1. Anti-Dementia Medications
Erman C. Fandialan MD, FPNA
Department of Clinical Neurosciences
University of the East Ramon Magsaysay
Memorial Medical Center

2. DEMENTIA
Clinical syndrome marked by the insidious onset and slow progression of a cognitive impairment which impairs at least two areas of cognitive function

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

4. Secondary Dementias Infection: CJD,HIV,Crypto Metabolic: Hypothyroid
Deficiency States: B12 def
Toxins: Alcohol, Drugs, Heavy Metals
Cancer: Brain Tumors, Carcinomatous Meningitis, Paraneoplastic Syndrome
Trauma: SDH, Boxers Dementia
Others: NPH, MS, Dialysis Dementia, Depressio
Vascular dementias

5. DIFFERENTIAL DIAGNOSIS OF DEMENTIA
Other Primary dementias:
Frontal lobe dementia
Parkinson’s disease
Progressive supranuclear palsy,others:
Vascular Dementias:
Multi-infarct dementia
SID,SVCVD (Binswanger’s disease)
Diffuse Lewy Body
Disease*
Vascular dementias
and AD
AD and Lewy body dementias AD 5%
10%
65% 5% 7% 8%
Small GW, et al. JAMA. 1997;278:
American Psychiatric Association. Am J Psychiatry. 1997;154(suppl):1-39.
Morris JC. Clin Geriatr Med. 1994;10:

6. Preventive Treatments in Alzheimer's Disease
Anti-oxidative agents: Vit.E, Folate,
Fish oil
Anti-inflammatory agents: NSAIDs?,etc.
Statins: Cholesterol Lowering Agents
Exercise: Physical and Mental

7. Drug Treatment of Alzheimer's disease
Treatment of specific behavioral symptoms (i.e.: hallucinations/delusion, agitation and aggression, depression, sleep disorders).
Treatment of Cognitive Loss- Cholinesterase Inhibitors
Additional treatments In AD:
Memantine
Beta Secretates Inhibitors
Immunization

8. 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

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

10. 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

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

12. 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

13. EMPIRICALLY EFFECTIVE MEDS FOR AGITATION
Atypical neuroleptics (best when agitation is clearly related to delusions or hallucinations)
Anticonvulsants
Trazodone
Beta-blockers
Buspirone
Benzodiazepines
Others

14. THE BEST NUMBER OF MEDICATIONS TO USE IS ZERO (or sometimes one)
WHEN IN DOUBT, GET RID OF MEDICATIONS!

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

16. Therapies for AD Acetylcholinesterase 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)

17. 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
The associated decline of cognitive function in AD with decreased cholinergic neurotransmission in the cortex, hippocampus, and amygdala is the basis for what is known as the cholinergic hypothesis of AD

18. Cholinergic Theory

20. CHOLINESTERASE INHIBITORS
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
Tacrine (Cognex)
Acridine
Butyrylcholine-esterase > acetylcholin-esterase
1-2 hours
Yes
hours 75
CYP*1A2, CYP2D6
80-160 4
Donepezil (Aricept)
Piperidine
acetylcholin-esterase
3-5 hours
No*
70-80 hour
96*
CYP2D6,* CYP3A4
5-10 1
Rivastigmine (Exelon)
Carbamate
acetylcholin-esterase = Butyrylcholine-esterase
0.5-2 hour
2 hour 40
Nonhepatic
6-12 2 No
Galantamin (Reminyl)
Phenanthrene Alkaloid
acetylcholin-esterase; allosteric nicotinic modulator
0.5-1.
hour
5-7 hour
10-20
CYP2D6, CYP3A4
16-24
From: Cummings, J.L. (2001). Treatment of alzheimer’s disease. Clinical Cornerstone, 3(4),

21. 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

22. 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.
The clinical significance of these mechanisms is unknown
These 2 mechanisms of action are synergistic

23. 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.
The clinical significance of these mechanisms is unknown
These 2 mechanisms of action are synergistic

24. 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
Nausea and vomiting were typically of mild-to-moderate severity; rates of discontinuation were < 4% for this adverse event
Patients who vomited usually had only 1 occurrence, and it tended to coincide with an increase in Reminyl (galantamine HBr) dose
The rates of nausea and vomiting were reduced to baseline levels soon after each dose increase
Nausea and vomiting were readily managed by dietary modification, dosing with meals, and use of antiemetics
In the open-label extension phase, patients usually regained the weight they lost during the initial phase of the study

25. 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
The pharmacokinetics of Reminyl® (galantamine HBr) are well suited to its purpose
Predictable levels
Readily absorbed
Active when needed
Few drug-drug interactions
Low potential for drug-drug interactions
Renally excreted

26. Galantamine HBr 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!!)
This slide summarizes the dosing of Reminyl® (galantamine HBr)
Clear dosing range established
Escalation step is 4 weeks
16 mg/day is the target maintenance dose
In appropriate patients, 24 mg/day can be used

27. New Treatments in Alzheimer's Disease
For cognitive loss
Memantine
Beta Secretase
Immunization in AD

28. Memantine Drug Treatment of Alzheimer's disease
low to moderate affinity, noncompetitive NMDA-receptor antagonist and protects the neuronal system from pathological activation of glutamate (reduces Ca influx)
Memantine is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. Can be used with Cholinesterase Inhibitors!

29. Beta Secretase inhibitors
Drug Treatment of Alzheimer's disease
Beta 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.

30. Metabolism of Amyloid Precursor Protein (APP)
Extracellular
sAPP
sAPP
Beta secretase
Alpha secretase A
Neuronal Membrane
Gamma secretase
Intracellular A
From: DeKosky, S.T. (2001). Epidemiology and pathophysiology of alzheimer’s disease. Clinical Cornerstone, 3(4),

31. THANK YOU