Brand name : NAMENDA US FDA Approval :October 2003 NMDA (N-methyl-D-aspartate) receptor antagonist Indicated for the treatment of moderate to severe Alzheimer’s Disease

1. Memantine
ByBy
Sirinoot JantharangkulSirinoot Jantharangkul
Memantine
By
Sirinoot Jantharangkul

2. MMemantineemantine
Brand name :Brand name : NAMENDANAMENDA
US FDA Approval :October 2003US FDA Approval :October 2003
NMDA (N-methyl-D-aspartate) receptorNMDA (N-methyl-D-aspartate) receptor
antagonistantagonist
IIndicated for the treatment of moderate tondicated for the treatment of moderate to
severesevere Alzheimer’s DiseaseAlzheimer’s Disease

3. Alzheimer’s DiseaseAlzheimer’s Disease
Degenerative disease ofDegenerative disease of
the brainthe brain
Prevalence : 50% in thosePrevalence : 50% in those
> 85 years> 85 years
More common in womenMore common in women
Average life span is 8-10Average life span is 8-10
years after diagnosisyears after diagnosis
Cause of death:
aspiration, infection,
malnutrition

4. Alzheimer’s DiseaseAlzheimer’s Disease
CauseCause
1.1. Genetic factorGenetic factor :: Early onset and Late onsetEarly onset and Late onset
Early onsetEarly onset : <65years: <65years
- Amyloid precursor protein (APP)- Amyloid precursor protein (APP) onon
chromosome 21, chromosome 14chromosome 21, chromosome 14
and chromosome 1and chromosome 1
Amyloid precursor protein (APP)Amyloid precursor protein (APP)
AmyloidAmyloid ββ- protein- protein

5. Alzheimer’s DiseaseAlzheimer’s Disease
Late onsetLate onset : >65years: >65years
- Apolipoprotein E4(Apo E4) on- Apolipoprotein E4(Apo E4) on
chromosome19chromosome19
2.Nongenetic factor2.Nongenetic factor
-- Inflammatory mediatorsInflammatory mediators
- Neurochemical- Neurochemical: reduction in choline: reduction in choline
acetyltransferaseacetyltransferase
- Heavy metal toxicity- Heavy metal toxicity : aluminium toxicity: aluminium toxicity

6. PathophysiologyPathophysiology
Two hallmake histopathology featuresTwo hallmake histopathology features
NeuriticNeuritic plaquesplaques
small spheres containingsmall spheres containing ββ-amyloid-amyloid
NeurofibrillaryNeurofibrillary tangletangle
Abnormal neuron containing bundles ofAbnormal neuron containing bundles of
paired helical filamentous structure woundpaired helical filamentous structure wound
around each other in the cytoplasmaround each other in the cytoplasm
40-90%reduction in choline40-90%reduction in choline
acetyltransferaseacetyltransferase

7. Cholinergic HypothesisCholinergic Hypothesis
Role:Role: Acetycholine is an importantAcetycholine is an important
neurotransmitter in brain regionsneurotransmitter in brain regions
involved in memoryinvolved in memory
Loss of ACh in AD correlates withLoss of ACh in AD correlates with
impairment of memoryimpairment of memory
Treatment approach:Treatment approach: Enhancement ofEnhancement of
cholinergic function may stabilize orcholinergic function may stabilize or
improve cognitive function and affectimprove cognitive function and affect
behavior and daily functioningbehavior and daily functioning

8. Acytylcholinesterase inhibitorsAcytylcholinesterase inhibitors
– TacrineTacrine
– DonepezilDonepezil
– RivastigmineRivastigmine
– GalantamineGalantamine
IIndicated for the treatment ofndicated for the treatment of mind tomind to
moderatemoderate Alzheimer’s DiseaseAlzheimer’s Disease

9. Glutamatergic HypothesisGlutamatergic Hypothesis
GlutamatergicGlutamatergic is a major excitatoryis a major excitatory
neurotransmitter in the cortex andneurotransmitter in the cortex and
hippocampushippocampus
Essential for learning and memoryEssential for learning and memory
processesprocesses
NMDA type glutamate receptors mayNMDA type glutamate receptors may bebe
over activated in AD ( glutamatergicover activated in AD ( glutamatergic
excitotoxicity)excitotoxicity)

10. Glutamatergic excitotoxicityGlutamatergic excitotoxicity

11. NMDA receptor antagonistNMDA receptor antagonist
– MemantineMemantine
IIndicated for the treatment of moderate tondicated for the treatment of moderate to
severesevere Alzheimer’s DiseaseAlzheimer’s Disease

12. Memanti
ne

13. Memantine
Structural formula:
For oral administration as
capsule-shaped, film-coated tablet
s containing 5 mg and 10 mg of m
emantine hydrochloride
Molecular
weight :215.76

14. Mechanism of
action

15. Mechanism of
action

16. Mechanism of
action

17. Pharmacokinetics
Absorption
– Bioavailability of approximately
100%
– Food has no effect on the
absorption of memantine.
– T max : 3-7 hours
Distribution
– Vd : 9-11 l/kg
– Protein binding : low(45%)

18. Pharmacokinetics
Metabolism and Elimination
– little metabolism
– the majority of an administered dose
eliminated as the parent drug via
•the kidneys :75% to 90%
•the feces : 10 %to 25%
– A small amount of the drug is
converted to three polar metabolites
•N-glucuronide
•6-hydroxy memantine
•1-nitroso-deaminated memantine
– terminal elimination half-life of

19. Drug interactions
NMDA antagonists
– amantadine, ketamine, and
dextromethorphan
Renal tubular secretion
– HCTZ,cimetidine and ranitidine
ect.
Urine alkalinzers
– Carbonic anhydrase
inhibitor,sodium bicarbonate

20. Contraindication
s
Hypersensitivity to
memantine or any
components of the
memantine formulation.

21. Adverse events
–Dizziness
–Headache
–Somnolenc
e
–Hypertensi
on
–Constipati
on
–Vomiting
–Back pain
–Fatigue

22. Precaution
Special Populations
– Hepatic Impairment: have not
been investigated, but would be expe
cted to be only modestly affected.
– Renal Impairment:No dosage
adjustment is needed in patients wit
h mild or moderate renal impairment.
A dosage reduction is recommended
in patients with severe renal impairm
ent
Carcinogenesis
–

23. Precaution
Impairment of Fertility
– No impairment of fertility or
reproductive performance was seen i
n rats
Pregnancy
– Category B: Memantine given orally
to pregnant rats and pregnant
rabbits during the period of
organogenesis was not teratogenic u
p
Nursing Mothers:

24. Dosage and
administrationThe recommended target dose is
20 mg/day.
The recommended starting dose
is 5 mg once daily.
The minimum recommended
interval between dose increases
is one week.
– should be increased in 5 mg
increments to 10 mg/day (5 mg

25. Clinical
studies

26. Memantine in
Moderate-to-Severe
Alzheimer’s Disease
Barry Reisberg, M.D., Rachelle
Doody, M.D., Ph.D., Albrecht
Stoffler, M.D.,
Frederick Schmitt, Ph.D.,
Steven Ferris, Ph.D.,
and Hans Jorg Mobius, M.D.,
Ph.D., for the Memantine Study

27. Patients and
methodsdouble-blind randomized 2-arm multi-
center study
Patients
– 252 out-patients
– required the patients to be over the
age of 50
– diagnosed with Alzheimer’s disease
(DSM-IV)
– MMSE(Mini-Mental State Examination)
scores: 3 to 14
– GDS(Global Deterioration Scale): stage 5

28. Patients and
methodsEfficacy variables
– CIBIC-Plus (Clinician’s Interview-Based
Impression of Change Plus Caregiver In
put)
– ADCS-ADL (Alzheimer’s Disease
Cooperative Study Activities of Daily
Living Inventory)
– Severe Impairment Battery
– FAST(The Functional Assessment
Staging scale)
Measures of safety
– physical examinations;vital signs,

29. Results

30. Results

31. Results

32. Conclusions
Memantine reduced clinical
deterioration
– Activities of daily living
– Cognitive performance
in moderate-to-severe
Alzheimer’s disease, a phase
associated with distress for pa
tients and burden on caregive

33. Rivastigmine monotherapy and
combination therapy with
memantine in patients with mod
erately severe Alzheimer’s
disease who failed to benefit fro
m previous cholinesterase
inhibitor treatment
T. DANTOINE, S. AURIACOMBE,M.
SARAZIN, H. BECKER,4 J-J PERE, I .
BOURDEIX
2006 Blackwell Publishing Ltd Int
J Clin Pract, January 2006, 60, 1, 1
10–118

34. Patients and
methodsPatients
– male and female ,202 out patients
– least 50 years of age
– AD according to the Diagnostic and
Statistical
Manual of Mental Disorders-IV (DSM-
IV) criteria
– Mini-Mental State Examination (MMSE)
scores of <18
– Global Deterioration Scale (GDS) scores
of > 4

35. Patients and
methodsStudy disign: Prospective,
multicenter, open-label study that comp
rised two phases,switched from either
donepezil or galantamine
rivastigmine treatment phase (3-16mg/day)rivastigmine treatment phase (3-16mg/day)
rivastigmine+memantine 5-20mg/drivastigmine+memantine 5-20mg/d
MMSE score ≥ baselineMMSE score < baseline
completed
Ph.
1
16
wksPh.
2
12

36. Patients and
methodsOutcome Measures
–Efficacy
•Primary end point: MMSE
•Secondary end point:
–Mini-Zarit Inventory (Burden of
Caregiver)
–Neuropsychiatric Inventory (NPI)
–Ten-point Clock-drawing test
–Delis–Kaplan Executive Function
System (D-KEFS) verbal fluency t
est
– Safety: vital signs, adverse events,

39. Conclusions
When patients fail on donepezil
or galantamine,switching to
rivastigmine may improve
cognition and behaviour
Should they continue to
deteriorate, the addition of
memantine may be beneficial.

40. Conclusions
NMDA receptor antagonist
US FDA approved for
moderate to severe AD
Recommended dose of 20
mg /day
Can be used concomitantly
with AChEI
Good safety and tolerability

41. จบ
แล้ว......
ขอบคุณ
ครับ

43. Acytylcholinesterase inhibitorsAcytylcholinesterase inhibitors

44. Neurofibrillary tangleNeurofibrillary tangle
Tau proteinTau protein
Deposit intraneuronalDeposit intraneuronal
KinaseKinase PhosphatasePhosphatase
Neuronal deathNeuronal death
Hyperphosphorylated tau proteinHyperphosphorylated tau protein
Paired helical filaments (PHFs) tauPaired helical filaments (PHFs) tau
Disrupt microtubulesDisrupt microtubules
Loss of synapse & neuronal dysfunctionLoss of synapse & neuronal dysfunction

45. Glutamatergic excitotoxicityGlutamatergic excitotoxicity
Increased glutamate level
activation of NMDA receptors
Cognitive deficit from decreased signal:noise
Neuronal death from prolonged Ca 2+
influx

46. Symptoms andSymptoms and Progression
Progression: Early
– Memory loss (short term)
– Unable to lay down new memory
– Increased need for lists
– Difficulty managing money
– Anomia

47. Symptoms andSymptoms and Progression
Progression: Moderate
– Unable to use objects/execute complex
movements but no impairment in muscles
/senses (apraxia)
– Unable to draw complex figures or
conceptualize orientation in space
(constructional apraxia)
– Unable to perform routine household tasks

48. Symptoms andSymptoms and Progression
Progression: Severe
– Become lost in own home
– Unable to recognize family/friends
– Unable to speak (aphasia)
– Judgment extremely impaired
– Final stages: unable to eat, walk /
communicate

49. Mechanism of
actionlow to moderate affinity
uncompetitive NMDA receptor ant
agonist
preferentially to the NMDA
receptor-operated cation channels
low to negligible affinity for
GABA, benzodiazepine, dopamine,
adrenergic, histamine and glycine
receptors and for voltage-depende
nt Ca2+, Na+ or K+ channels
blocked nicotinic acetylcholine
receptors

50. Results

52. The NMDA Receptor