This document summarizes the current drug treatments for Alzheimer's disease. It discusses the cholinergic hypothesis and how cholinesterase inhibitors like donepezil, rivastigmine, and galantamine work to enhance cholinergic function. It also covers memantine, an NMDA receptor antagonist approved for moderate to severe Alzheimer's. Experimental drugs discussed include nicotinic receptor agonists, gamma secretase inhibitors, antioxidants, PPAR agonists, statins, chelators, estrogens, NSAIDs, and vaccines. Overall, the document provides an overview of the pathophysiology of Alzheimer's and both approved and experimental pharmacologic approaches to treatment.

1. Drug treatment of Alzheimer`s
disease
Dr Naser Tadvi
Associate Professor, Pharmacology
KIMS, Narketpally

2. Objectives
• Introduction
• Pathophysiology of Alzheimer`s
• Drugs used in treatment of Alzheimer`s
– Approved drugs
• Cholinesterase Inhibitors
• Memantine
– Experimental drugs (Under evaluation)
• Nicotinic receptor agonists
• Gamma secretase inhibitors
• Others:
– 5 HT6 antagonists, Statins, NSAIDS, PPAR Agonists, Heavy metal
chelators, estrogen , Antioxidants

3. Introduction
• Alzheimers Disease (AD) is a devastating
neurodegenerative disorder manifested by
– detoriation in memory and cognition
– Impairment in performing activities of daily living
– Behavioural and neuropsychiatric disturbances
• Most common form of dementia in old age
• Risk of AD ↑es with age but AD is not a part of
normal ageing

4. Introduction
• Alzheimers disease was first described by
German Physician Dr Alois Alzheimer in 1906

5. Symptoms of Alzheimer`s Disease
• Language problem
– Cannot find right word or name for familiar
person, object, place
• Loss of recent memory
• Loss of sense of time and place
• Decline in activities of daily living
• Personality changes

6. Pathogenesis of Alzheimers
• Two microscopic features are
characteristic of Alzheimers`s
disease
– Extracellular amyloid plaques
• Consisting of amorphous extra cellular
deposits of A protein
– Neurofibrillary tangles
• Comprising of filaments of
phosphorylated Tau protein

7. Pathogenesis of
alzheimers
Disease

8. Pathogenesis of Alzheimers

9. Targets of drug action for AD

11. Cholinesterase inhibitors
TACRINE
DONEPEZIL
RIVASTIGMINE
GALANTAMINE

12. Cholinergic Hypothesis
• Role
– Acetylcholine (ACh) is an important neurotransmitter
in brain regions involved in memory
• Impact
– Loss of ACh in AD correlates with impairment of
memory
• Treatment approach
– Enhancement of cholinergic function may stabilize or
improve cognitive function and may affect behavior
and daily functioning

13. Tacrine
• Aminoacridine
• Dose dependent effect: 40 mg-160 mg/day
• Half life : 3-5 hrs
• Metabolized by CYP450
• Adverse effects:
– Nausea, vomiting, diarrhoea
– Hepatotoxicity
• No longer actively marketed

14. Donepezil
• Long plasma half life – 70 hrs
• Dose- 5 -10 mg daily
• Several controlled trials have shown modest
benefits in cognition and behaviour
• Not hepatotoxic
• Adverse effects: Nausea, diarrhoea, vomiting,
fatigue, muscle cramps, bradycardia
• Generally safe & well tolerated

15. Rivastigmine
• Higher affinity for brain AcHE than peripheral
• Inhibits both acetylcholinesterase &
butrylcholinesterase
• Half-life of 2 hours
• Dosing (bid) of 3 to 12 mg/day
• Patch 9.5 mg/24 hr available
• Metabolism is almost totally independent
of the hepatic cytochrome P450 system
• Gastrointestinal adverse events are common,
including weight loss

16. Galantamine
• Galantamine has a dual mechanism of action
– Competitive inhibition of acetylcholinesterase1
– Allosteric modulation of presynaptic and
postsynaptic nicotinic receptors
• Galantamine improves major aspects of AD
(eg, cognition, behavior, function)
• Galantamine is generally safe and well
tolerated

17. Chemistry:
a tertiary alkaloid , natural
or synthetic.
extracted from bulbs of the
Amaryllidaceae family
(snowdrops, daffodils)

18. Dual Mechanism of Action
Presynaptic nerve N = nicotinic
terminal M = muscarinic
ACh = acetylcholine
M receptor N receptor
Galantamine
Galantamine
• Choline ACh and other
ACh • Acetic acid neurotransmitters
Postsynaptic M receptor N receptor
nerve terminal

19. Galantamine: Potential Advantages
of Nicotinic Receptor Modulation
• May increase release of Ach in synaptic
cleft
• Increased resynthesis of Ach by
increasing uptake of choline
• May have a neuroprotective effect

20. Galantamine Safety (cont)
Galantamine Galantamine
Placebo 16 mg/day 24 mg/day
(n = 286) (n = 279) (n = 273)
Adverse events* (%) (%) (%)
Nausea 4.5 13.3 16.5
Vomiting 1.4 6.1 9.9
Anorexia 3.1 6.5 8.8
Agitation 9.4 10.0 8.1
Diarrhea 5.9 12.2 5.5
* 5% of patients receiving galantamine and
more often than in patients receiving placebo.

21. ChE Inhibitors: Pharmacokinetic
Characteristics
Dual AChE/
AChE Inhibitors BuChE Inhibitor
Characteristic Donepezil Galantamine Rivastigmine
Plasma half-life (hour) ~70 ~6 ~1
Brain half-life 70 6 12
Elimination 50% kidney
pathway Liver 50% liver Kidney
Metabolism by
2D6/3A4 isoenzymes Yes Yes Minimal
Administer with food? No Yes Yes

22. Drug Type of inhibition Duration of action and
Side effects
dosage
Tacrine ∼6 h Cholinergic side
Not CNS selective 2-3 times daily oral effects hepatotoxicity
dosage Monitoring for
hepatotoxicity needed
Donepezil CNS, AChE ∼24 h Slight cholinergic side
selective Once-daily oral dosage effects
Rivastigmine CNS selective ∼8 h Cholinergic side
Twice-daily oral dosage effects that tend to
subside with
continuing treatment
Galantamine Affects both AChE ∼8 h Slight cholinergic side
and BuChE Twice-daily oral dosage effects
Also enhances
nicotinic ACh
receptor activation
by allosteric action

23. Guidelines for Switching ChEIs
Donepezil or galantamine Donepezil or rivastigmine
to rivastigmine to galantamine
Unsatisfactory treatment
Is the patient
on donepezil 7-day washout is
stabilized on current
recommended or
therapy (ie, no NO
Patient experiencing until symptoms
Safety or tolerability tolerability
lack of response or resolve
problem problems)?
loss of efficacy
YES
Washout for 7 days or
No washout period until symptoms resolve
No washout period required
required Initiate rivastigmine
therapy at
3 mg daily (1.5 mg twice Initiate galantamine therapy at
daily) 8 mg daily (4 mg twice daily)
Minimum of 4 weeks 4 weeks
Monitor patient for efficacy, safety, and tolerability, Monitor patient for efficacy, safety, and tolerability, as
as with standard dosing guidelines with standard dosing guidelines
Escalate dose to 16 mg daily (8 mg twice daily) and
Escalate dose to 6 mg daily (3 mg twice daily) and recheck in 4 recheck in 4 weeks
weeks*

24. NMDA receptor antagonists
• Glutamate is principal excitatory
neurotransmitter in brain
• Which acts on post synaptic NMDA receptors
• Glutaminergic overstimulation may result in
neuronal damage (excitotoxicity)
• Implicated in dementia and pathogenesis of
Alzheimer`s disease
• Memantine is NMDA receptor antagonist

25. Memantine (Mechanism of action)
• NMDA receptor antagonist approved for
treatment of moderate to severe AD
– Uncompetitive
– low affinity
– voltage dependent
– Interacts with Mg2+ binding site of channel to
prevent excessive excitation while sparing normal
functions

26. Memantine (Pharmacokinetics)
• 100 % bioavailability
• T ½ = 60-80 hrs
• Rapidly crosses Blood brain barrier
• Undergoes little metabolism 75% -90%
excreted unchanged in urine
• Minimal drug interactions and food
interaction
• Starting dose – 5 mg OD , recommended
target dose is 20 mg/day

27. Memantine (Adverse effects)
• Dizziness
• Headache
• Confusion
• Constipation
• Agitation

28. Other NMDA receptor antagonists
• Remacemide
– Low affinity blocker
– Approved for treatment of epilepsy
• Riluzole
– Used in treatment of Amyotropic Lateral Sclerosis
• Newer glutamate antagonists in development
– L-701252
– LY-235959
– WIN-634802

29. Recent advances in Alzheimer`s
treatment

30. Nicotinic receptor agonists
• 4 2 & 7 nicotinic receptor types localized
in areas of brain associated with dementia and
memory loss
• 7 nicotinic receptor agonist :
– 4 OH-GTS21
• Protective action on cholinergic neurons
• Antiamnestic effect in Alzheimers disease type amnesia
– EVP-6124: Currently in phase2

31. Antioxidants
• Recent research has found link between
antioxidant intake and decreased incidence of
Alzheimers
– Garlic extract
– Curcumin
– Ginko biloba
– Vitamin E
– Green tea

32. Ginko Biloba
• Ancient use in China and Japan
as a tonic.
– Poor Circulation
– Inner ear disorders
– Absent-
mindedness, Dementia, Depressio
n, and Hypertension in the elderly
– Impotence in men
• Chinese used leaves and nuts
• Use dates back over 5000 years

33. Physiologic Mode of Action Cont’d
• Acts by releasing nitric oxide & PGI2
• ↑ blood flow throughout the circulatory system
& hence ↑oxygen & nutrient delivery to the
tissues including brain .
• ↓ blood viscosity
• ↑ in the release of neurotransmitters
• Antioxidant activity
• Prevention of free radical damage

34. Side effects
• hemorrhage, hematoma
(rupture of blood vessels),
and hyphema (bleeding in
eye).
• In all trials <0.5% reported
minor side effects including
headaches, GI distress and
allergic skin reactions.
• Overall, ginkgo is relatively
safe.

35. PPAR agonists
• PPAR agonists inhibit inflammatory gene
expression , alter Amyloid homeostasis &
exhibit neuroprotective effects
• 15-30 mg pioglitazone daily in patients of AD
– Improved agitation & regional cerebral blood flow
in parietal lobe
– cognitive and functional improvement

36. Gamma Secretase Inhibitors
• Disease modifying agents in AD
• Semagacestat
– ↓ plasma and CSF A- Concentration
– Phase 3 started in March 2008
• Interrupting Alzheimers Dementia by Evaluating
Treatment of Amyloid Pathology (IDENTITY -1 Trial)
– IDENTITY -2 trial started in September 2008
• Did not slow disease progression & worsened cognition
and the ability to perform activities of daily living
• ↑risk of skin cancer
• Eli Lily halted the development

37. 5-HT6 receptor antagonists
• SB-271046
– Enhanced retention of learned position in AD
experimental models
– No effect on learning during training phase
– ↑Neuronal Cell Adhesion Molecular (NCAM)
Polysialation : contributes to learning & increased
dendritic remodelling in CNS
• Dimeboline: antihistaminic from Russia
– In phase III for Alzheimer`s Disease

38. Statins
• Higher Cholesterol risk factor for AD
• Lovastatin prevented death of nerve cells in
animal experiments
• Results of various studies not promising
• No difference between drug and control in
terms of dementia, cognitive function and
neuropsychological tests

39. Heavy metal chelators
• Amyloid beta plaques bind copper and zinc &
removal of these metal ions promotes
dissolution of Plaques
• Levels of iron & zinc abnormally ↑ in brain in
AD
• Desferrioxamine : ↓ dementia in a trial
• Clioquinal: regression of Amyloid plaques in
animal models of AD

40. Estrogens
• AD more common in postmenopausal women
• Estrogen
– Modulate ApoE gene
– ↑ APP metabolism
– Protects against oxidative stress
– ↑cerebral blood flow & prevent neuronal atrophy
• Clinical trials are inconclusive

41. NSAIDS
• Inhibit COX enzymes
– ↓production of cytokines , & microglial activation
– ↓ platelet aggregation
– ↓ iNOS
– ↓ beta secretase
• Only Ibuprofen and Indomethacin have
demonstrated clinical benefit in Alzheimer`s
disease

42. Immunization for Alzheimers
disease?
• In one study, transgenic animals were
immunized with A 42, either before the onset
of AD-type neuropathologies (at 6 weeks of
age) or at an older age (11 months), when
amyloid- déposition and several of the
subsequent neuropathological changes were
well established.

43. Immunization for Alzheimers
disease?
• immunization of the Young animals essentially
prevented the development of -amyloid
plaque formation, neuritic dystrophy and
astrogliosis.
• Treatment of the older animals also markedly
reduced the extent and progression of these
AD-like neuropathologies.
• Hence the possibilty possibility that
immunization with amyloid-b may be effective
in preventing and treatingAD

44. TYPES OF VACCINATION
αβ peptide with adjuvant Anti- αβ antibody
A) Active immunization
Anti- αβ Antibody
B) Passive immunization

45. Active immunization
• Acute meningoencephalitis: drug withdrawn
• ACC-001:

46. Conclusion for first immunotherapy tests
Although immunisation with Aβ42 resulted in
clearance of amyloid plaques in patients with
Alzheimer’s disease, this clearance did not prevent
progressive neurodegeneration.
IMMUNOTHERAPY CAN BE ALWAYS A GOOD WAY FOR TREATMENT OF ALZHEIMER
DISEASE?
47

47. Passive immunization
Monoclonal antibodies
How to avoid meningoencephalitis symptoms ?
Anti- αβ Antibody
48

48. BAPINEUZUMAB
WHAT IS A –ZUMAB ?
of mouse humans 1994-
1975 1999
…momab …mumab
chimerics humanized 1988-
1984 1991
…ximab …zumab
HUMANIZATION
Immunogenic +++ less immunogenics
49

49. Mechanism of action

50. Safety Results
94 % Bapineuzumab
90 % mild to moderate
Most patients reported Adverse Effects in severity
90 % Placebo
AEs occuring >2 times as often as placebo rate and seen in >5% of bapineuzumab patients
Back pain 12,1% vs 5,5% Weight loss 6,5% vs 1,8%
Anxiety 11,3% vs 3,6% Paranoia 6,5% vs 0,9%
Vomiting 9,7% vs 3,6% Skin laceration 5,6 % vs 2,7%
Vasogenic Edema 9,7% vs 0% Gait disturbance 5,6% vs 1,8%
Hypertension 8,1% vs 3,6% Muscle spasms 5,6 % vs 0,9%

51. Conclusion
• AD is one of the most debilitating diseases
affecting the old age
• Clear benefit for treatment of symptoms in
mild to severe AD using AcHEIs & memantine
is seen
• Also there is cautious optimism for sucessful
disease modification using number of agents
currently under study