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21 Cards in this Set
- Front
- Back
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AD
-location -cause -symptom |
Most prevalent symptom of AD is Cognitive Decline
Lost new memory first then forget less recent memories Destruction of cholinergic neurons, Acetylcholine containing neurons, specifically In midbrain in the area called nucleus basalis. These neurons are dying, and they basically have extensive projections up to frontal cortex. Frontal Cortex is an area that is relevant to memory and thought planning & processing Brain shrinkage correlates with AD Diet affects shrinkage (from trans fats: bad) |
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Pathophysiology of AD
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Plaques and tangles
-Protein aggregates lead to apoptosis, interference of communication, etc |
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Cellular Mechanisms
(3) |
The 3 are:
1.ApoE 2. A-beta = amyloid beta Protein that is made inside the cell then transferred outside of cell and create clumps in synapse between neurons (or just flow around) Causes toxicity to the cell!!! 3. Tau: Located within the cell When hyperphosphorylated (phosphorylated at a bunch of different sites), causes clumping within the cells Clumping within the cells causing the tangles |
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Cholinergic Involvement in AD
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Destruction of ACh neurons is caused by, not the cause of AD
ACh is not the only neurotransmitter affected by AD |
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Other Contributing Factors of AD (2)
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1. Oxidative stress
2. Post-menopausal dec. in estrogen -Cholinergic modulator -Antioxidant |
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Other Neurotransmitter Involvement (3)
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-Destruction of 5-HT neurons in raphe and locus ceruleus
-MAOB activity increases -Glutamate neurotoxicity |
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Cholinesterase Inhibitors
(4) |
Tacrine
Donepezil Rivastigmine Galantamine |
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Tacrine
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First AChE inhibitor used (reversible, non-selective)
Hepatotoxicity Not commonly used now (liver toxicity and QID dosing) Anorexia, nausea/vomiting, diarrhea |
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Donepezil, Rivastigmine, Galantamine
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Donepezil—reversible AChE inhibition
Rivastigmine—reversible inhibition of AChE and butyrylcholinesterase Galantamine—selective, reversible AChE inhibition PLUS enhances activity on nAChR No clear clinical/p’col advantage of any one |
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Donepezil, Rivastigmine, Galantamine
Adverse Effects (8) |
GI (nausea, vomiting, diarrhea)
Urinary incontinence Salivation & sweating Muscle weakness Syncope Bradycardia Dizziness Headache |
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NMDA Receptor Antagonists
-drug (1) -MOA |
Memantine
MOA is probably through limitation of excitotoxicity -NMDA antagonism would INHIBIT learning |
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Memantine Adverse Effects (6)
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Constipation
Confusion Dizziness Headache Sedation Agitation |
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Other treatments for AD (5)
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NSAIDs
Antioxidants (including vitamin E) Retrospective outcome was promising, but prospective has been inconclusive Statins Estrogen replacement Ginkgo Biloba |
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Future treatments for AD
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Ab:
-Blocking aggregation -Vaccine to aid clearance -Block Ab production (BASE inhibitors) |
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If you are looking to treat someone with AD and they also weren’t responding to Donepezil, and doctor called you to switch them to another AChE inhibitors, Would u say u would need a wash out between these drugs? Do you need to give patient some time off before giving another AChE inhibitor?
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No, they have similar MOA; therapeutically you can switch back n forth without wash out period.
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What do you think AchE inhibitor in people with liver problems? Which one do you not give to someone with liver problem?
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Don’t give Tacrine!
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Memantine, NMDA antagonist, would it have an effect by itself? It would be limiting excitotoxcity, but would that by itself increase cognition in AD patient?
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No, Memantine is only limiting excitotoxicity & progression of the disease.
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What neurotransmitter is actually involved in learning & memory?
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Dopamine maybe a lil bit, but predominantly it is Achetylcholine. Ach is most important for learning & memory!
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When would you use Memantine?
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Use Memantine to decrease progression of disease, and Need AChE inhibitor to increase cognition!!!!
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When would you use acetylcholinesterase inhibitor and memantine TOGETHER?
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Use acetylcholinesterase inhibitor and Memantine together to be effective. Don’t give Memantine alone.
-Memory is not NMDA, but the Ach, so address it first. If not effective alone, then add memantine to decrease progression of disease. |
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Why didn’t adding choline back work?
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Is it b/c it didn’t cross BBB?
-That wasn’t the problem. Is it being reuptake with synapse too fast? Was the problem the most readily available way to increase Ach in synapse? -To block degradation; block that acetylcholinesterase to be most effective. |
