Anti-Dementia Medications

Erman C. Fandialan MD, FPNADepartment of Clinical Neurosciences

University of the East Ramon MagsaysayMemorial Medical Center

DEMENTIA Clinical syndrome marked by the insidious

onset and slow progression of a cognitive impairment which impairs at least two areas of cognitive function

• Alzheimer's diseaseAlzheimer's disease (>60%). (>60%).• Diffuse Lewy body disease (DLBD)Diffuse Lewy body disease (DLBD)• Frontotemporal dementia (Pick’s disease).Frontotemporal dementia (Pick’s disease).• Primary Progressive Aphasia (speech) Primary Progressive Aphasia (speech) • Posterior Cortical Atrophy (vision)Posterior Cortical Atrophy (vision)• Parkinson's disease.Parkinson's disease.• Hunington’s disease.Hunington’s disease.• Progressive Supranuclear PalsyProgressive Supranuclear Palsy

Primary DementiasPrimary Dementias

• Infection: Infection: CJD,HIV,CryptoCJD,HIV,Crypto• Metabolic: Metabolic: HypothyroidHypothyroid• Deficiency States: Deficiency States: B12 defB12 def• Toxins: Toxins: Alcohol, Drugs, Heavy MetalsAlcohol, Drugs, Heavy Metals• Cancer: Cancer: Brain Tumors, Carcinomatous Meningitis, Brain Tumors, Carcinomatous Meningitis,

Paraneoplastic SyndromeParaneoplastic Syndrome• Trauma: Trauma: SDH, Boxers DementiaSDH, Boxers Dementia• Others: Others: NPH, MS, Dialysis Dementia, DepressioNPH, MS, Dialysis Dementia, Depressio• Vascular dementiasVascular dementias

Secondary DementiasSecondary Dementias

DIFFERENTIAL DIAGNOSIS OF DIFFERENTIAL DIAGNOSIS OF DEMENTIADEMENTIA

Small GW, et al. Small GW, et al. JAMAJAMA. 1997;278:1363-1371.. 1997;278:1363-1371.American Psychiatric Association. American Psychiatric Association. Am J PsychiatryAm J Psychiatry. 1997;154(suppl):1-39.. 1997;154(suppl):1-39.Morris JC. Morris JC. Clin Geriatr MedClin Geriatr Med. 1994;10:257-276.. 1994;10:257-276.

AD

Vascular Dementias:Vascular Dementias:1.1. Multi-infarct dementiaMulti-infarct dementia2.2. SID,SVCVD SID,SVCVD

(Binswanger’s disease)(Binswanger’s disease)

Vascular dementiasVascular dementias and ADand AD

AD and LewyAD and Lewybody dementiasbody dementias

Other Primary dementiasOther Primary dementias::Frontal lobe dementiaFrontal lobe dementiaParkinson’s diseaseParkinson’s diseaseProgressive supranuclear Progressive supranuclear palsy,others:palsy,others:

5% 10% 65% 5% 7% 8%

Diffuse Lewy Body Disease*

Anti-oxidative agents:Anti-oxidative agents: Vit.E, Folate,Vit.E, Folate,Fish oilFish oil

Anti-inflammatory agents:Anti-inflammatory agents: NSAIDs?,etc.NSAIDs?,etc.

Statins:Statins: Cholesterol Lowering AgentsCholesterol Lowering Agents

Exercise:Exercise: Physical and MentalPhysical and Mental

Preventive Treatments in Alzheimer's DiseasePreventive Treatments in Alzheimer's Disease

• Treatment of specific behavioral symptomsTreatment of specific behavioral symptoms (i.e.: (i.e.: hallucinations/delusion, agitation and aggression, hallucinations/delusion, agitation and aggression, depression, sleep disorders).depression, sleep disorders).

• Treatment of Cognitive Loss- Treatment of Cognitive Loss- CholinesteraseCholinesterase InhibitorsInhibitors

• Additional treatments In AD:Additional treatments In AD:• MemantineMemantine• Beta Secretates InhibitorsBeta Secretates Inhibitors

• ImmunizationImmunization

Drug Treatment of Alzheimer's diseaseDrug Treatment of Alzheimer's disease

BEHAVIORAL PROBLEMS IN DEMENTIA

Present in 80% of cases Major source of caregiver stress,

institutionalization Common at all stages of the disease Much more treatable than the underlying

dementia Poorly described in the literature

THREE BASIC PRINCIPLES Simplicity Limited goals The “no-fail” environment

DEPRESSION 20-30% incidence in Alzheimer’s disease, often

early in the course of the illness Most important treatable cause of excess

disability Responds very well to treatment

ACUTE BEHAVIOR CHANGE I atrogenic I nfection I llness I njury I mpaction I nconsistency I s the patient depressed?

AGITATION Present in up to 80% of patients Up to 34% of patients are combative Few predictors Probably a very heterogeneous problem Cornerstone of treatment is nonpharmacologic

EMPIRICALLY EFFECTIVE MEDS FOR AGITATION

Atypical neuroleptics (best when agitation is clearly related to delusions or hallucinations)

Anticonvulsants Trazodone Beta-blockers Buspirone Benzodiazepines Others

THE BEST NUMBER OF MEDICATIONS TO USE IS

ZERO (or sometimes one)

WHEN IN DOUBT, GET RID OF MEDICATIONS!

Treatment Goals Slow the progressive deterioration Maintain current capabilities Delay nursing home placement

Therapies for ADAcetylcholinesterase Inhibitors:

1993: Tacrine (Cognex) approved by FDA 1996: Donepezil (Aricept) 2000: Rivastigmine (Exelon) 2001: Galantamine (Reminyl/Razadyne)

NMDA Receptor Antagonist 2003: Memantine (Abixa/Ebixa/Namenda/Axura)

Cholinergic Changes in AD The most prominent neurotransmitter

abnormalities are cholinergic Reduced activity of choline acetyltransferase

(synthesis of acetylcholine) Reduced number of cholinergic neurons in late

AD (particularly in basal forebrain) Selective loss of nicotinic receptor subtypes in

hippocampus and cortex

Cholinergic Theory

Tacrine (Cognex)

Acridine Butyrylcholine-esterase > acetylcholin-esterase

1-2 hours Yes 1.3-2.0 hours

75 CYP*1A2, CYP2D6

80-160 4 Yes

Donepezil (Aricept)

Piperidine acetylcholin-esterase

3-5 hours No* 70-80 hour 96* CYP2D6,* CYP3A4

5-10 1 No*

Rivastigmine (Exelon)

Carbamate acetylcholin-esterase = Butyrylcholine-esterase

0.5-2 hour Yes 2 hour 40 Nonhepatic 6-12 2 No

Galantamin (Reminyl)

Phenanthrene Alkaloid

acetylcholin-esterase; allosteric nicotinic modulator

0.5-1.

hour

Yes 5-7 hour 10-20 CYP2D6, CYP3A4

16-24 2 No

Name (Trade Name) Class Selectivity

Time to Max

Serum Conc.

Food Delay

Absorption

Serum Half-life

Protein Bindings (%)

Meta-bolism

Dose (mg/day)

Daily Dosings

Hepato-toxicity

From: Cummings, J.L. (2001). Treatment of alzheimer’s disease. From: Cummings, J.L. (2001). Treatment of alzheimer’s disease. Clinical CornerstoneClinical Cornerstone, 3(4), 27-36., 3(4), 27-36.

CHOLINESTERASE INHIBITORS

CHOLINESTERASE INHIBITORS

Presumably increases acetylcholine at synapses Improvement in cognition (? 6-12 months better) Improvement in function (ADLs, variable) Improvement in behavior (? basal ganglia) Slowing of disease course

Treatment delays nursing home placement There is loss of benefit with delay of treatment

Need to consider early intervention

Mechanisms of Action Increases amount of acetylcholine available in synaptic cleft by

inhibiting breakdown of acetylcholine By modulating activity at nicotinic receptors, it may increase

release of acetylcholine from surviving presynaptic nerve terminals

Combination action may diminish cholinesterase supersensitivity from developing, prolonging the benefit.

May provide greatest delay of illness progression May require increase of dose after patient declines below initial

baseline, to maintain benefit for longer term.

Galantamine HBr

Mechanisms of Action Increases amount of acetylcholine available in synaptic cleft by

inhibiting breakdown of acetylcholine By modulating activity at nicotinic receptors, it may increase

release of acetylcholine from surviving presynaptic nerve terminals

Combination action may diminish cholinesterase supersensitivity from developing, prolonging the benefit.

May provide greatest delay of illness progression May require increase of dose after patient declines below initial

baseline, to maintain benefit for longer term.

Galantamine HBr

GI Tolerability Nausea and vomiting: typically transient and related

to treatment initiation and dose escalation Among patients experiencing nausea, median duration

was 5 to 7 days Weight loss: reported as an adverse event in 5% of

patients, with none discontinuing treatment due to weight loss

Galantamine HBr

Galantamine HBr Pharmacokinetics

Linear pharmacokinetics Bioavailability: 90% Half-life: 7 hours

- can provide decrease inhibition at night!! Low (18%) plasma protein binding Hepatic metabolism via multiple pathways,

primarily CYP2D6 and CYP3A4 Renal excretion

Simple, one-step dose escalation 8 mg/day starting dose

for 4 weeks (4 mg bid) 16 mg/day maintenance dose

for at least 4 weeks (8 mg bid) The flexibility to increase to 24 mg/day

(12 mg bid) – should try after 12 weeks if further benefit sought

Taken preferably with morning and evening meals Later, better with morning meal, mid-afternoon snack. (Avoid nocturnal cholinergic activation!!)

Galantamine HBr

• MemantineMemantine

• Beta SecretaseBeta Secretase

• Immunization in ADImmunization in AD

New Treatments in Alzheimer's DiseaseNew Treatments in Alzheimer's DiseaseFor cognitive lossFor cognitive loss

• MemantineMemantine• low to moderate affinity, noncompetitive low to moderate affinity, noncompetitive

NMDA-receptor antagonist and protects the NMDA-receptor antagonist and protects the neuronal system from pathological activation of neuronal system from pathological activation of glutamate (reduces Ca influx)glutamate (reduces Ca influx)

• Memantine is indicated for the treatment of Memantine is indicated for the treatment of moderatemoderate to to severesevere dementia of the Alzheimer’s dementia of the Alzheimer’s type. Can be used with type. Can be used with CholinesteraseCholinesterase Inhibitors!Inhibitors!

Drug Treatment of Alzheimer's diseaseDrug Treatment of Alzheimer's disease

• Beta Secretase inhibitorsBeta Secretase inhibitors• also called BACE1 (β-site of APP cleaving enzyme) or

memapsin-2 — is an aspartic-acid protease important in the pathogenesis of Alzheimer’s disease

• Drugs to block this enzyme (BACE inhibitors) in theory would prevent the build up of beta-amyloid and may help slow or stop the disease. Several companies are in the early stages of development and testing of this new potential class of treatment.

Drug Treatment of Alzheimer's diseaseDrug Treatment of Alzheimer's disease

Neuronal MembraneNeuronal Membrane

ExtracellularExtracellular

Beta secretaseBeta secretase

Gamma secretaseGamma secretase

Alpha secretaseAlpha secretase

IntracellularIntracellular

sAPPsAPP

AA

sAPPsAPP

AA

Metabolism of Amyloid Precursor Protein (APP)Metabolism of Amyloid Precursor Protein (APP)

From: DeKosky, S.T. (2001). Epidemiology and pathophysiology of alzheimer’s disease. From: DeKosky, S.T. (2001). Epidemiology and pathophysiology of alzheimer’s disease. Clinical CornerstoneClinical Cornerstone, 3(4), 15-24., 3(4), 15-24.

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