Cognitive complaints and Impairment Flashcards
What are the major dopamine tracts?
- Nigostriatal (extra pyramidal motor system)
- Mesolimbic, mesocortical (cognition, emotion, substance abuse, psychosis)
What are the major dopamine targeting pharmacological agents?
- DA-agents (movement disorders, depression)
- DA antagonists (psychosis)
What are the major norepinephrine tracts?
- Synthesized in Locus Ceruleus
- Project to cortex, limbic, Reticular Activating System, spinal cord
What are the major norepinephrine targeting pharmacological agents?
- Adrenergic agents (depression, MAO-Is, tricyclics, venlafaxine)
- Andrenergic antagonists (tremor, anxiety, beta blockers)
What are the major serotonin tracts?
- Synthesized in raphe nuclei
- Project to cortex, limbic, striatum, cerebellum, blood vessels
What are the major serotonin targeting pharmacological agents?
Seretonergic agents (depression, migraine)
What are the major acetylcholine tracts?
- Synthesized in basal forebrain (n. basalis of Meynert)
- Proj to olfactory bulb, hippocampus, amygdala, cortical association areas
- NT of NMJ
- NT of ANS (except post-ganglionic sympa neurons)
What are the major acetylcholine targeting pharmacological agents?
- Anticholinergic agents (movement disorders)
- Cholinesterase inhibitors (MG, AD, organophosphates, nerve gas)
What cofactor is needed for the biosynthesis of GABA?
B6
What are the major GABA tracts?
- Widely distributed
- Major inhibitory NT of the CNS (along w/ glycine)
What are the major pharmacologic agents targeting GABA?
- GABA-A (binding sites for benzos, barbiturates)
- GABA-B (baclofen)
- GABA-ergic agents (ie AEDs)
What are the major glutamate tracts?
- Widely distributed, major excitatory NT of the brain
- Binds to NMDA-R (ligand, VGCC)
What are the major pharmacologic agents targeting glutamate?
- Glutamate excito-toxicity
- NMDA-R antagonists (memantine for AD)
Attentional disturbances are hallmark features of which disorders?
- Delirium (confusional state)
- Neglect syndromes
- ADHD
[ Also common in
- schizophrenia
- traumatic brain injury]
What are the alerting attentional networks of the brain?
Thalamic
(right) frontal & parietal activation
What are the orienting attentional networks of the brain?
-Superior. colliculus, frontal eye fields, temporopariental, parietal activation (spatial)
What are the executive attentional networks of the brain?
Anterior cingulate & DLPFC activation
What are examples of executive functions?
Mediated by frontal lobes:
- Volition
- Planning
- Purposeful action
- Performance
What part of the brain is responsible for executive function/working memory?
Dorsolateral prefrontal lobe
What part of the brain is responsible for “social intelligence”?
lateral orbitofrontal lobe
What part of the brain is responsible for motivation?
Medial ventral frontal lobe
What part of the brain is responsible for will and/or movement?
Anterior cingulate
What are 2 examples of pro-cholinergic agents?
Acetylcholinesterase inhibitors
- Donepezil
Acetylcholine precursors
- CDP-Choline
To what drug class does donepezil belong?
Acetylcholinesterase inhibitor
What is the action of donepezil?
Inhibition of synaptic acetylcholinesterase
Describe the kinetics of donepezil.
Well absorbed when taken orally
Highly protein bound, metabolized partially in liver, then excreted in bile.
Elimination half-life 50-70 hrs.
What adverse drug reactions are related to donepezil?
Nausea, vomiting (10%).
Sinus bradycardia and 1st degree AV block relative contraindications.
Monitor liver function tests.
What are the primary interactions with donepezil?
- Agents that inhibit hepatic metabolism via CYP450, 3A4, and 2D6 enzymatic pathways (e.g. ketoconazole and quinidine) may increase blood levels of donepezil.
- Inducers of hepatic metabolism (phenobarbital, phenytoin, carbamazepine, dexamethasone, rifampin) may decrease therapeutic blood levels.
In what other disorders can cholinesterase inhibitors be used?
- Traumatic brain injury
- Down Syndrome with Dementia
- Parkinson’s Disease
- Dementia with Lewy Bodies (DLB)
- Cholinergic deficits in Lewy Body Disorders greater than in AD => respond better with cholinesterase inhibitors
To what class does Methylphenidate (Ritalin) belong?
CNS stimulant, structurally related to amphetamine
How does methylphenidate act?
Blocks re-uptake of norepinephrine and dopamine. May also enhance release of catecholamines.
Describe the kinetics of methylphenidate.
Rapidly absorbed when taken orally
Peak levels in 1-2 hours
Metabolized in liver, excreted in urine
What adverse drug effects are associated with methylphenidate?
Nervousness, insomnia.
Potential for dependence and abuse.
What interactions are prominent with methylphenidate?
- Do not use with MAOIs.
- May potentiate the effects of Phenobarbital and phenytoin by delaying absorption
- Increase the noradrenergic effects of tricyclic antidepressants
- Increase the dopaminergiceffects of antiparkinsonian agents
- Potentiate the analgesic properties of meperidine.
What is Dextroamphetamine used for?
- ADD
- Treat attention and memory impairment following TBI
- Beneficial effects on cognition, depression, anergia, and impaired motivation following TBI
- Abuse concerns
What is atomexetine (straterra) used for?
- Norepinephrine re-uptake inhibitor
- Used in ADD
- Some use in TBI-related attentional deficits
What is duloxetine (cymbalta) used for?
- Selective norepinephrine re-uptake inhibitor
- Mainly used as an antidepressant but may have attention-enhancing properties
To what drug class does atomexetine belong?
Selective norepinephrine re-uptake inhibitor
What is the action of atomexetine?
Inhibition of norepinephrine transporter
Describe the kinetics of atomexetine.
- Rapid GI absorption.
- CYP2D6 metabolism.
What are adverse drug reactions with atomexetine?
Liver toxicity
Suicidal ideation
What interactions are prominent with atomexetine?
CYP2D6 inhibitors (e.g. quinidine)
What are the amantadine and memantine?
Moderate-affinity uncompetitive NMDA receptor antagonists
What are the actions of dopamine agonists (ropinirole)?
- increase dopamine release
- decrease presynaptic dopamine reuptake
- stimulate dopamine receptors
- enhance post-synaptic dopamine receptor sensitivity
What is modafinil used for?
- Approved for the treatment of excessive daytime somnolence in patients with narcolepsy
- May have a role in treatment of post-TBI fatigue and cognitive impairment
What are the mechanisms of actions of modafinil?
- Activation of hypocretin (orexin) neurons in the lateral hypothalamus
- Indirect dose-dependent reduction of gamma-aminobutyric acid (GABA) release
- Increases in glutamate release in the ventrolateral and the ventromedial thalamus
- Increases in dopamine in the nucleus accumbens
