Neurodegenerative Flashcards
Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne) are what drug class?
Cholinesterase Inhibitors
Alzheimers leads to deficits in cholinergic signaling, what will this do?
Cholinergic neuron loss in hippocampus (memory and learning) and frontal cortex (executive function)
Decreases in choline acetyltransferase activity, acetylcholine amount, acetylcholinesterases, choline transport, and nicotinic acetylcholine receptor expression
What is the cholinesterase inhibitors mechanism of action?
Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne)
Prevents action of acetylcholinesterase, thereby increasing acetylcholine concentrations in the synapse
Effects and side effects of cholinesterase inhibitors?
Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne)
Effects: slight improvement in cognitive function, indicated for mild to moderate Alzheimers but does not halt the disease
Side effects: nausea, diarrhea, dizzy, headache, bronchocontriction
What class of drug is Memantine (Namenda)?
NMDA Receptor Antagonist
What are the indications and side effects of Memantine (Namenda) - NMDA receptor antagonists?
Indications: moderate to severe Alzheimers, has modest benefits
Side effects: dizzy, headache, fatigue, sedation, hypertension, rash, diarrhea, weight gain, urinary frequency, anemia
What are the two possible mechanisms of action of Memantine (Namenda)?
- Blocking leaky channels help reduce calcium-induced excitotoxicity
- Blocking leaky channels help reduce background noise, making signals stronger
What are two protein aggregates that are seen in patient’s with Alzheimers that future treatments may be able to focus on?
Amyloid plaques (amyloid beta): Block synthesis, promote clearance, block plaque aggregation formation Neurofibrillary tangles (hyperphosphorylated tau): block aggregation of Tau
What are two ways that Amyloid-beta can be processed?
Amyloidogenic: APP (Amyloid Precursor Protein) gets cleaved by beta-secretase followed by gamma-secretase and the aggregates form plaque **Hallmark of Alzheimers
Nonamyloidogenic: APP gets cleaved by alpha-secretase followed by gamma-secretase, no Amyloid-beta is formed
What is the ApoE gene? What is the risk factor difference between ApoE2, ApoE3, and ApoE4?
ApoE gene encodes for a protein that facilitates clearance of Amyloid-beta
ApoE2: low risk for Alzheimers
ApoE3: normal risk for Alzheimers
ApoE4: increased risk (x3) for Alzheimers
What is Tau protein? What happens to it in Alzheimers? How are Neurofibrillary tangles formed?
Tau protein is in normal neurons in the microtubules
It becomes hyperphosphorylated in Alzheimers
Proteins become tangled and form Neurofibrillary tangles which correlates with neuronal death
What is Parkinson’s disease?
A movement disorder occurring mostly in the elderly, genetic risk factors but no obvious cause
Characterized by dyskinesias (difficulty of movement), muscle rigidity, tremor at rest, cognitive impairments, depression
What does the basal ganglia consist of and what is its function?
Basal Ganglia: striatum, globus pallidus, subthalamic nuclei, substantia nigra
Function: starts purposeful movement and suppresses unwanted movement
What two neurotransmitters must be balanced in order for controlled movement? Which is decreased in Parkinsons?
Dopamine and Acetylcholine
Dopamine in the Striatum is decreased in Parkinsons
Which classes of drugs are effective for Parkinsons? How do they work?
Dopaminergic agents: increase dopamine in the striatum and mimic dopamine (dopamine agonists), ex: Pramipexole and ropinirole
Anticholinergic agents: prevent cholinergic inhibition of dopamine release
How does Levodopa work?
Levodopa is a dopamine precursor, it is converted to dopamine. It is first line therapy for Parkinsons although the effectiveness of therapy wears off in a couple years (due to neurodegeneration)
What meds are given with Levodopa to help it reach the brain in a small enough dose to not cause problems in the periphery?
Levodopa is given with Carbidopa (peripheral decarboxylase inhibitor) and entacapone (COMT inhibitor) because Levodopa is degraded by decarboxylases and COMT
When effectiveness wanes, Entacapone is added
Levodopa side effects?
Dyskinesias (involuntary movements), “on-off” effect (fluctuations between hypokinesia and improvements)
Acute side effects that disappear in a few weeks include N/V, anorexia, hypotension, psychosis (schizophrenia-like symptoms)
What is the main drug interaction with Levodopa?
Non-selective MAOI’s cause an overload of dopamine and norepinephrine leading to peripheral side effects
What do Pramipexole and ropinirole do?
They are dopamine agonists, they mimic dopamine in the striatum
They are selective D2/D3 receptors, highly effective, fewer side effects than dopamine agonists that hit D1/D2 receptors, although they may cause hallucinations or compulsive behaviors
What is Selegiline?
MAO-B inhibitor, decreases dopamine degradation
It does not have unwanted effects of MAOI’s, not involved in NE metabolism
What is Amantadine do?
It is a synthetic antiviral that enhances dopamine release into the synapse
How do anticholinergic drugs work for Parkinsons? Hint: they are also muscarinic receptor antagonists
Since muscarinic receptors inhibit dopamine release, by blocking these receptors, more dopamine can be released
Muscarinic receptors are present in stratum where they inhibit dopamine release from dopamine neurons
Example: Benztropine
Side effects of anticholinergic drugs?
Dry mouth, constipation, impaired vision, urinary retention
What are Lewy bodies?
Found in Parkinsons, they are protein aggregates composed of alpha-synuclein protein. Alpha-synuclein function is unclear.
Anesthetic considerations: Memantine (NMDA receptor antagonist)
Clearance can be reduced by increasing urinary pH, be careful with bicarb
Anesthetic considerations: Cholinesterase inhibitors- Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne)
Prolong succinylcholine
Relative resistance to non-depolarizing muscle relaxants
Anesthetic considerations: Anticholinergic drugs (Example: Benzotropine)
Assess for anticholinergic side effects (increased HR)
Avoid drugs that impact cholinergic tone (TCA) or increase side effects (HR), if possible
Anesthetic considerations: Amantadine
Evaluate for anti-cholinergic like side effects, rule-out congestive heart failure side effect
Anesthetic considerations: Levodopa and decarboxylase inhibitors (Carbidopa)
Must receive every 6-12 hours. Administer 20 min pre-op and intra-op per NG (to avoid loss of effect, neuromuscular/respiratory failure)
Assess for side effects: cardiac dysrhythmias, adrenergic stimulation, orthostatic hypotension, GI
Anesthetic considerations: Synthetic dopamine agonists (Example: pramipexole and ropinirole)
Assess for side effects: CV, hypotension, pleuro-pulmonary fibrosis
Anesthetic considerations: Selegine (MAO-B)
Avoid ephedrine, meperidine (demerol). Use caution with vasoactive medications
Pronounced effect with neuromuscular blockers, sedatives, diuretics (titrate carefully)
