Pharm - Psych - Cognitive Dysfunction

Front 1

4 places to intervene for pt with cognitive dysfunction

Back 1

Primary prevention
secondary prev - e.g.stopping edema, ischemia, increased ICP, excitotoxicity.
enhancing recovery
tx deficits.

Front 2

Excitotoxicity

Back 2

Glutamate excitation results in too much Ca++, and this leads to...

Reactive oxygen species,
activations of calpains and caspases (trigger necrosis and apoptosis)
pro-inflammation.

(this still has to do with secondary prevention)

Front 3

Which requires energy - necrosis or apoptosis?

Back 3

apoptosis. it is an active process.

(this still has to do with secondary prevention)

Front 4

Difference between necrosis and apoptosis

Back 4

(this still has to do with secondary prevention)

Necrosis is short-term (days), involves calpains as the main protease, results in inflammation and immune response. No energy needed.

Apoptosis is longer term (weeks), caspases are the main proteases, doesn't activate inflamm and immune resp, and requires energy input.

Front 5

Potential mechanisms of preventing excitotoxicity, which in turn leads to glutamate and Ca++

Back 5

NMDA and AMPA antagonists (block glutamate receptor)

Block glutamate release

Block Ca++ entrance into cell.
Ca++ also produces cytokines and ROS to damage membrane. Also calpains and caspases.

Antioxidant, anti-inf, and neurotrophic factors.


(works in rodents, not sure about humans yet)

Front 6

Ways to enhance recovery

Back 6

Neurogenesis (already occurs in hippocampus-specifically the dentate gyrus)

synaptic reorganization and adaptation - specifically long-term potentation and dendritic spine density. Neurotrophins are critical for this.

Transplantation of stem/progenitor cells

NT augmentation


(none of these work all too well yet)

Front 7

Specific cognitive defects which need to be addressed

Back 7

Attention

Memory

Executive functions

Front 8

Alerting
An attentional network

Back 8

Alerting - interaction with env - thalamic activation

Front 9

Orienting
An attentional network

Back 9

Selective interaction

Parietal activation

Front 10

Executive
An attentional network

Back 10

Allocation of activation of attentional resources

Cingulate activation

Front 11

Cholinergics in attention

Back 11

Signal to noise modulation

Front 12

Glutaminergics in attention

Back 12

Metabo and iono receptors
Signal to noise modulation

Front 13

Catecholaminergics in attention

Back 13

Noradrenergic - Balancing alpha 1 and 2 tone.
Dopaminergic - Through modulation of reward circuitry and working memory.

Front 14

NTs with attention

Back 14

ACh, glutamate, DA, NE.

Narrow sweetspot for these NTs.

Front 15

Declarative memory (semantic and episodic) stored in...

Back 15

Hippocampus

Front 16

Which type of memory is highly dependent on language?

Back 16

Declarative, not procedural.

Procedural also not hippocampally-dependent.

Front 17

Which NT for long term potentiation?

Back 17

Glutamate

Front 18

Frontal-subcortical circuits

Back 18

There are 5, here are the 3 v. important ones:

Dorsolateral prefrontal - executive function. Working memory. Attention/cognition.
Lateral orbitofrontal - social intelligence. Phineas gage.
Anterior cingulate - motivation.

Front 19

Thalamus, frontal cortex, striatum - direct pathway

Back 19

Increase signal processing

Front 20

Thalamus, frontal cortex, striatum - indirect pathway

Back 20

Decrease signal processing

Front 21

Tx of higher order cognition deficit

Back 21

Catecholaminergics and cholinergics

Front 22

Tx of disorder motivational behavior

Back 22

DA agonists

Front 23

Tx of social compartment

Back 23

Mood stabilizers
Antidepressants
Atypical antipsychotics.

Front 24

Which drugs have FDA approval for tx impaired cognition following dementia (except ADD and senile dementia of Alzheimer's)

Back 24

none

Front 25

Example of a drug that is "arousal enhancing"

Back 25

Modafinil - inc release of DA and NE

Front 26

NMDA noncomp antagonists

Back 26

Amantadine, memantine.

Front 27

Pt with memory or sensory gating deficit, rx them...

Back 27

pro-cholinergics

Front 28

Pt with diminished arousal, slowed and inefficient info processing and/or attentional deficits.
Rx them...

Back 28

Psychostimulants

Front 29

Psychostimulants

Back 29

Methylphenidate
Dextroamphetamine
Bromocriptine
L-DOPA/Carbidopa

Front 30

Methylphenidate

Back 30

Psychostimulant

Short half-life.

Front 31

Dextroamphetamine

Back 31

Psychostimulant

Freq. used in tx ADD, attention/mem following TBI.

Secondary to methylphenidate usually.

Has long-acting preparations available.

Front 32

Bromocriptine

Back 32

Psychostimulant (DA agonist)

Improves exec func and motivation.

Front 33

L-DOPA/carbidopa

Back 33

Psychostimulant

Helps impaired motivation, hypoarousal, inattention, and executive function.

Front 34

Atomoxetine (Strattera)

Back 34

Catecholaminergic agonist

NE-reuptake inhibitor. Helps with attention

Front 35

Duloxetine (Cymbalta)

Back 35

Catecholaminergic agonist
Selective NE-reuptake inhibitor.
Mainly an antidepressant but may have attention-enhancing properties

Front 36

Medication of AD

Back 36

Inhibits AChE
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Reminyl/RAZADYNE)

NMDA Receptor antag
Memantine (Namenda)

Front 37

Donepezil (Aricept)

Back 37

Centrally selective AChE inhibitor. Limited systemic effects. May help for cognitive impairment after TBI.

Front 38

Rivastigmine (Exelon)

Back 38

AChE inhibitor.

Improves some aspects of
memory func.

Front 39

Cholinesterase inhibitors found to be useful in...

Back 39

Alzheimer's, Down's with dementia, PD, Dementia with Lewy Bodies

Front 40

NMDA receptor antagonists and DA agonists

Back 40

Amantadine - may prev glutamate excitotoxicity.
memantine

These both increase DA release, inhibit presynaptic reuptake, stimulate DA receptors, and enhance post-syn DA receptor sensitivity.

Front 41

Modafinil

Back 41

Tx excessive daytime somnolence in pts with narcolepsy.
May also help with post-TBI fatigue and cognitive impairment.

May...
activate hypocretin (orexin) in lateral hypothal.
Reduce GABA release
Increase glutamate release in thalamus.
Increase DA in nucleus accumbens.

Front 42

General tx scheme of pt with poor cognition

Back 42

Elim non-essential meds with adverse effects on cognition.
Treat comorbidities
Smart dosing and monitoring.

Major forms of tx are psychostimulants (for problems with arousal, speed of processing and sustained attention) and pro-cholinergics (for impaired memory or gating).