Neurology Pt 1 Alzheimers and Parkinson's Flashcards
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 =(
2) Decarboxylase Inhibitors
(1)
Carbidopa
- always used with levodopa (Sinemet)
- NOT ACTIVE ALONE
Cholinesterase Inhibitors Adverse Effects
- Donezepil:
- Galantamine:
- Rivastagmine:
- ALL (3) - (_____ titrate dose)
- ____cardia, d_____, s______
- Urinary ______
- Hyper______, sw_______
Adverse effects of too much _______ activity include hyperhidrosis, increased urinary frequency, dyspepsia, lacrimation
Acetycholine
Which of the following agents is selective in its inhibitory properties when given at low doses and should be avoided with dietary products high in tyramine content?
- Carbidopa
- Levodopa
- Amantadine
- Selegiline
Selegiline
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
6) Acetylcholine Receptor Antagonists
(2)
Benztropine (Cogentin)
Trihexyphenidyl (Artane)
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
COMT Inhibitors
Agents (3)
- Tolcapone
- Entacapone
- Opicapone
Acetylcholine Receptor Antagonists
AE
(Anticholinergic)
- Sedation, depression, confusion
- Dry mouth, blurred vision, constipation, urinary retention
- Patients often find them difficult to tolerate
Neurotransmitters and Receptors cont.
- Gaba-primary inhibitory transmitter*
- Glutamate-primary excitatory transmitter*
Alzheimer’s Disease
Characterized by?
Acetylcholine Deficiency
Memantine (Namenda)
Adverse Effects
- Constipation
- HA, confusion, dizziness, hallucinations
- HTN
Neurotransmitters and Receptors cont.
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
Parkinson’s Disease
What’s the issue?
Lack of Dopamine
Goal: Increase Dopamine
COMT Inhibitors
AE (5)
- Hepatotoxicity (tolcapone)- requires LFT monitoring (rarely used)
- Orthostatic hypotension
- Diarrhea
- Hallucinations
- Brown-orange urine discolation (almost exclusively w entacapone* - something unique about this drug)
Memantine
Indication
Moderate to severe Alzheimer’s disease
- often used in combination with cholinesterase inhibitor
Acetylcholine Receptor Antagonists
MOA
Competes with Ach at muscarinic receptors (anticholinergic)
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
- AE
- 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
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
MN was recently started on a new medication in addition to her Levodopa/carbidopa/entacopone (Stalevo). Since initation she has been experiencing dry mouth, trouble urinating and constipation. From the information provided, which of the following agents is most likely the cause of her newly experienced side effects?
- Ropinorole (Requip)
- Benztropine (Cogentin)
- Donepezil (Aricept)
- Pimavanserin (Nuplazid)
Benztropine (Cogentin)
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
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 antagonists
- Adenosine A2A receptor antagonist (NOT ON EXAM)
3) COMT Inhibitors
(3)
Entacapone (Comtan)
Tolcapone (Tasmar
Opicapone (Ongentys)
Acetylcholine Receptor Antagonists
Admin
Always used as adjunctive
Three histopathological hallmarks can impair neurotransmitter function of ________ leading to _____ deficits
- 3.
Acetylcholine, memory
- Beta-amyloid-rich senile plaques (lots of ongoing research)
- Neuritic plaques and neurofibrillary tangles
- Neuronal degeneration
Interactive Case
CD is a 68 yo F who presents to your clinic after hearing you were the expert in PD pharmacology. She has been taking Levodopa/carbidopa for 6 months. She complains of N/V and believes it is because she is taking too many pills (plus her friend said Carbidopa always made her sick). She asks if it would be okay to just take levodopa?
What is your response?
ABSOLUTELY NOT
Interactive Case
- AB is a 73 yo M with PMH of HTN, HLD, DM, progressive loss of memory, difficulty reading, and most recently depression and agitation
- He is diagnosed with Alzheimer’s Disease and referred to you for management
- You decide to prescribe Donepezil (Aricept)
Alzheimers is deficiency in acetycholine
Donepezil = cholinesterase inhibitor
AE: SLUDGE
Galanatmine -> weight gain? switched to aricept
Memantine (Namenda)
Route
Oral
- Available as combination with donepezil (Namzaric) which is also given PO
Memantine
Drug Interactions
No CYP 450 drug interactions
Monamine Oxidase (MAO) Inhibitors
Agents (3)
Selegiline
Rasagiline
Safinamide
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*
Neurotransmitters and Receptors
- Serotonin is responsible for a myriad of things*
- Notice there are so many different receptors*
- ex) dopamine has like 4 receptors
Where do CNS drugs primarily work?
- 1) Supplementing the NT*
- ex) deficiency in norepi, give norepi*
PD Associated Psychosis
- ~20-50% of pts with PD develop _______
- Manifested by visual _____
- ____ disease vs. _____?
- Intrinsic Disease: Dopamine deficiency can __-regulate ____ function -> p____ and h_____ (visual)
- ADE: _______ concentrations of dopamine may also cause psychosis
- First drug approved to treat hallucinations and delusions of PD
- Psychosis
- hallucinations
- Intrinsic vs. Adverse drug effects (ADE)
- up, 5-HT, psychosis, hallucinations
- Supratherapeutic
- 2 reasons for psychosis in PD: intrinsic, ADE*
- Overcompensation of Serotonin is the cause of the psychosis (not the dopamine)*
- But not always the case. So we have to investigate if pt experienced after adding a new drug.? Or have they had this disease for awhile and been on drugs for awhile? that might be more intrinsic*
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)
Pimavanserin (Nuplazid)
- MOA:
- ____ data to support clinical benefit (1/4 trials)
- Serious adverse affects
- worsening ______, ___ prolongation, d____
- Boxed Warning:
- Cause of death _____ (cardiac, respiratory, infectious)
- Use with _____ and _____ closely
- Investigate whether _______ are an _ _
- Increased _______ can also cause hallucinations
- Selectively blocks serotonin (5-HT)
- Limited
- hallucinations, QTC, death
- Increased mortality in elderly patients with dementia related psychosis (all antipsychotics)
- unclear
- caution, monitor
- hallucinations, AE
- dopamine
- All antipsychotics have increased mortality, but causes are unclear…*
- So with that -> USE CAUTION if your going to prescribe if you see pt has QTC prolongation or psychosis “I don’t think its safe for the pt”*
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
1) Dopaminergic agents
(2)
- Levodopa (L-DOPA)
- Amantadine (Symmetrel)
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*
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
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
- 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
Memantine (Namenda)
MOA
NMDA (glutamate receptor) antagonist
- Attenuates (reduces) excitotoxic effects of glutamate (neuroprotective)
- Glutamate is very excitatory but very neurotoxic as well*
Cholinesterase Inhibitors
- May _____ deterioration of ______ function
- Preserves m_____, l_____, a______
- Does not effect:
- slow, cognitive
- memory, learning, attention
- underlying degenerative process
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*
MAO Inhibitors
-
Selegiline/Rasagiline are selective for MAO-B at __ doses
- Enhances and prolongs effects of _____
- At high doses it starts to inhibit ____
- Safinamide (Xadago) - ____ selective MAO-B inhibitor
-
low
- dopamine
- MOA-A
- more
- Given at very low doses* is V efficacy*
- Safinamide most recently approved*
Cholinesterase Inhibitors
MOA
Selectively inhibits cholinesterase (enzyme that hydrolyzes (inactivates) Ach) in the CNS
- Increases Ach concentrations in the cerebral cortex
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*
Pathophysiology
- ___ receptors impacted
- _____ _____ -*> protein degradation -> terminal degredation
- D2
- -* Lewy Bodies
4) MAO-B Inhibitors
(3)
Safinamide (Xadago)
Selegline (Eldepryl)
Rasagline (Azilect)
Acetylcholine Receptor Angagonists
Favorable effects (2)
Helps reduce tremor (too much Ach creates the famous parkinson TREMOR*)
Favorable effects on rigidity and bradykinesia
Cholinesterase Inhibitor Adverse Effects
- D
- U
- M
- B
- E
- L
- S
- Diarrhea
- Urination
- Miosis
- Bronchospasm
- Emesis
- Lacrimation
- Salivation
Goals of Therapy
- Improve ____ and _ _ _
- Prevent long term ______, minimize _____ disability
- Slow disease _______
- Maximize ___ therapy and minimize _ _
- symptoms, QOL
- complications, functional
- progression
- drug, AE
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*
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
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
- Neurotransmitters
COMT Inhibitors
How is it given?
Used in combination with levodopa/carbidopa to enhance its effectiveness and manage wearing off
Entacapone combined with Levodopa/Carbidopa (Stalevo)
Combo of all three is so common that we have Stalevo
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
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
Cholinesterase Inhibitors
Indication
For mild to moderate disease
COMT Inhibitors
MOA
Inhibits peripheral metabolism of levodopa through inhibition of Catechol-O-methyl transferase (COMT)
Acetylcholine Receptor Antagonists
Agents (2)
Benztropine
Trihexyphenidyl
MOA Inhibitors
Interactions (2)
- At high doses (which should be avoided in PD), MAO-A can be inhibited
- Avoid foods/drinks high in tyramine (eg aged cheese, smoked meat, red wines, others)
- Reduction in tyramine catabolism -> hypertensive crisis
Tyramine also targets monoamine oxidase - so if you give someone these inhibitors it can cause a buildup of tyramine -> HTN crisis
MAO Inhibitors
MOA
Irreversibly inhibits the monamine oxidase (MAO) enzyme system
- MAO-A - catabolize Serotonin and Norepinephrine
- MAO-B - catabolize Dopamine
- 2 subtypes: breaks down diff neurotransmitters, we’re focusing on MAO-B*
- MAO B inhibitors prevent breakdown of dopamine*
MOA Inhibitors
Admin
As a class, always used as adjunctive therapy
- NOT GIVEN AS MONOTHERAPY*
- more refractory disease of parkinsons, this drug has really fallen out of favor dt the adverse effects*
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
MAO Inhibitors
AE (3)
- Augments levodopa toxicities (dyskinesias, psychiatric symptoms)
- Nausea, dizziness, orthostatic hypotension, hallucination, insomnia
- Serotonin syndrome with other serotinergic agents esp bc a lot of times given with antidepressants
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
