Komiskey 4-15-08 Drugs For Alzheimer’S Disease

Front 1

CNS Changes with Aging

Back 1

Reduced numbers of receptors

Subtle structural and physiological changes consistent with Alzheimer's and Vascular Dementia

Increased susceptibility to anti-cholinergics

Front 2

anti-cholinergic properties

Back 2

urinary retention; constipation; dry mouth; blurred vision; sedation; cognitive dysfunction

Front 3

Genetics causing Rare early-onset (before age 60) familial forms of dementia

Back 3

Mutations of chromosomes 1, 14, 21

(Down’s syndrome)

Front 4

Late-onset AD
APOE*4 allele incr risk & decr onset age in dose-related fashion (Apolipoprotein E4 on chromosome 19)

What allele may be protective?

Back 4

APOE*2 allele may have protective effect

Front 5

Mutations of ______________ lead to the most aggressive form of familial Alzheimer's disease (FAD)

Back 5

Presenilin 1 (PS1)

chromosome 14

Front 6

chromosome of Presenilin 2

Back 6

chromosome 1

Front 7

Protective behaviors against AD

Back 7

Intellectual stimulation
Regular physical exercise
Regular social interaction
Mediterranean diet
Fruit & vegetable juice
Vitamin E (<400mg)?
Statins?
NSAID’s?

Front 8

Risk factors for AD

Back 8

Advancing age
APOE €4
(in some populations)
Environmental exposure to Aluminum
Head injury
Poor cardiovascular health
Smoking

Front 9

Mediterranean diet

Back 9

Fruits & vegetables
Low saturated fat
Supplemented with
B vitamins
Curry
Omega-3 fatty acids

Front 10

Ddx for AD

Back 10

Alzheimer’s disease- 70%
Vascular dementia- 10-20%
Dementia associated with Lewy bodies (associated with PD features)
Frontal lobe- Picks: <5%

Alcohol
Parkinson's disease [PD]
Delirium
Depression
Neurosyphilis
Creutzfeldt-Jakob (1/167,000 in U.S. annually)
NPH (ataxia>incontinence> cognition)
“Normal”

Front 11

10 Warning signs of AD

Back 11

1. Memory loss that affects job skills
2. Difficulty performing familiar tasks
3. Problems with language
4. Disorientation to time and place
5. Poor or decreased judgment
6. Problems with abstract thinking
7. Misplacing things
8. Changes in mood or behavior
9. Changes in personality
10. Loss of initiative

Front 12

Dramatically reduced neurotransmitters in AD

Back 12

CAT / ACH synthesis
ACH-Esterase
Choline transporter
GLU-activity

Front 13

Moderately reduced neurotransmitters in AD

Back 13

Norepinephrine-activity
Dopamine-activity
Serotonin-activity
some peptides

Front 14

Unchanged neurotransmitters in AD

Back 14

GABA
free amino acids
most peptides

Front 15

Amyloid beta is carved from what

Back 15

APP = amyloid beta precursor protein

Front 16

Enzyme for amyloid beta carving fro APP

Back 16

beta-secretase (cuts outside cell memb) (helped by aspartic acids)

Presenilin protein (component of gamma-secretase) (cuts remaining stump --> A-beta is released)

Front 17

protein that keeps microtubules (“RR tracks”)
aligned down length of neuron (tau = “RR ties”)

Back 17

Tau

Front 18

why does neuron die with Tua protein dysfunction

Back 18

neurons can’t get nutrients down length of curled and tangled axon…dies

Front 19

Amyloid precursor Protein (APP) cleavage

by alpha secretase : Is this amyloidogenic?

Back 19

no

Front 20

Amyloid precursor Protein (APP) cleavage
by beta or gamma secretase: Is this amyloidogenic?

Back 20

forms Amyloid-beta-protein (Aß)
consisting of 40 to 42 amino acids.

Front 21

Cholinesterase Inhibitors

Back 21

Donepezil (Aricept):1996
Rivastigmine (Exelon):2000
Galantamine (now Razadyne (ER) formerly Reminyl)
tacrine [Cognex®]
donepezil [Aricept®]
galantamine [Razadyne®]

Front 22

Acetylcholine is an important neurotransmitter
dealing with learning and memory

Back 22

FYI

Front 23

mixed type inhibitor of acetycholinesterase, meaning that it exhibits both noncompetitive and competitive components of inhibition

also a reversible inhibitor of butyrylcholinesterase.

Back 23

tacrine [Cognex®]

Front 24

a selective and reversible acetylcholinesterase inhibitor

a mixed type inhibitor of acetycholinesterase, meaning that it exhibits both noncompetitive and competitive components of inhibition

Back 24

donepezil [Aricept®]

Front 25

What about Tacrine [Cognex] and rivastigmine [Exelon®] would cause increased toxicity of cocaine?

Back 25

butyrylcholinesterase breaks down cocaine.

Front 26

-a slowly reversible (pseudo-irreversible) inhibitor of acetylcholinesterase and butyrylcholinesterase.
- inhibits acetylcholinesterase
in a noncompetitive manner.

Back 26

rivastigmine [Exelon®]

Front 27

-a competitive and reversible inhibitor of acetylcholinesterase.
-also acts as a positive allosteric modulator at nicotinic acetylcholine receptors including the alpha-4-beta-2-subtype.

Back 27

galantamine [Razadyne®]

Front 28

drug causing Heart Problems side effect

Back 28

galantamine [Razadyne®]

Front 29

Dementia behaviors may improve with cholinesterase inhibitors

Back 29

-

Front 30

Are wandering and pacing corrected with anti-psychotics?

Back 30

no

Front 31

do CIs reduce inpatient delirium episodes?

Back 31

Maybe

Front 32

Atypical Antipsychotics (treat dementia-related psychosis) Name some.

Back 32

Abilify (aripiprazole), Zyprexa (olanzapine), Seroquel (quetiapine), Risperdal (risperidone), Clozaril (clozapine) and Geodon (ziprasidone)
Risperidone

Front 33

a moderate affinity, voltage-dependent, noncompetitive NMDA receptor antagonist

a voltage-dependent, reversible, noncompetitive antagonist at serotonin 5-HT3 receptors

a noncompetitive open channel blocker at some subtypes of neuronal nicotinic acetylcholine receptors, including alpha4beta2 subunit-containing receptors and alpha7 subunit-containing receptors

Back 33

memantine [Namenda®]

Front 34

Pharmacokinetics of memantine [Namenda®]

Back 34

Is essentially 100% bioavailable after oral administration and exhibits a linear pharmacokinetic profile that is not affected by food, age, or sex.
Has a terminal half-life of 60-80 hours.
Volume of distribution of 9 to 11 L/kg
Peak plasma concentration is achieved between 5 and 8 hours
This drug must be extensively distributed into tissues, leaving low concentrations in the plasma

Front 35

Metabolism and Elimination of memantine [Namenda®]

Back 35

Undergoes little metabolism
Largely (75-90%) excreted unchanged in urine
Remainder (10-25%) converted to polar metabolites with minimal pharmacological activity
Dose-independent elimination

Front 36

Side effects of memantine [Namenda®]

Back 36

Side effects include pain, abnormal crying, leg pain, fever, increased appetite.
Adverse drug reactions include: dizziness, confusion, headache, hallucinations, tiredness.
Less common side effects include: vomiting, anxiety, hypertonia, cystitis, and increased libido.
Doses of up to 400 mg have been tolerated

Front 37

The abnormal movements induced by Huntington's disease can be attenuated with WHAT?

Back 37

The abnormal movements induced by Huntington's disease can be attenuated with dopamine receptor antagonists or with a GABA-B receptor agonist (baclofen).

Front 38

dopamine antagonists

Back 38

haloperidol, chlorpromazine

Front 39

Loss of GABA inhibition causes DA hyperactivity = involuntary, writhing movements.
Mirror image of WHAT DISEASE, so use drugs the opposite way

Back 39

parkinson's

Front 40

Huntington's
One of a group of trinucleotide-repeat neurodegenerative diseases i.e. 50 or more repetitions of the ___ sequence (glutamine) in certain genes

Back 40

CAG

Front 41

Huntingtin gene interacts with _________ that cause neural excitotoxicity and apoptosis, which is enhanced by mutant proteins, producing neuronal death

Back 41

Huntingtin gene interacts with caspases that cause neural excitotoxicity and apoptosis, which is enhanced by mutant proteins, producing neuronal death

Front 42

"Alternative” medicines in the management of dementia

Back 42

curcumin (curry pigment) - reduces accumulation of amyloid in mice brains

Front 43

A small, orally-administered amyloid antagonist that binds to soluble amyloid-beta (Aβ) peptide and interferes with the amyloid cascade

Back 43

Tramiprosate – Alzhmed

Front 44

R-flurbiprofen (Flurizan™)

Back 44

The single enantiomer of racemate flurbiprofen, tarenflurbil (R-flurbiprofen), is currently in clinical trials for the treatment of metastatic prostate cancer and Alzheimer's disease.

Flurbiprofen is a member of the phenylalkanoic acid derivative family of non-steroidal anti-inflammatory drugs (NSAIDs) used to treat the inflammation and pain of arthritis.

Front 45

Dominantly inherited AD is associated with overproduction, abnormal clearance, or increased deposition of ________ (______)

Amyloid plaques are a neuropathologic hallmark of AD

Amyloid plaque deposition precedes development of: ______________ _______ and Clinically expressed AD

Improved cognition in transgenic mice accompanies plaque clearance by immunotherapy

Back 45

Dominantly inherited AD is associated with overproduction, abnormal clearance, or increased deposition of amyloid (Aβ_42)

Amyloid plaques are a neuropathologic hallmark of AD

Amyloid plaque deposition precedes development of: Neurofibrillary tangles and Clinically expressed AD

Improved cognition in transgenic mice accompanies plaque clearance by immunotherapy