiodarone inhibits 2C9 CYP 3A4 Substrates The importance of bioavailability Dresser CMAJ 2004 The importance of inhibition of CYP 3A4 on bioavailability of substrates Very low (<10%) Low (10% to 30%) atorvastatin, felodipine Intermediate (30% to 70%) simvastatin, lovastatin, buspirone 3A4 inhibition: levels amio, CBZ, CyA, diazepam, diltiazem, nifedipine, sildenafil, triazolam High (>70%) 3A4 inhibition: levels alprazolam, amlodipine, dexamethasone, quetiapine Dresser Can J Clin Pharm 2002 Examples: DI related to the patient Patient with renal failure } Acyclovir is renally cleared Patient with low albumin Rx with Acyclovir 800mg 5x/d CNS confusion, sedation Rx phenytoin 300mg/d CNS confusion, sedation } ↑ unbound phenytoin ( ↑ free fraction) Patient with Parkinson‟s disease Rx with metoclopramide 10mg qid Increased bradykinesia } Metoclopramide blocks action of Sinemet at the D2 receptor What is P-glycoprotein? Membrane glycoprotein 1976: found in cancer cells Expressed in gut, kidney, brain………….. A “natural defense mechanism” P-glycoprotein Substrates Inhibitors Inducers digoxin macrolides rifampin loperamide diltiazem amiodarone antifungals dexamethasone St. John‟s wort midazolam protease inhibitors quinidine cyclosporine chemo (various) cyclosporine colchicine verapamil ritonavir Examples: P-glycoprotein DIs Patient on digoxin Rx with clarithromycin Digoxin toxicity with 7 days } Dig po bioavailability 50-70% Clarith inhbits p-g increasing dig bioavailability Patient on diltiazem CD 240mg/d Rx amiodarone Slow heart rate } ↑ bioavailability of diltiazem Case #1 80 y.o. man with stable CHF GP diagnoses acute gout Rx Ramipril 5mg od, metoprolol 100 mg BID, furosemide 40mg od Rx Ibuprofen 400mg qid 2 days later patient presents with ankle edema Diuretic-NSAID Interaction •PGE2 inhibits NaCl reabsorption (via the Na, K, Cl co-transporter) •PGE2 inhibits free water and Na reabsorption (via the collecting duct) •Diuretics increase PGs •Inhibition of PG synthesis by NSAIDs (ibuprofen, naproxen, sulindac) can diminish natriuresis and diuresis induced by furosemide, HCT, triamterene, spironolactone •Effect is potentiated by salt restriction Brenner and Rector's The Kidney, 8th ed. Case #2 80 y.o. woman with previous TIA GP diagnoses osteoarthritis Rx ASA 81mg daily Rx Ibuprofen 400mg qid 2 months later patient presents with stroke ibuprofen X ASA Arachadonic acid Case #3 55 y.o. man with stable angina GP diagnoses arrhythmia Rx ASA, metoprolol 100 mg BID Rx Amiodarone 200mg daily 10 days later patient presents to hospital HR 42 bpm BP 90/50 Case #3 What happened? Metoprolol is metabolized by 2D6 Amiodarone inhibits 2D6 Beta blockade is enhanced Case #4 Patient receiving Tylenol #3 1 tab tid for back pain GP diagnoses depression Rx Paroxetine 20mg daily 2 days later pain is worse Case #4 What happened? Codeine is a prodrug converted to morphine by CYP 2D6 Paroxetine inhibits CYP 2D6 abolishes analgesic effect of codeine CYP 2D6 Involved in metabolism of 15-20% of drugs Not inducible 7-10% of Caucasians no functional CYP 2D6 “poor metabolizers” Interactions involving CYP 2D6 Drugs metabolized by CYP 2D6 CYP 2D6 inhibitors codeine amiodarone carvedilol, metoprolol SSRIs haloperidol, risperidone haloperidol Case #5 Patient with epilepsy well controlled on carbamazepine CR 400 BID Begins taking St. John‟s wort for depressed mood 3 weeks later GTC seizure; [CBZ] 11 mol/L Case #5 What happened? CBZ is metabolized by CYP 3A4 St. John‟s wort induces 3A4 Enhanced metabolism of CBZ lower level; treatment failure How could it have been avoided? CYP 3A4 substrates Cardiac drugs Benzodiazepines (some) triazolam, diazepam, alprazolam, midazolam “Statins” verapamil, nifedipine, diltiazem, amlodipine, nifedipine, amiodarone atorvastatin, lovastatin, simvastatin Miscellaneous carbamazepine, cyclosporine, antiretrovirals, Interactions involving CYP 2D6 CYP 2D6 inducers Anti-epileptic drugs carbamazepine phenobarbital phenytoin St. John‟s Wort, rifampin Dexamethasone CYP 2D6 inhibitors erythro, clarithro (not azithromycin) grapefruit juice, amiodarone indinavir, nelfinavir, saquinavir… itraconazole, ketoconazole Case #6 Patient with constipation Poorly managed with docusate 100mg BID Begins taking mineral oil 30 mL daily 3 weeks later Anal leakage of mineral oil and puritis ani Case #6 What happened? Mineral oil Prevents reabsorption of fecal water Poorly absorbed Combination with docusate will inc absorption If absorbed, not metabolized→ fatty liver Aspiration lipoid pneumonia Reduces absorption of fat-soluble vitamins Anal leakage → itching (pruritis ani) Rectal enema OK for fecal impaction Strategies to Minimize Drug Interactions in Practice Optimizing Drug Therapy Rational Prescribing Benefits of drugs Avoid under treatment ADR risk increases with the number of drugs used Approaches Explicit criteria (Beers list….) Implicit criteria (complete assessment) Drug utilization tools Explicit Criterion-based Expert opinion, consensus Fail to take into account all health indicators or patient preferences or burden of co-morbid diseases Implicit Clinician uses patientspecific information and published evidence to form judgments about appropriateness Dependent on user‟s knowledge & attitudes Explicit criteria Beers list- drugs to avoid Arch Intern Med 2003;163(22):2716-2724. IPET (improving prescribing in the elderly tool) Can J Clin Pharmacol 2000;7(2):103-107 STOPP (screening tool of older person‟s potentially inappropriate prescriptions) Age Ageing 2008;37(6):673-79. START (screening tool to alert doctors to right treatment) Int J Clin Pharmacol Ther 2008;46(2):72-83 MAI (medication appropriateness index) J Clin Epidemiol 1992;45(10):1045-51. Minimizing Drug Interactions Entertain DDI with any new drug esp. when a low therapeutic index drug onboard warfarin, digoxin, glyburide, statins, theophylline Or other high alert drugs benzodiazepines, diphenydramine, antipsychotics, anticonvulsants Use a Safer Alternative Drug class Safest Options SSRIs citalopram, sertraline Antibiotics penicillins cephalosporins azithromycin newer quinolones Statins pravastatin Traps to avoid Overestimating renal function Starting with too high dose Failure to attribute S&S to drugs Use of anticholinergic drugs Altered ability to tolerate drugs when ill Resources ePocrates www.epocrates.com LexiDrugs www.skyscape.com Medical Letter ADR www.medicalletter.com iFacts (Drug interactions) www.factsandcomparisons.com Drug-Interactions http://medicine.iupui.edu/clinpharm/DDIs/ Rx Files www.rxfiles.ca Global rph www.globalrph.com POGOe http://www.pogoe.org/front2 Hansten and Horn Textbook of Drug Interactions Micromedex Recap How pharmacists address DTP‟s Clinical presentation of ADR/ ADI Anticholinergic load Various types of drug interactions with examples Cases to illustrate medication complexity in the elderly Strategies to avoid DIs and promote safe prescribing in the elderly Drug Interaction Game Digoxin Donepezil Oxybutinin Major, ↑ dig Ibuprofen Glyburide Diltiazem Septra Mod, absorp Mod, absorp Levothyroxine Metoprolol Ramipril Mod, cog Cipro Amoidarone Iron Mod, HR Mod,↑ AV node block Major, Mod, BP effect of ACEI lowering effect Mod, ↑AV node block Major, BG