Dementia, Parkinson's, and Movement Disorders Flashcards
What is Alzheimer’s Disease?
A progressive neurodegenerative disease characterized by a loss of function and death of nerve cells in several areas of the brain
What type of neurons are predominantly lost in Alzheimer’s Disease?
Cholinergic neurons
What types of drugs are Alzheimers patients particularly sensitive?
Anti-cholinergics
What do drugs for Alzheimers Disease aim to do?
Increase ACh activity/concentration either direclty (by using an agonist) or indirectly (by using an AChI)
How does the cholingergic neuron loss cause an exacerbation of Alzheimer’s Disease?
The neuron loss causes excess glutamate which is an excitatory Neurotransmitter
The excess glutamate causes noisy brain signaling and increases neuronal cell death in the brain
What drug is used to treat the excess glutamate caused by neuronal cell loss?
Memantine
What are the goals of Alzheimer’s Disease therapy?
1) Maintain quality of life
2) Maximize function in daily activities
3) Enhance cognition, mood, and behavior
4) Foster a safe environment
5) Promote social engagement, as appropriate
What is the mainstay of Alzheimer’s Disease Therapy?
Acetylcholinterase inhibitors (AChI)
What do AChI do to treat Alzheimer’s?
They attempt to offset loss of presynaptic cholinergic function to slow decline of memory and enhance ability to perform activities of daily living
The AChI used to treat Alzheimer’s are more specific for what receptors?
More selective for ACh muscarinic receptors in the brain
Which AChI is also approved for use in Parkinson’s Dementia?
Rivastigmine
What are the AChI ADR’s?
mostly muscarinic in nature = SLUDGE BBB
BRADYCARDIA Dizziness Lightheadedness Increased Urinary Frequency N/D Concern for dose dependent GI bleed
What is the MOA of Memantine?
Less glutamate activity causes less noise and therefore better signal in the brain = improved cognitive test scores and functioning
When is Memantine used in AD treatment?
In severe or progressed Alzheimers Disease
What is the ADR of memantine?
Headache
What is Parkinson’s Disease?
Progressive
Combo of: Rigidity Bradykinesia Tremor Hypokinesia Postural Instability
What is Parkinson’s disease caused by?
LOW DOPAMINE
Selective loss of dopaminergic neurons in the nigrostriatal pathway
What drugs cause DA depletion from neurons and cause drug induced Parkinsonism?
Drugs of Abuse
Reserpine
Tetrabenazine
Deutetrabenazine
What drugs cause DA receptor blockade and cause drug induced Parkinsonism?
Antipsychotics: typical > atypical
Metoclopramide
What are other non-motor symptoms of Parkinson’s?
Affective disorder Personality changes Abnormalities of autonomic function Sensory complaints Fatigue Sleep Disorders
What is the hallmark therapy for Parkinson’s?
Exogenous Dopamine Supplementation
What are the endogenous barriers to therapy optimization of Parkinson’s?
Blood Brain Barrier Amino Acid transporter DOPA decarboxylase MAO COMT
What is Levodopa broken down by?
In periphery and centrally = COMT
What only breaks down Dopamine in the brain?
MAO-B
What is the first line therapy options for Parkinson’s?
Dopamine Replacement Therapy (levodopa)
Dopamine Receptor Agonist
+/- enzyme inhibitors to decrease DA breakdown
What are additional lines of therapy for Parkinson’s?
Muscarinic Receptor Antagonists
Pimavanserin
Behavioral Therapy
Family/Social dynamic
What is the target for Dopamine Receptor Agonists?
D2 receptors in basal ganglia
Why are Dopamine Receptor Agonists better to use over L-Dopa?
1) there are no enzyme conversion concerns
2) They have better BBB penetration; They don’t have to compete with Amino acid transporter like L-dopa
3) They are more selective for DA receptor activation
4) Less response fluctuations and dyskinesias
What receptors does Bromocriptine hit?
D2/D3/D4
Less selective for these than non-ergot derivatives
What other indications is Bromocriptine used in?
Hyperorlactinemia Pituitary adenoma Cocaine withdrawal Alcohol dependence Mastalgia
What are non-ergot DA agonists?
Used as monotherapy in mild parkinson’s or as an adjunct to Sinemet in advanced disease
D2/D3 receptors only
Often used for Restless leg syndrome also
What are the two DOC’s for Non-ergot DA agonists?
Pramipexole
Ropinirole
What are the Dopamine Receptor Agonists ADRs?
GI
Cardiovascular
Dyskinesias
Mental Disturbances
Who do you have to be cautious in using Dopamine Receptor Agonists in?
Patients with:
Psychotic illness (schizophrenia)
Recent MI
Uncontrolled Hypertension
What is Levodopa?
Oral Dopamine Replacement
Enters brain by LAT
Rarely used as monotherapy
Peripheral DA ADRs by activating chemotrigger zone
Need for combo with enzyme inhibitor
What is carbidopa?
DOPA decarboxylase inhibitor
Inhibits peripheral conversion of L-DOPA to DA
Never given as monotherapy
When levodopa is given alone, what percentage of the dose actually gets into the brain?
1-3%
When Sinemet is given, what percentage of the levodopa dose actually gets into the brain?
10%
What symptom of Parkinson’s is Sinemet most effective at treating?
Bradykinesia
What may reduce levodopa entry into the brain due to competition for LAT?
Protein
What are the ADRs of Sinemet?
N/V Tachycardia Ventricular Abnormalities Hypertension Increased peripheral catecholamine formation Depression Anxiety Dose related dyskinesias Response fluctuations
When are the best results of Sinemet therapy seen and what are the disadvantages?
Best results in first 3-4 years of treatment
Must dose adjust over time due to DA related ADRs
Does not stop progression of the disease
What are the response fluctuations seen in Sinemet therapy?
End of Dose Akinesia
On/Off Phenomenon
What is the end of dose akinesia?
Related to dosing times
Wearing off reaction towards time when next dose is due
What is the on/off phenomenon?
Unrelated to dosing
On = marked akinesia Off = improved mobility, often marked dyskinesia
Less incidence with more continuous DA exposure
What can occur due to Carbidopa use?
Increased metabolic breakdown of levodopa through COMT and MAO-B pathways
What is Catechol-O-Methyltransferase (COMT)?
Central DA metabolizer
Peripheral L-DOPA metabolizer
What is Monoamine Oxidase (MAO)?
Metabolizes catecholamines
MAO-B = DA selective
What is Tolcapone?
Inhibits central and peripheral COMT
HEPATOTOXICITY
What is Entacapone?
Inhibits Peripheral COMT only
What is Selegiline?
MAO-B irreversible inhibitor
Dietary restrictions with tyramine by formulation/dose
Metabolized to amphetamine derivatives
What is Rasalgaline?
Irreversible MAO-B Inhibitor
What is Safinamide?
Reversible MAO-B inhbitor
What are the drug interactions to be aware of with MAO-B inhibitors?
Serotonin Syndrome with SSRIs
What do antimuscarinics help with in Parkinson’s treatment?
relieves tremor and rigidity
What is Apomorphine?
Potent DA receptor agonist used as a “RESCUE” from off phenomenon
Injection that works within 10 minutes
ADR: NAUSEA
What is Pimavanserin used to treat in Parkinson’s?
Treats the hallucinations and delusions associated with the psychosis that can come if too much DA is given to the patient
Who must you be cautious in using Pimarvanserin with?
Elderly
Qtc prolongation
What is Huntington’s Disease?
Autosomal dominant inherited disorder
Causes progressive chorea and dementia
What is the chorea related to in Huntington’s disease?
Imbalance of DA, ACh, and GABA in basal ganglia causing overactivity of DA nigrostatial pathway and GABA neuron degeneration which reduces and imapirs GABA activity
What is Reserpine?
Inhibits VMAT to reduce reuptake of catecholamines
Binds to and destroys catecholamine stroage vesicles, not allowing them to be stored resulting in sympathetic dysfunction
ADRs: Hypotension, depression, sedation, diarrhea, nasal congestion
What is Tetrabenazine?
More selective than reserpine for dopamine
Depletes pre-synpatic DA stores; mildly antagonizes D2 receptors
Less ADRs
What are the treatment considerations for Restless Leg syndrome?
D2 agonists (non-ergot) Gabapentin
What are the treatment considerations for tremors?
Propanalol
Benztropine
