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Download Falling - Dr Ted Williams
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Ted D. Williams, PharmD PGY1 Resident Syracuse VAMC 2010 ALTERED STATES OF CONSCIOUSNESS OUTLINE • • • • • • Dementia Delirium Sundowning Anticholinergic Tolerance Anticholinergic Poisoning EBM Review of Falls DEMENTIA DEFINED Impairment of memory AND at least one other cognitive domain Aphasia Apraxia loss of the ability to execute or carry out learned purposeful movements Agnosia difficulty in producing or comprehending spoken or written language loss of ability to recognize objects, persons, sounds, shapes, or smells Executive Function planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions, restraining inappropriate actions •Shadlen, M, Larson, E. Dementia syndromes. UpToDate. Last updated 2/13/2009 DEMENTIA TYPES Alzheimer's Disease (AD) Parkinsonian Lewy Body May not be ACh dependent Vascular Frontotemporal Usually not ACh dependent Medication/Alcohol Metabolic DELIRIUM DEFINED Disturbance of consciousness with reduced ability to focus, sustain or shift attention Often present with baseline dementia (22-89%) Short Onset (hours to days), tending to fluctuate Duration is days to months •DSM-IV delirium •Francis, J, Young, GB. Diagnosis of delirium and confusional states. UpToDate online database. Last Updated 2/3/10 •Francis, J. Prevention and treatment of delirium and confusional states. UpToDate online database. Last updated 1/20/10 SUNDOWNING A working definition: The appearance of exacerbation of behavioral disturbances associated with the afternoon and/or evening hours. Often considered a specific type of delirium •Volicer, L, et al. Sundowning and Circadian Rhythms in Alzheimer’s Disease. American Journal of Psychiatry 2001;158:704-711 SUNDOWNING Etiology Unclear, though common in dementia, esp. AD Changes in suprachiasmatic nucleus (SCN) many account for changes in circadian rhythms The SCN receives inputs from specialized photoreceptive retinal ganglion cells, via the retinohypothalamic tract. dorsomedial SCN (dmSCN) are believed to have an endogenous 24-hour rhythm SCN sends information to other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and melatonin •Volicer, L, et al. Sundowning and Circadian Rhythms in Alzheimer’s Disease. American Journal of Psychiatry 2001;158:704-711 •Suprachiasmatic nucleus. http://en.wikipedia.org/wiki/Suprachiasmatic_nucleus SUNDOWNING & CIRCADIAN RHYTHMS •Volicer, L, et al. Sundowning and Circadian Rhythms in Alzheimer’s Disease. American Journal of Psychiatry 2001;158:704-711 DEMENTIA PATHOPHYSIOLOGY Leading theory is the Cholinergic Deficit Model Acetylcholine is a ubiquitous CNS neurotransmitter Deficiencies can interrupt normal signal transduction •Hshieh, TT, et al. Cholinergic deficiency hypothesis in delirium: A synthesis of current evidence. Journal of Gerontology: Medical Sciences. 2008:63;764-772 ACETYLCHOLINE DEFICIENCIES Impaired Acetylcholine synthesis Malnutrition Thiamine Niacin Cellular hypoglycemia Precursor Cholinergic neuron apoptosis Citric Acid Cycle interruption Synaptic derangement Post Synaptic M1 Receptor blockade M2-4 do not affect dementia/delirum M2 are found in the peripheral nervous system Inhibition of Pre synaptic signal transduction Opioids Cannabanoids •Hshieh, TT, et al. Cholinergic deficiency hypothesis in delirium: A synthesis of current evidence. Journal of Gerontology: Medical Sciences. 2008:63;764-772 TREATMENT OF DEMENTIA Disease modifying agent None currently available Symptom Management Cognitive Behavioral DEMENTIA TREATMENTS - COGNITIVE Acetylcholine Esterase Inhibitors Rivastigmine Donepezil Galantamine Efficacy Most studies fail to show clinically significant improvements, though many reach statistical significance Very few head-to-head trials Select agent based on tolerance, no demonstrated difference in side effect profiles between agents N/V/D Muscarinic Side Effects If no improvement Consider discontinuing Consider anticholinergics which may be interfering •Qaseem, A, et al. Current Pharmacologic Treatment of Dementia: A clinical practice guideline from the American college of physicians and the American academy of family physicians. Annals of Internal Medicine 2008;148:370-378. VA FORMULARY CRITERIA Requires the use of the dementia ordering form Requires a confirmed diagnosis of dementia with scoring tool and patient score Galantamine SA preferred over Galantamine IR Rivastigmine generally reserved for Parkinson’s Disease RIVASTIGMINE Half life 2 hours Metabolism occurs at acetylcholinesterse to inactive metabolite Metabolite is excreted renally Duration of action 10 hours Irreversible binding to Acetylcholinesterase Transdermal kinetics Onset 1 hour Peak concentration 8 hours 9.5 mg/24 hours drug exposure is similar to an oral dose of 6 mg twice daily DONEPEZIL Competitive, reversible inhibition Half life 70hours CYP2D6, CYP3A4. Glucoronidation GALANTAMINE Competitive, reversible inhibition Half life 7 hours CYP2D6, CYP3A4. DEMENTIA BEHAVIORAL SYMPTOMS DEMENTIA TREATMENTS - BEHAVIORAL ANTICHOLINERGIC Acetylcholine esterase inhibitors CALM-AD Trial. NEJM 2007;357:1382-1392 Placebo Controlled RCT n=272 Donepezil 10mg vs. placebo for 12 weeks No significant difference in Cohen-Mansfield Agitation inventory DEMENTIA TREATMENTS – BEHAVIORAL ANTIPSYCHOTICS Antipsychotics Used to control agitation or aggression Increased risk of mortality with prolonged us ANTIPSYCHOTIC EFFICACY IN DEMENTIA Schneider, LS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. NEJM 2006;355:1525-1538 n=421, RCT placebo vs. olanzapine, risperidone or quetiapine No significant differences in changes in multiple cognitive scales, inculding Clinical Global Impression of Change (CGIC, a validated, Alzheimer’s Disease scale) Attainment of minimal or greater improvement on the CGIC scale at week 12 while the patients continued to receive the phase 1 drug Quetiapine discontinued earlier (9.1wks) due to lack of efficacy vs. risperidone(26.7wks) or olanzapine (22.1wks) p= 0.002 ANTIPSYCHOTIC EFFICACY IN DEMENTIA Sultzer, DL, et al. Clinical symptom responses to atypical antipsychoitc medications in alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165:844854 Same data as Schneider in NEJM, but different analysis …the difference in the change scores…at the last observation in phase 1. The last-observation analysis was chosen because of the substantial percentage of patients who discontinued phase 1 treatment... Excluded everyone who discontinued medication ANTIPSYCHOTIC EFFICACY IN DEMENTIA “…yet these improved last-observation ratings occurred at or very near the time when the clinician…intended to changed the treatment.” •Sultzer, DL, et al. Clinical symptom responses to atypical antipsychoitc medications in alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165:844-854 ANTIPSYCHOTIC SAFETY Safety of Antipsychotics Increased risk of mortality (black box warning) Meta-analysis JAMA 2005;294:1934-1943 Second-generation antipsychotics (SGA) associated with increased risk in all cause mortality OR=1.54;CI 1.06-2.23 Retrospective by Schneider et al. Cohort by Gill Annals of Internal Medicine 2007;146:775-786 n=27259 pairs Initiation of SGA associated with increased risk of death Community dwelling: HR=1.31 CI 1.02-1.70 AR=0.2% LTC: HR=1.55 CI 1.15-2.07 AR=1.2% DEMENTIA TREATMENTS – BEHAVIORAL ANTIPSYCHOTICS Prospective RCT by Ballard, et al (DART-AD) Lancet 2009;8:151-57 n=165 Patient randomized to either continue existing first or second generation antipsychotics or receive placebo Continuation group had an increased risk of mortality. 12 Month HR 0.58, CI 0.36-0.92 24-month survival 46% vs 71% 36-month survival 30% vs 59% “…there is still an important but limited place for atypical antipsychotics…particularly [for] aggression.” “…urgent need to put an end to unnecessary and prolonged prescribing.” DELIRUM PREVENTION Environmental modification Orienting stimuli help prevent delirium Windows with normal daylight Clocks Structured activities & lighting Medications 30% of cases attributable to drug toxicity ANTICHOLINERGIC POISONING Symptoms Red as a beet - vasodilation Dry as a bone - anhidrosis Hot as a hare - hyperthermia Blind as a bat - mydriasis Mad as a hatter – delirium Full as a flask – urinary retention Differential Infection Serotonin syndrome Salicylate overdose Hypoglycemia ANTICHOLINERGIC POISONING - TREATMENT Delirium Haloperidol has very weak anticholinergic effects Risperidone has no anticholinergic effects Decontamination Physostigmine IV ACEI which passes BBB Limited evidence, but not much available on any treatment possible, but contact poison control •Su, M, Goldman,M. Anticholinergic poisoning. UpToDate online database. Last Updated 6/12/10 ANTICHOLINERGIC TOLERANCE Richardson, GF, et al. Tolerance to daytime sedative effects of H1 antihistamines. Journal of Clinical Psychopharmacology 2002;22:511-515 Randomized, double blinded, placebo control cross over in 15 healthy men 18-50yo Diphenhydramine 50mg BID vs. Placebo After 4 days, tolerance to sedative effects develops FALL RISK OF VARIOUS MEDIATIONS Lee, J. et al. Medical illnesses are more important than medications as risk factors of falls in older community dwellers? A cross-sectional study. Age and ageing 2006;35:246-251 ACEI, Beta blockers, diuretics, and psychotropics were not associated with falls or recurrent falls in outpatients Statins, ASA, NSAIDS, APAP all were associated with falls FALL RISK OF VARIOUS MEDIATIONS Walker, et al. Medication use as a risk factor for falls among hospitalized elderly patients. AJHP 2005;62:24952499 Found a group of miscellaneous drugs with the risk of hypotension were used more frequently in patients who fell than patients who did not Oxybutynin Second generation antihistamines Anti-hyperglycemics Antiepileptics including gabapentin Gastrointestinal agents (PPIs, anti-emetics, H2RA) CCB Nitrates Found significant association between NSAIDS (including ASA 81mg) and fall risk (OR 10.02, CI 2.6-38.58, p=0.002) FALL RISK OF VARIOUS MEDIATIONS Woolcott, JC et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Archives of Internal Medicine 2009;169:1952-1960 Drug Class OR CI Antihypertensives 1.26 1.08-1.46 Diuretics 1.03 0.84-1.26 Beta Blockers 1.14 0.97-1.33 Sedatives 1.31 1.14-1.50 Neuroleptics/ Antipsychotics 1.71 1.44-2.04 Antidepressants 1.72 1.40-2.11 Benzodiazepines 1.60 1.46-1.75 Narcotics 0.89 0.5-1.58 NSAIDs 1.65 0.98-2.77 CONCLUSIONS Sundowning is not synonymous with delirium “Acute” delirium can last for weeks Acetylcholineesterase Inhibitors are modestly effective for dementia, but have not been demonstrated effective for acute delirium Antipsychotics for delirium Marginal demonstrated efficacy beyond aggitation/aggression Increased risk of mortality demonstrated in RCT Indicated only after behavioral/environmental factors have been corrected Keep the doses low, and the durations short Those oddball medications that cause hypotension/dizziness, might actually be contributors to falls
