neurodegenerative diseases Flashcards
Pramipexole & ropinirole
mech of action
Dopamine Agonists at D2 and D3 receptors
Muscarinic Receptor Antagonists - side effects
- Dry mouth
- constipation
- impaired vision
- urinary retention
MAO - action
- oxidation of monoamines (dopamine, norepi)
- break down of dopamine and norepi
Anticholinergic Agents - mech of action
Prevent cholinergic inhibition of dopamine release
cholinesterase inhibitors - anesthetic consideration
- prolongation of succinylcholine
- relative resistance to non-depolarizing muscle relaxants
Tau protein - normally found in …
in microtubules of neurons to keep organization
Cholinesterase Inhibitors - Mechanism of Action?
- Prevents action of acetylcholinesterase which breaks down Ach
- Thereby ↑ acetylcholine concentrations in the synapse
used for Alzheimer’s
Dopamine Agonists - mech of action
Mimic dopamine in the striatum
ApoE3 gene and AD
Normal Risk for AD
mechanism of action for
- Donepezil (Aricept)
- Rivastigmine (Exelon)
- Galantamine (Razadyne)
Prevents action of acetylcholinesterase (which breaks down Ach -> increased Ach)
How does Parkinson’s affect the balance between dopamine and cetylcholine affecting movement
↓ dopamine in the striatum (basal ganglia) creats an imbalance between DA & ACh -> moevemnt disorder
Levodopa - Adverse Drug Interaction
non-selective MAO Inhibitors & levodopa -> an overload of dopamine & norepinephrine -> may cause peripheral side effects
location of cholinergic neuron loss in Alzheimer’s
- hippocampus (memory & learning)
- frontal cortex (executive function & decision making)
Mementine (Namenda) - mech of action
Blocking “leaky” NMDA channels:
- ↓ Ca2+ induced excitotoxicity
- reduce background noise, making signals relatively stronger -> allows to perceive the learning signals
Parkinson’s characteristics (presentation)
- Dyskinesias: difficulty of movement
- Difficulty starting movement & difficulty stopping movement once started
- Muscle rigidity
- Tremor at rest
- Cognitive impairments, depression
anticholinergic drugs - anesthetic consideration
- assess aticholoinergic side effects (especially HR)
- avoid drugs that impact cholinergic tone (TCAs)
- avoid drugs that increase side effects (ex: HR)
Levodopa & carbidopa - anesthetic considerations
- must be give Q 6-12 hrs
- administer 20 min preop and interop per NG tube to avoid sudden loss of effect (to avoid neuromuscular/respiratory failure)
- assess side effects: cardiac dysrhythmia, adrenergic stimulation, orthostatic hypertension, GI
Tau hyperphosphorylation effects
- can no longer support microtubules
- aggregate together -> correlates with neuronal death d/t neuron losing it’s shape
Amyloid Precursor Protein (APP) - Non-Amyloidogenic Pathway
APP protein gets cleaved by α-secretase followed by γ-secretase
(makes a protein P3)
why is entacapone added to the parkinson’s pharm regimen?
added when effectiveness of Levodopa/Carbidopa wanes
why is Levodopa given with carbidopa
- Despite large doses of Levodopa, when given alone only a small amount of will reach the brain
- large amounts of dopamine cause problems in the periphery -> levodopa needs carbidopa ->
- to cross the the blood brain barrier → then metabolized to dopamine
- same amount of Levodopa can reach the brain with a smaller dose
What are the cholinergic related deficits in Alzheimer’s
- Choline acetyltransferase activity
- Acetylcholine amount
- Acetylcholinesterases
- Choline transport
- Nicotinic acetylcholine receptor expression
how is the balance between dopamine and cetylcholine affecting movement
when Dopamine (DA) & Acetylcholine (ACh) are balanced -> results in controlled movement
Benztropine - class
Muscarinic Receptor Antagonists
Selegiline - mech of action
- MAO-B inhibitor -> ↓ dopamine degradation
- increases DA in the synapse
MAO-B is not involved in NE metabolism
nonselevtive MAO inhibitors action
will block the natural pathway for MAO’s in converting dopamine & NE to other substances thus → ↑ dopamine & NE
Mementine (Namenda) - side effects
- Dizziness,
- Headache,
- Fatigue,
- Sedation,
- Hypertension,
- Rash,
- Diarrhea,
- Weight Gain,
- Urinary Frequency,
- Anemia
Basal Ganglia - Function
- starts purposeful movement
- suppresses unwanted movement
Memantine (Namenda) - class of drug
NMDA Receptor Antagonist - examples
Dopaminergic Agents - mechanism of action
↑ amounts of dopamine in striatum
by
↑ delivery or ↓ degradation
Synthetic dopamine agonist - anesthetic considerations
assess for side effects :
- CV
- hypotension
- pleuropulmonary fibrosis
- Nausea
- diarrhea
- dizziness
- headache
- bronchoconstriction
Cholinesterase Inhibitors - side effects
ApoE4: gene and AD
- one copy
- two copies
↑ Risk for AD
- One copy: 3 fold ↑ risk
- Two copies: 12-15 fold ↑ risk
Blocking “leaky” NMDA channels:
- ↓ Ca2+ induced excitotoxicity
- reduce background noise, making signals relatively stronger -> allows to perceive the learning signals
used for Alzheimer’s
NMDA Receptor Antagonist - mechanism of action
Parkinson’s pharmacotherapy strategies
Dopaminergic Agents
&
Anticholinergic Agents
Levodopa - side effects
- Involuntary movements (dyskinesias)
- ‘On-off’ effect: fluctuations between hypokinesia & improvements
Levodopa - acute/transient side effects
- Nausea
- Anorexia
- Hypotension
- Psychosis: schizophrenia like symptoms with excess dopamine
ApoE gene - action
encodes for a protein that facilitates the clearance of Aβ
Parts of basal ganglia involved in Parkinson’s
- Striatum,
- Globus Pallidus,
- Subthalamic nuclei,
- Substantia nigra
Selergine - anesthetic considerations
- avoid ephedrine, meperidine
- use extreme caution with vasoactive medications
- pronounced effect with neuromuscular blockers, sedative agents, diuretics - titrate very carefully
- Donepezil (Aricept)
- Rivastigmine (Exelon)
- Galantamine (Razadyne)
Cholinesterase Inhibitors - Examples
mechanism of action for galantamine (Razadyne)
blocks cholinesterase activity => prevents breakdown of Ach
ApoE2 gene and AD
Lower risk for AD
who degrades levodopa
- dopamine decarboxylases (DDC)
- catecholamine O-methyltransferase (COMT)
Amyloid Precursor Protein (APP) -Amyloidogenic Pathway
- APP gets cleaved by β-secretase followed by γ-secretase
- makes Aβ 40/42
- Aβ 40/42 aggregates forms plaques in the brain
what is Levodopa
Precursor to Dopamine
what are the protein aggregates in Alzheimer’s?
- Amyloid plaques (amyloid β or Aβ)
- Neurofibrillary tangles (hyperphosphorylated tau)
Pramipexole & ropinirole - side effects
- fewer than old dopamine agonists
- hallucinations
- compulsive behaviors (eating, gambling, etc)
ApoE genotype - action
perevents the clearance of Aβ
Muscarinic Receptor Antagonists - mech of action
- muscarinic receptors (presynaptic) are present in striatum where they inhibit dopamine release from dopamine neurons
- Blockade of muscarinic receptors relieves the inhibition of dopaminergic neurons -> more dopamine release
Amantandine - mech of action
- Dopamine usually sits in presynaptic vesicles & amantadine helps dopamine release into synapse
- Enhances dopamine release into synapse
Memantine (Namenda) anesthetic consideration
clearance is reduced with higher pH (careful with bicarbonate)
amantadine - anesthetic consideration
- evaluate for anti-cholinergic like side effects
- rule out CHF side effect
carbidopa - class
- peripheral dopamine decarboxylase inhibitor
- prevents levodopa from being converted to dopamone in the periphery
entacapone - class
- COMT (catecholamine O-methyltransferase) inhibitor
- prevents levodopa from being converted to dopamone in the periphery
mechanism of action for Rivastigmine (Exelon)
blocks cholinesterase activity => prevents breakdown of Ach
