Cognitive disorders unit 9

Delirium vs. Dementia

DeliriumRapid onsetPrimary defect in

attentionFluctuates during the

course of a dayVisual hallucinations

commonOften cannot attend to

MMSE or clock draw

DementiaInsidious onsetPrimary defect in short

term memoryAttention often normalDoes not fluctuate

during dayVisual hallucinations

less commonCan attend to MMSE or

clock draw, but cannot perform well

Cognitive DIsorders

Delirium Fluctuating cognitive impairment and

disturbance of consciousness Psychosis and Insomnia

Treating Delirium

Primary goal treat underlying cause Cause: Anticholinergic toxicity

Physiostigmine salicylate 1 to 2 mg IV or IM with repeated doses in 15 to 30 minutes may be indicated

Treatment

Psychosis Haloperidol

2 to 6 mg IM, repeated in an hour if necessary

Depending on patient’s age, weight and physical condition.

Once patient is calm begin oral medication Liquid concentrate or tablet 2 daily oral doses, 2/3 of the dose at bedtime

Effective daily dose of Haloperidol 5 to 40 mg for most patients

Treatment

Atypical antipsychotics Risperidone: for those with side effects

from haloperidol or contraindications Starting dose: .5mg HS or BID Olanzapine: agent of choice for patients

with PD with hallucinations/delirium Starting dose 2.5mg PO HS or BID Clozapine, quetiapine, aripiprazole may

also be considered although clinical trial experience is limited.

Treatment

Insomnia Best treated with benzodiazepines with

short or intermediate half-lives Lorazepam 1 to 2 mg at bedtime

Dementia

The treatment for dementia is aimed at : Symptomatic treatment of memory

disturbance Symptomatic treatment of memory

disturbance

What are the common forms of dementia?

There are four main types of dementia: Alzheimer’s disease (60%; of cases)

Vascular dementia (30–40%; including about 20% where dual pathology exists)

Dementia with Lewy bodies (15% of cases)

Fronto-temporal dementia (5%) Percentages total more than 100

because of variability in studies

How is Alzheimer’s disease characterised? Alzheimer’s disease may be characterized by

a diffuse pattern of cortical deficits including: Aphasia – loss or impairment of language caused by brain dysfunction

Apraxia – inability to execute learned movements on command

Agnosia – inability to recognize or associate meaning to a sensory perception

Acalculia – inability to perform arithmetical calculations

Agraphia – inability to write Alexia – inability to read

Vascular dementia

Vascular dementia is the second most common cause of dementia. It results from vascular or circulatory lesions or from diseases of the cerebral vasculature leading to ischaemia or infarction.

Clinical features of vascular dementia problems concentrating and

communicating depression accompanying the dementia symptoms of stroke, such as physical

weakness or paralysis memory problems (although this may not

be the first symptom) a 'stepped' progression, with symptoms

remaining at a constant level and then suddenly deteriorating

epileptic seizures periods of acute confusion.

Clinical features of vascular dementia

Other symptoms may include: hallucinations (seeing things that do not exist) delusions (believing things that are not true) walking about and getting lost physical or verbal aggression restlessness incontinence.

Clinical features of Dementia with Lewy Bodies

Dementia of six months’ duration with: Periods of confusion

Fluctuations in cognition (especially attention and alertness)

Visual hallucinations Spontaneous extrapyramidal signs such as

rigidity or slowing (mild parkinsonism) Bradykinesia (paucity of movement)

Acetylcholinesterase Inhibitors Can improve cognitive functions in

patients diagnosed with: Alzheimer’s disease Vascular dementia and Diffuse Lewy body disease

Acetylcholinesterase Inhibitors Donezepil Rivastigmine Galantamine Tacrine

Used very rarely due to its hepatotoxicity

Acetylcholinesterase Inhibitors Donezepil

Adminestered once daily Generally well tolerated Dose: 5mg oral/ day for 4 weeks then

increase dose to 10mg/day Effective in Parkinsonian cognitive

impairment

Acetylcholinesterase Inhibitors Donezepil PHARMACODYNAMICS / KINETICS

Absorption: Well absorbed Protein binding: 96%, primarily to albumin

(75%) & alpha1-acid glycoprotein (21%)

Metabolism: Extensively to four major metabolites (two are active) via CYP2D6 and 3A4; undergoes glucuronidation

Acetylcholinesterase Inhibitors Donezepil PHARMACODYNAMICS / KINETICS Bioavailability: 100% Half-life elimination: 70 hours; time to

steady-state: 15 days

Time to peak, plasma: 3-4 hours Excretion: Urine (as unchanged drug)

Acetylcholinesterase Inhibitors Donezepil Significant Adverse Effects in

>10% Central nervous system: Headache Gastrointestinal: Nausea, diarrhea

Significant Adverse Effects in <10% Cardiovascular: Syncope, chest pain,

hypertension, atrial fibrillation, hypotension, hot flashes

Central nervous system: Fatigue, insomnia, dizziness, depression, abnormal dreams,

somnolence

Acetylcholinesterase Inhibitors Significant Adverse Reactions in

<10% cont. Dermatologic: Bruising Gastrointestinal: Anorexia, vomiting,

weight loss, fecal incontinence, GI bleeding ,

bloating, epigastric pain Genitourinary: Frequent urination Neuromuscular & skeletal: Muscle cramps

, arthritis, body pain

Acetylcholinesterase Inhibitors Significant Adverse Reactions in <1%

Cholecystitis, CHF, delusions, dysarthria, dysphasia, dyspnea, eosinophilia, hallucin

ations, heart block, hemolytic anemia, hyponatre

mia, intracranial hemorrhage, neuroleptic mali

gnant syndrome, pancreatitis, paresthesia, rash,

seizures, thrombocytopenia

Acetylcholinesterase Inhibitors Contraindication

Hypersensitivity to donepezil, piperidine derivatives, or any component of the formulation

Acetylcholinesterase Inhibitors Rivastigmine

Dose: 1.5mg oral BID with titration every 2 weeks up to 6mg BID

Acetylcholinesterase Inhibitors Rivastigmine PHARMACODYNAMICS /

KINETICS Absorption: Fasting: Rapid and

complete within 1 hour Distribution: Vd: 1.8-2.7 L/kg Protein binding: 40%

Acetylcholinesterase Inhibitors Rivastigmine PHARMACODYNAMICS / KINETICS Metabolism: Extensively via

cholinesterase- mediated hydrolysis in the brain;

metabolite undergoes N-demethylation and/or

sulfate conjugation hepatically

Acetylcholinesterase Inhibitors Rivastigmine PHARMACODYNAMICS / KINETICS Bioavailability: 40% Half-life elimination: 1.5 hours Time to peak: 1 hour Excretion: Urine (97% as

metabolites); feces (0.4%)

Acetylcholinesterase Inhibitors Rivastigmine

Significant Adverse Reactions in >10% 21Central nervous system: Dizziness ( %) (17%) vvv vvvvv : ( 4 7 %), (31%), 19 17diarrhea ( %), anorexia ( %) (13%)

Acetylcholinesterase Inhibitors Rivastigmine

Significant Adverse Reactions in 2-10% 9Central nervous system: Fatigue ( %), 9 8insomnia ( %), confusion ( %), depression (

6%), ( 5 %), ( 5 %), ( 5

%), (4%), (3%) 3Cardiovascular: Syncope ( %), hypertension (3%) : ( 9 %), 5 4constipation ( %), flatulence ( %), weight loss

(3%)

Acetylcholinesterase Inhibitors Rivastigmine Significant Adverse Reactions in 2-

10% cont. 7Genitourinary: Urinary tract infection ( %) & : ( 6 %), (4%)tremor : ( 4 %) : ( 4 %), - (3%)flu like syndrome

Acetylcholinesterase Inhibitors Rivastigmine

Contraindication vv vvvvvvvvvvvvv vvvvv vvvvvvvvv, vv vvv vvv vvvvvv vv vvv vvvv v,

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Acetylcholinesterase Inhibitors Galantamine Newer agent Galantamine has shown modest benefit

in patients with a clinical diagnosis of eithervascular dementia or combination of AD and CVA

Dose: 4 4Initial: mg twice a day for weeks 8If mg per day tolerated vv v vv vvvvv , 8

vv v v vvvvv >=4 16If mg per day tolerated 12, increase to mg

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Acetylcholinesterase Inhibitors Galantamine PHARMACODYNAMICS /

KINETICS Absorption: Rapid and complete Distribution: 1.8-2.6 L/kg; levels in

the brain are 2-3 times higher than in plasma Protein binding: 18%

Acetylcholinesterase Inhibitors Galantamine PHARMACODYNAMICS / KINETICS Metabolism: Hepatic; linear, CYP2D6

and 3A4; metabolized to epigalanthaminone and

galanthaminone both of which have acetylcholinesterase inhibitory activity 130 times less than galantamine

Acetylcholinesterase Inhibitors Galantamine PHARMACODYNAMICS /

KINETICS Bioavailability: 80% to 100% Half-life elimination: 6-8 hours Time to peak: 1 hour Excretion: Urine (25%)

Acetylcholinesterase Inhibitors Galantamine Significant Adverse Reactions in>10%

6 24Gastrointestinal: Nausea ( % to %) (4% 13%), (6% 12%)

Significant Adverse reactions in 1-10% Cardiovascular: Bradycardia (2 % to 3 %),

- syncope (0 .4 % to 2 .2 %: dose related), chest p ai n

(>or=1%) Central nervous system: Dizziness (9 %),

headache (8%), depression (7%), fatigue (5%), insomnia (5 %), somnolence (4 %), tremor (3 %)

Acetylcholinesterase Inhibitors Galantamine ADVERSE REACTIONS SIGNIFICANT <1% Aggression, alkaline phosphatase increased,

aphasia, apraxia, ataxia, atrial fibrillation, AV block, bundle branch block, convulsions, dehydration,

delirium, diverticulitis, dysphagia, epistaxis, esophageal perforation, gastrointestinal bleeding,

heart failure, hypokalemia, hypokinesia, hypotension, melena, palpitations, paranoid reaction, paresthesia,

vertigo

Symptomatic Treatment of Behavioral Disturbance in Dementia Patients

Delusions and hallucinations: rivastigmine, risperidol, quetiapine Depression: citalopram, fluoxetine>>

TCA Agression and anxiety: trazodone,

carbamazepine, valproate, gabapentin