Neurology Pt 1 Alzheimers and Parkinson's Flashcards
Central Nervous System
- _____ and _____ cord
- Integrates _____ information and generates ______ output
- Billions of _______ and surrounding _____ cells
- _______ are responsible for the flow of information
- ___________- chemicals relay, amplify, and modulate signals
- Excitatory or Inhbitory
- brain, spinal
- sensory, motor
- neurons, glial
- Neurons
- NeurotransmittersAttach Sounds
Neuron
- Building block of the CNS
- Process/transmit information
- Classified based on f_____, l_____, and n______ released
- Form dendritic trees - receive from other neurons and transmit to cell body =
- Cell body =
- Carries signal from cell body eventually to synapse =
- Junction of neurons where NT are released to interact with receptors or other neurons
- ultimately stimulates channels that allow _____ and ______ allowing for necessary communication/processes
- function, location, neurotransmitter
- Dendrites
- Soma
- Axons
-
Synapse
- opening, closing
Voltage vs. Ligand Gated Channels
- Voltage - ____ mediated
- Primarily located on the initial segment of the axon as well as axon itsself (___ action potential)
- Ligand - ______ mediated
- Ligand (inotropic) receptor - _____ opens
- Metabotropic receptor - engages _-protein to produce ______ messanger (_____-gated)
- Calcium-___synaptic-____ channel function
- Potassium-___synaptic-____ opening of channel
- ion
- fast
- neurotransmitter
- directly
- G, second, voltage
- pre, inhibit
- post, slow
- Voltage such as Na, Ca, K*
- Ligand more neurotransmitter based*
Where do CNS drugs primarily work?
- 1) Supplementing the NT*
- ex) deficiency in norepi, give norepi*
Neurotransmitters and Receptors
- Serotonin is responsible for a myriad of things*
- Notice there are so many different receptors*
- ex) dopamine has like 4 receptors
Neurotransmitters and Receptors cont.
- Gaba-primary inhibitory transmitter*
- Glutamate-primary excitatory transmitter*
Neurotransmitters and Receptors cont.
Alzheimer’s Disease
Characterized by?
Acetylcholine Deficiency
Acetylcholine (Ach)
- Neurotransmitter responsible for _____ contraction (n____ receptors) and ________ component of the autonomic nervous system (_______ receptors)
- Central Nervous System
- Assists in: l____, m_____, neuro_____, c______
- Peripheral Nervous System
- _____ relaxation, skeletal and _____ contraction
- muscle (nicotinic), parasympathetic (muscarinic)
- learning, memory, neuroplasticity, concentration
- Cardiac, muscle
What is Alzheimers?
Accounts for __-__% of dementia
A progressive degenerative disease ultimately resulting in cerebral atrophy
50-75%
Primary risk factors for Alzheimers
Age and Family Hx
- Cerebral trauma, Vascular disease
Signs and Symptoms of Alzheimers
- Difficulty performing ____ t____
- Difficulty r_____ and w______
- Loss of _______
- D_____, D______, A_______
- basic tasks
- reading, writing
- memory
- Delusions, Depression, Agitation
Three histopathological hallmarks can impair neurotransmitter function of ________ leading to _____ deficits
- 3.
- Beta-amyloid-rich senile plaques (lots of ongoing research)
- Neuritic plaques and neurofibrillary tangles
- Neuronal degeneration
Pharmacological Considerations
- Cholinergic pathways are damaged -> ____ of Ach transmission
- Overstimulation of _____ receptor by ______ -> neuronal damage
- Inhibition of ________ receptors -> impairs cognition
- loss
- NMDA, glutamate
- nicotinic
Perhaps inhibiting glutamate will prevent further progression of disease
Goals of Therapy
- Improve _ _ _
- Improve or slow the loss of ____/_____
- Maintain and maximize independent ______
- Minimize _ _ of drug therapy
- QOL
- memory/cognition
- function
- AE
NO CURE =(
Medications Used in the Tx of Alzheimer’s
2 classes, 5 agents
-
Cholinesterase Inhibitors
- Donepezil (Aricept)
- Rivastigmine (Exelon)
- Galantamine (Razadyne)
-
NMDA receptor Antagonist
- Memantine (Namenda)
-
Combination
- Donepezil + Memantine (Namzaric)
- Not many tx options unfortunately*
- Aricept and Memantine most common*
- Onset: takes about 2-4 wks for these drugs to kick in*
Cholinesterase Inhibitors
MOA
Selectively inhibits cholinesterase (enzyme that hydrolyzes (inactivates) Ach) in the CNS
- Increases Ach concentrations in the cerebral cortex
Cholinesterase Inhibitors
Indication
For mild to moderate disease
Cholinesterase Inhibitors
Agents
Routes
Donepezil (Aricept) - oral, ODT
Rivastigmine (Exelon) - oral, transdermal patch
Galantamine (Razadyne) - oral
Oral disintegrating tablet since alot of older adults have trouble swallowing
Cholinesterase Inhibitors
- May _____ deterioration of ______ function
- Preserves m_____, l_____, a______
- Does not effect:
- slow, cognitive
- memory, learning, attention
- underlying degenerative process
Cholinesterase Inhibitors Adverse Effects
- Donezepil:
- Galantamine:
- Rivastagmine:
- ALL (3) - (_____ titrate dose)
- ____cardia, d_____, s______
- Urinary ______
- Hyper______, sw_______
Cholinesterase Inhibitors
Drug Interactions
Anticholinergic drugs (drugs that block cholinergic receptors)
Donepezil is a minor substrate of CYP3A4
- Anticholinergic = blocks acetylcholine receptors*
- Know that its a minor substrate, will not question on enzymes*
Cholinesterase Inhibitor Adverse Effects
- D
- U
- M
- B
- E
- L
- S
- Diarrhea
- Urination
- Miosis
- Bronchospasm
- Emesis
- Lacrimation
- Salivation
Cholinergic Crisis Signs and Symptoms
What is it?
- S
- L
- U
- D
- G
- E
To much Ach from inactivity of AchE enzyme that usually breaks it down
- Salivation
- Lacrimation
- Urination
- Defecation
- Gastric upset
- Emesis
Memantine (Namenda)
MOA
NMDA (glutamate receptor) antagonist
- Attenuates (reduces) excitotoxic effects of glutamate (neuroprotective)
- Glutamate is very excitatory but very neurotoxic as well*
Memantine
Drug Interactions
No CYP 450 drug interactions
Memantine
Indication
Moderate to severe Alzheimer’s disease
- often used in combination with cholinesterase inhibitor
Memantine (Namenda)
Adverse Effects
- Constipation
- HA, confusion, dizziness, hallucinations
- HTN
Memantine (Namenda)
Route
Oral
- Available as combination with donepezil (Namzaric) which is also given PO
Parkinson’s Disease
What’s the issue?
Lack of Dopamine
Goal: Increase Dopamine
Background
- Degenerative disease of the _____ ______, resulting in gradual decline in _____, ______, and _____ functioning
- Severe loss (~80%) of dopaminergic neurons of the substantia nigra
- Presence of _____ _____ (intracellular inclusions)
- Creates _______ of acetylcholine and dopamine
- __ treatment = progresses to an ______ state (5-10 yrs)
- Mortality due to ______ (aspiration pneumonia, clotting disorders, etc)
- basal ganglia, motor, autonomic, cognitive
- Lewy bodies
- imbalance
- No, akinetic
- imobility
- Occurs when you have about 80% loss of dopaminergic neurons***
- Due to Lewy Bodies that block transmission of neuro signals*
- Homeostasis of acetylcholine and dopamine messed up*
- IMMOBILITY*-**All the effects usually secondary to immobility*
Dopamine (DA)
- Catecholamine, synthesized in dopaminergic neurons from tyrosine
- DA receptors ( __ total, grouped into D_ and D_)
- D1 - _____ synthesis of cyclic AMP (_____)
- D2 - _____ synthesis of cyclic AMP, suppresses CA currents, activate K currents (_____)
- Neostriatum of the basal ganglia regulates flow of information from the _____ cortex to the motor neurons of the _____ cord
- 5, D1, D2
- stimulate, excitatory
- inhibit, inhibitory
- cerebral, spinal
5 diff dopamine receptors - 2 types
Pathophysiology
- ___ receptors impacted
- _____ _____ -*> protein degradation -> terminal degredation
- D2
- -* Lewy Bodies
Pharmacologic Targets
_____ and _______ function depend on the coordinated ____ of _____ and ______
How to treat?
1) _____ Dopamine
2) _____ Acetylcholine
Motor, Cognitive, interaction, Dopamine, Acetylcholine
1) Increase
2) Decrease
Presentation
- ________ Symptoms
- ________ (slow/lack of movements)
- Muscular _______ (e.g. cogwheel)
- ______ tremor (e.g pill rolling)
- ______ instability
- ____ (e.g shoulder shrugs)
- Dys______
- Loss of _____
- A_______
- Extrapyramidal
- Bradykinesia
- Muscular Rigidity
- Resting tremor
- Postural instability
- Tics
- Dystonia voice changes
- Loss of Smell
- Anxiety
Risk Factors
(3)
- Age
- Natural loss of DA neurons of the corpus striatum (70-80% loss)
- Terminal of DA neuron degenerates
- Lewy bodies form in the soma of DA neuron which results in protein degradation amongst others
- Environmental exposures (amphetamine and cocaine use)
- Hereditary
- Chromosomal mutations
Goals of Therapy
- Improve ____ and _ _ _
- Prevent long term ______, minimize _____ disability
- Slow disease _______
- Maximize ___ therapy and minimize _ _
- symptoms, QOL
- complications, functional
- progression
- drug, AE
Medications Used in the Treatment of Parkinson’s Disease
(7)
- Dopaminergic agents (think replacement)
- Decarboxylase Inhibitor
- Caetchol O methyl transferase (COMT) inhibitors
- MAO-B Inhibitors
- Dopamine receptor agonists (NOT ON EXAM)
- Acetylcoline receptor agonists
- Adenosine A2A receptor antagonist (NOT ON EXAM)
1) Dopaminergic agents
(2)
- Levodopa (L-DOPA)
- Amantadine (Symmetrel)
2) Decarboxylase Inhibitors
(1)
Carbidopa
- always used with levodopa (Sinemet)
- NOT ACTIVE ALONE
3) COMT Inhibitors
(3)
Entacapone (Comtan)
Tolcapone (Tasmar
Opicapone (Ongentys)
4) MAO-B Inhibitors
(3)
Safinamide (Xadago)
Selegline (Eldepryl)
Rasagline (Azilect)
6) Acetylcholine Receptor Antagonists
(2)
Benztropine (Cogentin)
Trihexyphenidyl (Artane)
- Dopamine in the periphery =
- Goal is to get levodopa to the?
- 2 enzymes that break down down in the periphery (2)
- Does nothing and wreaks havoc
- Brain
- COMT, Decarboxylase
Levodopa
- What is it?
- Metabolized by what in the peripheral tissue?
- If given as a monotherapy, what happens?
- Always give it with?
- Biosynthetic precursor of dopamine
- Increases concentration of dopamine in the brain
- Decarboxylase and Catechol-O-methyl transferase (COMT)
- Less than 1% reaches the brain (always need decarboxylase inhibitor and often also needs COMT-inhibitor)
- ALWAYS give in combo with carbidopa
- What dopamine itself causes - GI upset*
- Too much dopamine = depression, delirium, paranoia, hallucinations -> makes sense bc in schizophrenia they have too much dopamine*
Levodopa
AE (4)
- N/V (Antacid 30-60min before may help)
- Orthostatic hypotension, Sedation
- Depression, Delirium, Paranoia, Delusions, Hallucinations (CNS effects associated with long-term use)
- Motor fluctuations (end of dose wearing off: peak-pose dyskinesa)
Breakthrough dyskinesia
Levodopa
- Always combined with _____
- Examples of combined formulations
- Carbidopa
- Sinemet, Sinemet CR, Parcopa ODT
- Rytary (new formulation that has advanced control release to reduce motor fluctuations, less frequently dosed, can be opened and sprinkled unlike sinemet (not interchangeable with), expensive/should not be first line)
Carbidopa
MOA
Decarboxylase Inhibitor
- Inhibits conversion of levodopa to dopamine in peripheral tissues (thereby decreasing GI and CV effects)
- Increases amount of levodopa in the brain
Carbidopa
- Always give in combination with ______ (_____)
- Titrate dose ____ up to __ mg of carbidopa daily
- Reduce incidence of peripheral conversion = reduced _ _
- Wearing off Phenomenon, what is it?
- Levodopa (Sinemet)
- Slowly, 75
- Loss of efficacy over time (proven effective for 2-5 yrs) OR Fluctuation in response to meds occurs over time and may need higher doses
Story time: Carbidopa is that friend you bring to the grocery when you are super hungry to stop you from grabbing too much food and not getting to your destination> always have carbidopa by your side bc it inhibits dopamine breakdown in periphery
