Tx of Alzheimers Flashcards
Ach has which two receptors. What is Ach’s affinity to each?
Nicotonic- fast on and fast off
Muscarinic- slow on and slow off
High, equal affinity to each.
Glutamate has 2 receptor types. What are they?
Fast on and fast off
AMPA, Kainata and NMDA
Slow on and slow off
How is glutamate synthesized in the axon terminal and then removed from the synapse
Krebs- product of glucose metabolism.
Glutamine transported from extracellular space and converted to glutamate then put into vesicles.
Removed when taken back into the axon terminal and repackaged. Or taken up by astrocytes and converted to glutamine.
Cellular function of glutamate agonist
Increases probability of action potential or release of second messenger molecule.
Important in learning and memory.
Glutamate fast on/fast off receptor. How does it work
AMPA and Kainate are simple ion channels. When glutamate binds, they open and allow Na+ into the cell to depolarize.
NMDA receptors are blocked by an Mg ion at resting membrane potentials. Binding of glutamate has no effect- channel will not open.
Once the membrane is depolarized by AMPA/Kainate, then the Mg is expelled and ion flow can occur.
NMDA receptors are permeable to which 3 NT
Na+, K+, and Ca++
Less selective than other receptor channels
Increase in intracellular Calcium further depolarizes the neuron BUT has consequences- cell damage.
How to dx alzheimer
Clinical presentation, not age.
Pathophysiology and symptoms of alzheimers
Pathophysiology- damage to the neocortex by aggregation beta amyloid protein into particles then amyloid plaques then into fibrils and tangles.
symptoms- Impairment of memory and judgment, impairment of abstract thinking, changes in personality.
Progression from beta amyloid proteins to fibrils and tangles.
Beta amyloid proteins are monomers present in the brain at all ages. Normal. Admin of antibody here has no effect.
They can polymerize into particles. Particles are active molecules that induce memory loss. Can tx at this stage with antibody. (new research- may be detectable in retina/lens)
particles aggregate to form plaques.
Then fibrils and tangles will form with other proteins.
This damages neurons and causes a decrease in available Ach and glutamate.
Results in memory loss, decreased cognitive function and personality changes.
How do cholinesterase inhibitors help w alzheimers
Bind reversibly to acetylcholinesterase. Inhibit activity of enzyme. Leads to an increase in Ach in the synapse- maximizes remaining pool of Ach by inhibiting break down.
NOT disease modifying or a cure. Effects of drugs will decrease as cell death continues.
Adverse effects of cholinesterase inhibitors
Tremor, nausea, bradycardia, diarrhea, anorexia, myalgia.
Parasympathetic like symptoms since increasing levels of Ach/preventing breakdown.
How do glutamaergic antagonists help w alzheimers
Bind to glutamine receptors on the post-synaptic neuron, preventing the binding of glutamine NT.
Blocking of NMDA receptors reduces cytotoxic effect on neuron caused by Ca influx across the plasma membranes.
Which drug is first choice? Cholinesterase inhibs or glutamaergic antagonists
cholinesterase inhibitors
