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Altered states of consciousness

Ted D. Williams, PharmD PGY1 Resident Syracuse VAMC 2010. Altered states of consciousness. Dementia Delirium Sundowning Anticholinergic Tolerance Anticholinergic Poisoning EBM Review of Falls. Outline. Impairment of memory AND at least one other cognitive domain Aphasia

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Altered states of consciousness

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  1. Ted D. Williams, PharmD PGY1 Resident Syracuse VAMC 2010 Altered states of consciousness

  2. Dementia • Delirium • Sundowning • Anticholinergic Tolerance • Anticholinergic Poisoning • EBM Review of Falls Outline

  3. Impairment of memory AND at least one other cognitive domain • Aphasia • difficulty in producing or comprehending spoken or written language • Apraxia • loss of the ability to execute or carry out learned purposeful movements • Agnosia • 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 Dementia Defined • Shadlen, M, Larson, E. Dementia syndromes. UpToDate. Last updated 2/13/2009

  4. Alzheimer's Disease (AD) • Parkinsonian • Lewy Body • Vascular • Frontotemporal • Medication/Alcohol • Metabolic Dementia Types May not be ACh dependent Usually not ACh dependent

  5. 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 Delirium Defined • 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

  6. 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 Sundowning • Volicer, L, et al. Sundowning and Circadian Rhythms in Alzheimer’s Disease. American Journal of Psychiatry 2001;158:704-711

  7. 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 Sundowning • 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

  8. Sundowning & Circadian Rhythms • Volicer, L, et al. Sundowning and Circadian Rhythms in Alzheimer’s Disease. American Journal of Psychiatry 2001;158:704-711

  9. Leading theory is the Cholinergic Deficit Model Acetylcholine is a ubiquitous CNS neurotransmitter Deficiencies can interrupt normal signal transduction Dementia Pathophysiology • Hshieh, TT, et al. Cholinergic deficiency hypothesis in delirium: A synthesis of current evidence. Journal of Gerontology: Medical Sciences. 2008:63;764-772

  10. Impaired Acetylcholine synthesis • Malnutrition • Thiamine • Precursor • Cholinergic neuron apoptosis • Niacin • Cellular hypoglycemia • 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 Acetylcholine deficiencies • Hshieh, TT, et al. Cholinergic deficiency hypothesis in delirium: A synthesis of current evidence. Journal of Gerontology: Medical Sciences. 2008:63;764-772

  11. Disease modifying agent • None currently available • Symptom Management • Cognitive • Behavioral Treatment of dementia

  12. 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 Dementia treatmentS - Cognitive • 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.

  13. 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 VA Formulary Criteria

  14. 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 Rivastigmine

  15. Competitive, reversible inhibition • Half life 70hours • CYP2D6, CYP3A4. Glucoronidation Donepezil

  16. Competitive, reversible inhibition • Half life 7 hours • CYP2D6, CYP3A4. Galantamine

  17. Dementia Behavioral Symptoms

  18. 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 - Anticholinergic

  19. Antipsychotics • Used to control agitation or aggression • Increased risk of mortality with prolonged us Dementia treatmentS – Behavioral - Antipsychotics

  20. 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

  21. 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 • 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

  22. “…yet these improved last-observation ratings occurred at or very near the time when the clinician…intended to changed the treatment.” 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;165:844-854

  23. Safety of Antipsychotics • Increased risk of mortality (black box warning) • Meta-analysis by Schneider et al. • 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 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% Antipsychotic Safety

  24. 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.” Dementia Treatments – Behavioral - Antipsychotics

  25. Environmental modification • Orienting stimuli help prevent delirium • Windows with normal daylight • Clocks • Structured activities & lighting • Medications • 30% of cases attributable to drug toxicity Delirum Prevention

  26. 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 44 329

  27. 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 Anticholinergic poisoning - treatment • Su, M, Goldman,M. Anticholinergic poisoning. UpToDate online database. Last Updated 6/12/10

  28. 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 Anticholinergic Tolerance

  29. 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

  30. Walker, et al. Medication use as a risk factor for falls among hospitalized elderly patients. AJHP 2005;62:2495-2499 • 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

  31. 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 Fall Risk of various mediations

  32. 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 Conclusions

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