Pharmacologic management of dementia

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Pharmacologic management of dementia

• Worapoj Rarak M.D

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Categories of dementia pharmacology

• Symptomatic treatment of memory disturbance
• Symptomatic treatment of behavioral disturbance

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Symptomatic treatment of memory disturbance
Acetylcholinesterase inhibitorsAcetylcholinestera
se inhibitors can improve cognitive function in
patients with Alzheimers disease Vascular
dementia and Diffuse Lewy body disease
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Symptomatic treatment of memory disturbance
Acetylcholinesterase inhibitors Tacrine
hepatotoxicity, rarely used Donepezil
Rivastigmine Galantamine
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Acetylcholinesterase inhibitors
Donepezil -Well-tolerate -Once daily
administration -Also effective in Parkinsons
disease with cognitive impairment -Dose 5mg
oral a day for 4 wks then increase dose to 10mg
a day
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Acetylcholinesterase inhibitors
Donepezil 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
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Acetylcholinesterase inhibitors
Donepezil 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)
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Acetylcholinesterase inhibitors
Donepezil ADVERSE REACTIONS SIGNIFICANT gt10
Central nervous system Headache
Gastrointestinal Nausea, diarrhea
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Acetylcholinesterase inhibitors
Donepezil ADVERSE REACTIONS SIGNIFICANT 1-10
Cardiovascular Syncope, chest pain,
hypertension, atrial fibrillation,
hypotension,hot flashes Central nervous
system Fatigue, insomnia, dizziness,
depression, abnormal dreams, somnolence
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Acetylcholinesterase inhibitors
Donepezil ADVERSE REACTIONS SIGNIFICANT
1-10 Dermatologic Bruising
Gastrointestinal Anorexia, vomiting, weight
loss, fecal incontinence, GI bleeding, bloating,
epigastric pain Genitourinary Frequent
urination Neuromuscular skeletal Muscle
cramps, arthritis, body pain
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Acetylcholinesterase inhibitors
Donepezil ADVERSE REACTIONS SIGNIFICANT
lt1 Cholecystitis, CHF, delusions, dysarthria,
dysphasia, dyspnea, eosinophilia,
hallucinations, heart block, hemolytic anemia,
hyponatremia, intracranial hemorrhage,
neuroleptic malignant syndrome, pancreatitis,
paresthesia, rash, seizures, thrombocytopenia
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Acetylcholinesterase inhibitors
DonepezilDrug interactionIncrease serum level
of donepezil amiodarone, cimetidine, delavirdine,
fluoxetine, paroxetine, propafenone, quinidine,
and ritonavir clarithromycin, erythromycin,
delavirdine, diltiazem dirithromycin, disulfiram,
fluoxetine, fluvoxamine, indinavir,
itraconazole, nevirapine,ketoconazole metronidazol
e, nefazodone, propoxyphene quinupristin-dalfopris
tin, saquinavir, verapamil zafirlukast, zileuton
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Acetylcholinesterase inhibitors
DonepezilDrug interactionDecrease serum level
of donepezil phenytoin, carbamazepine,
dexamethasone, rifampin, and phenobarbital
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Acetylcholinesterase inhibitors
Donepezil Contraindication Hypersensitivity to
donepezil, piperidine derivatives, or any
component of the formulation
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Acetylcholinesterase inhibitors
Donepezil Warning Precaution May cause
bradycardia and/or heart block with or without a
history of cardiac disease syncopal episodes
have been associated with donepezil.
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Acetylcholinesterase inhibitors
Donepezil Warning Precaution Use with caution
in patients with sick sinus syndrome or other
supraventricular cardiac conduction
abnormalities, in patients with seizures, COPD,
or asthma avoid use in nursing mothers. Use
with caution in patients at risk of ulcer
disease (ie, previous history or NSAID use), or
in patients with bladder outlet obstruction.
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Acetylcholinesterase inhibitors
Rivastigmine -Dose 1.5mg oral BID with
titration every 2 weeks up to 6mg BID
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Acetylcholinesterase inhibitors
Rivastigmine PHARMACODYNAMICS / KINETICS
Absorption Fasting Rapid and complete within
1 hour Distribution Vd 1.8-2.7 L/kg
Protein binding 40
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Acetylcholinesterase inhibitors
Rivastigmine PHARMACODYNAMICS / KINETICS
Metabolism Extensively via cholinesterase- media
ted hydrolysis in the brain metabolite undergoes
N-demethylation and/or sulfate conjugation
hepatically
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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)
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Acetylcholinesterase inhibitors
Rivastigmine ADVERSE REACTIONS SIGNIFICANT gt10
Central nervous system Dizziness (21)
headache (17) Gastrointestinal Nausea
(47), vomiting (31), diarrhea (19), anorexia
(17) abdominal pain (13)
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Acetylcholinesterase inhibitors
Rivastigmine ADVERSE REACTIONS SIGNIFICANT
2-10 Central nervous system Fatigue (9),
insomnia (9), confusion (8), depression (6),
anxiety (5), malaise (5), somnolence (5),
hallucinations (4), aggressiveness (3)
Cardiovascular Syncope (3), hypertension (3)
Gastrointestinal Dyspepsia (9),
constipation (5), flatulence (4), weight loss
(3)
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Acetylcholinesterase inhibitors
Rivastigmine ADVERSE REACTIONS SIGNIFICANT
2-10 Genitourinary Urinary tract infection
(7) Neuromuscular skeletal Weakness (6),
tremor (4) Respiratory Rhinitis (4)
Miscellaneous Increased diaphoresis (4),
flu-like syndrome (3)
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Acetylcholinesterase inhibitors
Rivastigmine Drug interaction Anticholinergics
Effects may be reduced with rivastigmine
Beta-blockers May increase risk of
bradycardia Calcium channel blockers (diltiazem
or verapamil) May increase risk of bradycardia
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Acetylcholinesterase inhibitors
Rivastigmine Drug interaction Cholinergic
agonists Effects may be increased with
rivastigmine Cigarette use increases the
clearance of rivastigmine by 23 Digoxin
Increased risk of bradycardia with concurrent
use
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Acetylcholinesterase inhibitors
Rivastigmine Drug interaction Neuromuscular
blockers Depolarizing neuromuscular blocking
agents effects may be increased with
rivastigmine NSAIDs Although not seen in
clinical studies, patients may be at increased
risk for peptic ulcers or gastrointestinal
bleeding with concomitant use
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Acetylcholinesterase inhibitors
Rivastigmine ContraindicationHypersensitivity to
rivastigmine, other carbamate derivatives, or any
component of the formulation
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Acetylcholinesterase inhibitors
Rivastigmine Warning PrecautionSignificant
nausea, vomiting, anorexia, and weight loss are
associated with use occurs more frequently in
women and during the titration phase.Use with
caution in patients with a history of peptic
ulcer disease or concurrent NSAID use
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Acetylcholinesterase inhibitors
Rivastigmine Warning Precaution patients with
sick sinus syndrome, bradycardia or
supraventricular conduction conditions, urinary
obstruction, seizure disorders, or pulmonary
conditions such as asthma or COPD
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Acetylcholinesterase inhibitors
Galantamine -Newer agent -Galantamine has shown
modest benefit in patients with a clinical
diagnosis of either vascular dementia or
combination of AD and CVA -Dose Initial 4 mg
twice a day for 4 weeks If 8 mg per day
tolerated, increase to 8 mg twice daily for gt or
4 weeks If 16 mg per day tolerated, increase to
12 mg twice daily range 16-24 mg/day in 2
divided doses
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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
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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
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Acetylcholinesterase inhibitors
Galantamine PHARMACODYNAMICS / KINETICS
Bioavailability 80 to 100 Half-life
elimination 6-8 hours Time to peak 1 hour
Excretion Urine (25)
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Acetylcholinesterase inhibitors
Galantamine ADVERSE REACTIONS SIGNIFICANT gt10
Gastrointestinal Nausea (6 to 24) , vomiting
(4 to 13), diarrhea (6 to 12)
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Acetylcholinesterase inhibitors
Galantamine ADVERSE REACTIONS SIGNIFICANT 1-10
Cardiovascular Bradycardia (2 to 3), syncope
(0.4 to 2.2 dose-related), chest pain (gt or
1) Central nervous system Dizziness (9),
headache (8), depression (7), fatigue (5),
insomnia (5), somnolence (4), tremor (3)
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Acetylcholinesterase inhibitors
Galantamine ADVERSE REACTIONS SIGNIFICANT 1-10
Gastrointestinal Anorexia (7 to 9), weight
loss (5 to 7), abdominal pain (5), dyspepsia
(5), flatulence (gt or 1) Genitourinary
Urinary tract infection (8), hematuria (lt1 to
3), incontinence (gt or 1) Hematologic
Anemia (3) Respiratory Rhinitis (4)
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Acetylcholinesterase inhibitors
Galantamine ADVERSE REACTIONS SIGNIFICANT lt1
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, Paroniria, vertigo
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Acetylcholinesterase inhibitors
Galantamine Drug interaction Amiodarone
Concurrent use may lead to bradycardia
Anticholinergic agents (eg, atropine,
benztropine, tolterodine) Galantamine may
antagonize anticho- -linergic actions Beta
blockers without ISA activity Concurrent use
may lead to bradycardia
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Acetylcholinesterase inhibitors
Galantamine Drug interaction Cimetidine
Increased bioavailability of galantamine by 16
Cholinergic agonists May have synergistic
effects Digoxin Concurrent use may lead to AV
block Diltiazem Concurrent use may lead to
bradycardia
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Acetylcholinesterase inhibitors
Galantamine Drug interaction Ketoconazole
Increased galantamine levels (AUC increased by
30) NSAIDs Concurrent use may increase risk
of gastrointestinal ulcer because of increased
gastric acid secretion.
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Acetylcholinesterase inhibitors
Galantamine ContraindicationHypersensitivity to
galantamine or any component of the formulation
Severe liver dysfunction(Child-Pugh score
10-15) Severe renal dysfunction (Clcrlt9
mL/minute)
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Acetylcholinesterase inhibitors

• Galantamine
• Warning Precaution- May exaggerate
  neuromuscular blockade effects
• of depolarizing neuromuscular-blocking agents
• like succinylcholine.
• Vagotonic effects on the SA and AV nodes may
• lead to bradycardia or AV block.
• -Use caution in peptic ulcer disease (or in
  patients
• at risk of ulcer disease) seizure disorder
  asthma
• COPD mild to moderate liver dysfunction
• moderate renal dysfunction.

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Symptomatic treatment of behavioral disturbance

• Delusions and hallucinations rivastigmine,
• risperidol, quetiapine
• Depression citalopram, fluoxetinegtgt TCA
• Agression and anxiety trazodone, carbamazepine,
  valproate, gabapentin

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Symptomatic treatment of behavioral disturbance

• Delusions and hallucinations rivastigmine,
• Risperidol, quetiapine
• Depression citalopram, fluoxetinegtgt TCA
• Agression and anxiety trazodone, carbamazepine,
  valproate, gabapentin

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Symptomatic treatment of behavioral disturbance
Quetiapine -Dose start at 25mg at bed
time, Titrating up to a maximum of 75mg BID
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Symptomatic treatment of behavioral disturbance
Quetiapine PHARMACODYNAMICS / KINETICS
Absorption Rapidly absorbed following oral
administration Distribution Vd 10 /- 4
L/kg Protein binding, plasma 83 Metabolism
Primarily hepatic via CYP3A4 forms two
inactive metabolites
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Symptomatic treatment of behavioral disturbance
Quetiapine PHARMACODYNAMICS / KINETICS
Bioavailability 100 Half-life elimination
Mean Terminal 6 hours Time to peak, plasma
1.5 hours Excretion Urine (73 as metabolites,
lt1 as unchanged drug) feces (20)
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Symptomatic treatment of behavioral disturbance
Quetiapine ADVERSE REACTIONS SIGNIFICANT gt10
Central nervous system Agitation, dizziness ,
headache, somnolence Endocrine metabolic
Cholesterol increased (11), triglycerides
increased (17) Gastrointestinal Weight gain
(gt or 7 body weight, dose related), xerostomia
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Symptomatic treatment of behavioral disturbance
Quetiapine ADVERSE REACTIONS SIGNIFICANT 1-10
Cardiovascular Postural hypotension,
tachycardia, palpitations, peripheral edema
Central nervous system Anxiety, fever, pain
Dermatologic Rash Gastrointestinal
Abdominal pain(dose related) , constipation,
dyspepsia (dose related), anorexia, vomiting,
gastroenteritis
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Symptomatic treatment of behavioral disturbance
Quetiapine ADVERSE REACTIONS SIGNIFICANT 1-10
Hematologic Leukopenia Hepatic AST
increased, ALT increased, GGT increased
Neuromuscular skeletal Dysarthria, back
pain, weakness, tremor, hypertonia, dysarthria
Ocular Amblyopia Respiratory Rhinitis,
pharyngitis, cough, dyspnea Miscellaneous
Diaphoresis, flu-like syndrome
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Symptomatic treatment of behavioral disturbance
Quetiapine Drugs interaction -Anti HT additive
hypotension effect -Azole antifungal increase
level up to 335 -Cimetidine decrease serum
clearance of Quetiapine 20 -Sedative drugs
additive effect -Levodopa inhibit antiparkinson
effect . -Metoclopramide increase risk of EPS
symptom
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Symptomatic treatment of behavioral disturbance
Quetiapine Drugs interaction Quetiapine serum
level will be decreased with aminoglutethimide,
carbamazepine, nafcillin, nevirapine,
phenobarbital, phenytoin, and rifamycins Increase
d with azole antifungals, ciprofloxacin,
clarithromycin, diclofenac, doxycycline,
erythromycin, imatinib, INH nefazodone,
nicardipine, propofol, protease
inhibitors quinidine, and verapamil.
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Symptomatic treatment of behavioral disturbance
Quetiapine ContraindicationHypersensitivity to
quetiapine or any component of the formulation
severe CNS depression bone marrow suppression
blood dyscrasias severe hepatic disease, coma
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Symptomatic treatment of behavioral disturbance
Quetiapine Warning Precaution-May be sedating,
use with caution in disorders where CNS
depression is a feature. -Use with caution in
Parkinson's disease. -Caution in patients with
hemodynamic instability prior myocardial
infarction or ischemic heart disease,
hypercholesterolemia thyroid disease
predisposition to seizures subcortical brain
damage hepatic impairment, esophageal
dismotility
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Symptomatic treatment of behavioral disturbance
Quetiapine Warning Precaution-May cause
anticholinergic effects (confusion, agitation,
constipation, xerostomia, blurred vision,
urinary retention) -May cause hyperglycemia -
use with caution in patients with diabetes or
other disorders of glucose regulation.
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Symptomatic treatment of behavioral disturbance
Citalopram -Antidepressant, Selective Serotonin
reuptake inhibitor -Dose Initial 20 mg/day,
generally with an increase to 40 mg/day(duration
gt 1wk) Maximum dose 60mg/day
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Symptomatic treatment of behavioral disturbance
Citalopram PHARMACODYNAMICS / KINETICS
Distribution Vd 12 L/kg Protein binding,
plasma 80 Metabolism Extensively hepatic,
including CYP, to N-demethylated, N-oxide, and
deaminated metabolites Bioavailability 80
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Symptomatic treatment of behavioral disturbance
Citalopram PHARMACODYNAMICS / KINETICS Half-life
elimination 24-48 hours average 35 hours
(doubled with hepatic impairment) Time to peak,
serum 1-6 hours, average within 4 hours
Excretion Urine (10 as unchanged drug)
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Symptomatic treatment of behavioral disturbance
Citalopram ADVERSE REACTIONS SIGNIFICANT gt10
Central nervous system Somnolence, insomnia
Gastrointestinal Nausea, xerostomia
Miscellaneous Diaphoresis
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Symptomatic treatment of behavioral disturbance
Citalopram ADVERSE REACTIONS SIGNIFICANT 1-10
Central nervous system Anxiety, anorexia,
agitation, yawning Dermatologic Rash,
pruritus Endocrine metabolic Sexual
dysfunction Gastrointestinal Diarrhea,
dyspepsia, vomiting, abdominal pain, weight gain
Neuromuscular skeletal Tremor, arthralgia,
myalgia Respiratory Cough, rhinitis,
sinusitis
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Symptomatic treatment of behavioral disturbance
Citalopram Drugs interaction Citapopram level
will be decreased with aminoglutethimide,
carbamazepine, phenytoin Naficillin, nevirapine,
phenobarbital and rifampin Increased with
delavirdine, fluconazole, fluvoxamine,
gemfibrozil, isoniazid, omeprazole, and
ticlopidine azole antifungals, ciprofloxacin,
clarithromycin, diclofenac, doxycycline,
erythromycin, imatinib, isoniazid, nefazodone,
nicardipine, propofol
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Symptomatic treatment of behavioral disturbance
Citalopram Drugs interaction -Beta blocker
increase level of Beta blockerSerotonin syndrome
with -MAO inhibitors -Linezolid -Pethidine,
tramadol -Nefazodone -Ritronavia -Serotonin
agonist -NSAID increase risk of GI bleeding
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Symptomatic treatment of behavioral disturbance
Citalopram Contraindication Hypersensitivity to
citalopram or any component of the formulation
hypersensitivity or other adverse sequelae
during therapy with other SSRIs concomitant
use with MAO inhibitors or within 2 weeks of
discontinuing MAO inhibitors.
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Symptomatic treatment of behavioral disturbance

• Citalopram
• Warning Precaution- Potential for severe
  reaction when used with
• MAO inhibitors
• May precipitate a shift to mania or hypomania in
  
• patients with bipolar disorder
• Use with caution in patients with hepatic or
  renal
• dysfunction and in elderly patients.
• - May cause hyponatremia/SIADH- May cause or
  exacerbate sexual dysfunction

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Symptomatic treatment of behavioral disturbance
Trazodone -Serotonin reuptake inhibitor -Dose
start at 25mg at bed time with 25-50 mg/day dose
increase every 3 days if tolerated usual dose
75-150 mg/day
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Symptomatic treatment of behavioral disturbance
Trazodone PHARMACODYNAMICS / KINETICS Onset of
action Therapeutic 1-3 weeks Protein binding
85 to 95 Metabolism Hepatic Half-life
elimination 7-8 hours
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Symptomatic treatment of behavioral disturbance
Trazodone PHARMACODYNAMICS / KINETICS Time to
peak, serum 30-100 minutes delayed with food
(up to 2.5 hours) Excretion Primarily urine
secondarily feces
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Symptomatic treatment of behavioral disturbance
Trazodone ADVERSE REACTIONS SIGNIFICANT gt10
Central nervous system Dizziness, headache,
sedation Gastrointestinal Nausea,
xerostomia
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Symptomatic treatment of behavioral disturbance
Trazodone ADVERSE REACTIONS SIGNIFICANT 1-10
Cardiovascular Syncope, hypertension,
hypotension, edema Central nervous system
Confusion, decreased concentration, fatigue,
incoordination Gastrointestinal Diarrhea,
constipation, weight gain/loss
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Symptomatic treatment of behavioral disturbance
Trazodone ADVERSE REACTIONS SIGNIFICANT 1-10
Neuromuscular skeletal Tremor, myalgia
Ocular Blurred vision Respiratory Nasal
congestion
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Symptomatic treatment of behavioral disturbance
Trazodone Drugs interaction other
psychotropics(low potency antipsychotics) may
result in additional hypotension ethanol,
barbiturates, benzodiazepines, narcotic
analgesics increase CNS depression
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Symptomatic treatment of behavioral disturbance
Trazodone Drugs interactionTrazodone increase
level of amphetamines, selected
beta-blockers, dextromethorphan, fluoxetine,
lidocaine, mirtazapine, nefazodone, paroxetine,
risperidone, ritonavir, thioridazine, tricyclic
antidepressants
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Symptomatic treatment of behavioral disturbance
Trazodone Drugs interactionTrazodone decrease
level of codeine, hydrocodone, oxycodone, and
tramadol.
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Symptomatic treatment of behavioral disturbance
Trazodone Drugs interactionTrazodone level will
be decrease with aminoglutethimide,
carbamazepine, nafcillin, nevirapine,
phenobarbital, phenytoin, and rifamycins.
Increase with azole antifungals, ciprofloxacin,
clarithromycin, diclofenac, doxycycline,
erythromycin, imatinib, isoniazid, nefazodone,
nicardipine, propofol, protease inhibitors,
quinidine, and verapamil.
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Symptomatic treatment of behavioral disturbance
Trazodone Drugs interaction MAO inhibitors
Concurrent use may lead to serotonin syndrome
avoid concurrent use or use within 14 days
Linezolid Merperidine, Serotonin agonist may
increaserisk of serotonin syndrome
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Symptomatic treatment of behavioral disturbance
Trazodone ContraindicationHypersensitivity to
trazodone or any component of the formulation
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Symptomatic treatment of behavioral disturbance

• Trazodone
• Warning Precaution- Priapism
• - Not recommended for use in a patient during the
  
• acute recovery phase of MI
• Use withcaution in patients who are receiving
• concurrent or recent therapy with a MAO
  inhibitor- Use with caution in CVS , CVA ,
  epilepsy ,hepatic and renal dysfunction

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Thank you for your attention