CNS I and II (Dopamine and pals)

Question 1

1. You need ____ to make dopamine and from there it is packaged into and stored in ____ by what?

Answer 1

TYROSINE; vesicles; VMAT2 (vesicular monamine transporter)

Question 2

2. To terminate dopamine’s actions, what things can be used?

Answer 2

1. MAO A or B (in mito inside the presyn neuron) after using the dopamine transporter (DAT) to bring dopamine back in
2. COMT can break down dopamine

Question 3

3. For the five dopamine pathways, list what they are and origin and destination:

Answer 3

1. Nigrastriatal: controls MOVEMENT (substantia nigra to basal ganglia or striatum)
2. Mesolimbic: controls REWARD and PERCEPTION (midbrain ventral tegmental area to nucleus accumbens)
3. Mesocortical: controls EXECUTIVE FUNCTION (midbrain ventral tegmental area and sends axons to areas of prefrontal cortex)
4. Tuberoinfundibular pathway: controls pituitary PROLACTIN function (hypothalamus to anterior pituitary gland)
5. Thalamic

Question 4

4. Consequences of hyperfunctioning in four dopamine pathways :

Answer 4

1. Mesolimbic: addiction, hallucinations (HAM)
2. Mesocortical: hyperVIGILANCE
3. Nigrostriatal: dyskinetic movement
4. Tuberoinfundibular: HYPOprolactinemia

Question 5

5. Hypofunctioning in four dopamine pathways consequences :

Answer 5

1. Mesolimbic: amotivation, apathy
2. Mesocortical: inattention
3. Nigrostriatal: dyskinetic movement, PARKINSONISM
4. Tuberoinfundibular: HYPERprolactinemia

Question 6

6. Basic concept of what the X- and Y-axes are in the inverted U shaped curve:

Answer 6

X axis: want to be in the MIDDLE of the U (too low is distractible/inattentive and PARKINSONISM, vs. too high being hyperVIGILANT, addicted, hallucinating, dyskinetic)
Y axis: Want to be higher in terms of OPTIMAL FUNCTIONING

Question 7

7. For COMT, what can lead to too much DA breakdown?

Answer 7

Abnormal gene (valine substitution) that leads to agggressive COMT and too much DA broken down (now perhaps DEPRESSION)

Question 8

8. Facts about levodopa:

Answer 8

1. Precursor to DA and crosses BBB
2. In CNS, converted to DA proper and can promote better MOVEMENT by improving nigrostriatal functioning
3. SE: dosed too HIGH, can lead to dyskinetic movements and hallucinations;
   Do NOT start patients on this because you could have those dyskinetic movements over a span of 15-30 years

Question 9

9. When do we use carbidopa?

Answer 9

COMBINED WITH LEVODOPA: prevents PERIPHERAL dopamine activity and lowers FATIGUE, DIZZINESS, NAUSEA (potentially associated with levodopa)

Question 10

10. SE’s of levodopa:

Answer 10

1. Psychosis
2. Mania
3. Dyskinesia
4. Hypervigilant;
   also hypotension, nausea, anxiety/agitation, fatigue (Hyper FAN)

Question 11

11. Depression could come from a low _____ state; what two molecules can help with production of dopamine?

Answer 11

DA (amotivation and no reward/enjoyment in life);
L-methylfolate allows DA neurons to make more DA with tyrosine conversion, and SAMe can help do the same, both INCREASING THE 1-CARBON CYCLE

Question 12

12. SE’s of drugs like L-methylfolate or s-adenosyl methionine:

Answer 12

None, maybe GI upset

Question 13

13. What does an NDRI do and give an example? Side effects

Answer 13

NE-DA reuptake inhibitor;
Bupropion antidepressant:
1. Blocks DAT (aka dopamine reuptake inhibition, DRI)
2. DA in the synapse increased and INCREASED DA activity in mesocortical pathway –> lower depression syndromes;

SE’s: less aggressive in CNS and not a 100% agonist of DA system; if too much, think insomnia, jitteriness/hypervigilance, seizures (HIS);
Increased NE: anxiety, agitation, dry mouth, nausea, sweating, palpitations, slight increase in BP (think fleeing from an animal)

Question 14

14. For ADHD, what drugs can be used and what are their mechanisms?

Answer 14

Stimulants like amphetamines and methylphenidate products;
1. Amphetamines (dextroamphetamine, mixed amphetamine salts, lisdexamfetamine): block DAT, maybe REVERSE it, increase VMAT2 to eject more DA
2. Methylphenidate products: blocks DA transporter;
DONE THROUGHOUT THE BRAIN so greater DA and NE side effects, whereas bupropion is limited more to the cortex

Question 15

15. Random fact about lisdexamfetamine:

Answer 15

PRODRUG!!

Question 16

16. Classification of modafinil/armodafinil:

Answer 16

1. Stimulant class of medications (pseudostimulants?)
2. Class IV addictive (less addicting)
3. Good for fatigue due to narcolepsy, apnea, shifwork (NAS)
4. Less severe but similar SE’s to other stimulants and might increase p450-3A4

Question 17

17. Modafinil/armodafinil mech:

Answer 17

1. Increase histamine activity in tuberomammillary nucleus (TMN), activating alertness in frontal cortex
2. Could increase OREXIN activity
3. Requires operating DAT system and might block this pump, akin to DRI
4. Could actually manipulate NE receptors post-synaptically

Question 18

18. With stimulants, what SE’s are we looking at?

Answer 18

1. Addiction now an issue
2. Super high doses: psychosis
3. Moderate doses: appetite and weight loss
4. Any dose: NE and DA side effects

Question 19

19. What do MAOi’s do? Give examples; SE’s of these guys?

Answer 19

MAOi’s irreversibly inhibit MAO-A/B within the neuron and allow DA buildup;
1. Selegiline (MAO-B inhibitor at low dose) for PARKINSON’S or depression (full MAO A+B inhibition)
2. Rasagiline (MAO-B inhibitor) for PARKINSON’S!!
Notice these guys can both SELECTIVELY INHIBIT MAOB;
SE’s: hypotension, dizziness, insomnia, WEIGHT GAIN!! HDWI-fi
MAOi of MAO-A can interfere with breakdown of serotonin and NE which could have fatal drug-drug interactions

Question 20

20. In which case can you have a hypertensive crisis?

Answer 20

Food source with TYRAMINE (heart attack or stroke) when on a MAOi that knocks out MAO-A;
think spoiled meat/fish, fava beans, aged cheese, tofu, smoked meats!!

Question 21

21. MAOi leads to less breakdown of ___, leading to ____ syndrome; what drugs shouldn’t be given in this case and what are SE’s?

Answer 21

serotonin; serotonin;
think antidepressants, narcotic pain meds, antihistamines;
SE’s: tremor, muscle spasm, inc/dec vitals, hyperthermia, delirium, coma, death (

Question 22

22. Entacapone, tolcapone: what do they try to do, SE’s

Answer 22

Inhibit COMT, which could help degrade dopamine or NE otherwise; use for PARKINSON patients;
Enta: nausea, fatigue, diarrhea, dyskinesias
Tol: Also has liver failure

Question 23

23. D2 receptor agonism: what does phasic mean and what can this treat? Examples of drugs? SE’s

Answer 23

Phasic = rapidly fluctuating;
increase DA activity in Parkinson's or RLS;
1. bromocriptine
2. pramipexole
3. ropinerole
4. apomorphine injections;
SE's: nausea, fatigue, dizziness, mania

Question 24

24. D3 receptor agonism: what does tonic mean? example of drug,

Answer 24

Tonic = gradual fluctuation and undulate rather than peak and trough;
Aripiprazole (antipsychotic for schizo but also approved to treat depression)
Receptors: partial agonist at D3 (alertness, energy) and D2; at D3, 30% receptor activity so net increase in DA activity

Question 25

25. Amantadine: therapeutic, mech, SE's

Answer 25

Thera: treat Parkinson's and influenza Mech: release DA from terminal vesicles, block DAT, stim D2 receptors SE's: nausea, dizziness, psychosis, insomnia, seizures!! Nausea DIPS

Question 26

26. What can deplete the synapse of dopamine?

Answer 26

1. Reserpine: blocks VMAT and used for hypertension, but less NE and DA means more depression, and less BP and maybe less psychosis, respectively 2. Tetrabenazine: used to treat Huntington's chorea (VMATi to help lessen movements)

Question 27

27. FGA Mech of Action and where do the high potency agents work?

Answer 27

Mech: D2 receptor antagonism and occurs in all DA pathways High potency: HIGH AFFINITY for D2 receptor antagonism; in mesolimbic alleviates psychosis and in nigrostriatal can cause low DA and extrapyramidal side effect (PARKINSON'S)

Question 28

28. FGA High potency SE's:

Answer 28

If DA activity is too low 1. Akathisia (restlessness) 2. Dystonia (muscle spasm) 3. Parkinsonism (potentially reversible) 4. Neuroleptic Malignant Syndrome (hyperthermia, muscle rigidity, vital sign instability, rhabdo)

Question 29

29. How do anti-Ch drugs relate to Parkinson's? Examples? SE's

Answer 29

Inhibit Ch tone in basal ganglia = improving dopaminergic flow/tone in nigrostriatal pathway (very effective in EPS caused by first and second generation antipsychotics); Benztropine, triheyphenadyl, diphenhydramine SE's: Hallucinations, delirium, confusion, AND dry mouth, blurred vision, tachy, constipation

Question 30

30. Chronic D2 receptor antagonism could cause

Answer 30

permanent movement disorder called tardive dyskinesia

Question 31

31. For the low potency FGA's,

Answer 31

there is low affinity for D2 antagonism and they also deal with other receptors: 1. H1 receptor antagonism: fatigue and increased appetite/weight 2. Anti-Ch: dry mouth, blurry vision, constipation 3. Alpha 1 receptor antagonism (orthostasis 4. D2 receptor antagonism chronically: EPS

Question 32

32. Examples of high potency FGA drugs are; low potency FGA drugs are

Answer 32

High potency: Haloperidol, fluphenazine, thiothixine; | Low potency: chlorpromazine, thioridazine

Question 33

33. SGA mech of action; how is it improved over FGA's?:

Answer 33

1. D2 receptor antagonism (improve psychosis, mania, aggression: PAM) 2. Serotonin 2a antagonism (lessen EPS risk); IMPROVED SELECTIVITY since the blocking is going on primarily in the mesolimbic system (where psychosis reigns)

Question 34

34. Dones main SE; Pines main SE's

Answer 34

Dones: Possible more EPS/TD (like the FGA's) Pines: More sedating with its anti-H1 activity; more METABOLIC SYNDROME induced, so weight gain and eating more (think DIABETIC patient)

Question 35

35. SGA SE's besides those listed for the dones and pines?

Answer 35

Think suicide risk <25 and stroke in dementia patients!!

Question 36

36. Clozipine: thera, mech, SE's, misc

Answer 36

Thera: used for refractory schizo Mech: antagonize D2 and 5HT2a; also D1 and D4; block NMDA glutamate receptors SE's: risk of agranulocytosis (monitor WBC and ANC); most metabolic risk of any agent Misc: Little to zero EPS/TD