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