ted d. williams, pharmd pgy1 resident syracuse vamc 2010
TRANSCRIPT
ALTERED STATES OF CONSCIOUSNESS
Ted D. Williams, PharmDPGY1 ResidentSyracuse VAMC 2010
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
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
• Shadlen, M, Larson, E. Dementia syndromes. UpToDate. Last updated 2/13/2009
DEMENTIA TYPES
Alzheimer's Disease (AD)
Parkinsonian Lewy Body Vascular Frontotemporal Medication/Alcohol Metabolic
Usually not ACh dependent
May not be ACh dependent
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 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
• 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;165:844-854 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
“…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 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%
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
44 329
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;62:2495-2499 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
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