CNS I and II (Dopamine and pals) Flashcards
- You need ____ to make dopamine and from there it is packaged into and stored in ____ by what?
TYROSINE; vesicles; VMAT2 (vesicular monamine transporter)
- To terminate dopamine’s actions, what things can be used?
- MAO A or B (in mito inside the presyn neuron) after using the dopamine transporter (DAT) to bring dopamine back in
- COMT can break down dopamine
- For the five dopamine pathways, list what they are and origin and destination:
- Nigrastriatal: controls MOVEMENT (substantia nigra to basal ganglia or striatum)
- Mesolimbic: controls REWARD and PERCEPTION (midbrain ventral tegmental area to nucleus accumbens)
- Mesocortical: controls EXECUTIVE FUNCTION (midbrain ventral tegmental area and sends axons to areas of prefrontal cortex)
- Tuberoinfundibular pathway: controls pituitary PROLACTIN function (hypothalamus to anterior pituitary gland)
- Thalamic
- Consequences of hyperfunctioning in four dopamine pathways :
- Mesolimbic: addiction, hallucinations (HAM)
- Mesocortical: hyperVIGILANCE
- Nigrostriatal: dyskinetic movement
- Tuberoinfundibular: HYPOprolactinemia
- Hypofunctioning in four dopamine pathways consequences :
- Mesolimbic: amotivation, apathy
- Mesocortical: inattention
- Nigrostriatal: dyskinetic movement, PARKINSONISM
- Tuberoinfundibular: HYPERprolactinemia
- Basic concept of what the X- and Y-axes are in the inverted U shaped curve:
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
- For COMT, what can lead to too much DA breakdown?
Abnormal gene (valine substitution) that leads to agggressive COMT and too much DA broken down (now perhaps DEPRESSION)
- Facts about levodopa:
- Precursor to DA and crosses BBB
- In CNS, converted to DA proper and can promote better MOVEMENT by improving nigrostriatal functioning
- 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
- When do we use carbidopa?
COMBINED WITH LEVODOPA: prevents PERIPHERAL dopamine activity and lowers FATIGUE, DIZZINESS, NAUSEA (potentially associated with levodopa)
- SE’s of levodopa:
- Psychosis
- Mania
- Dyskinesia
- Hypervigilant;
also hypotension, nausea, anxiety/agitation, fatigue (Hyper FAN)
- Depression could come from a low _____ state; what two molecules can help with production of dopamine?
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
- SE’s of drugs like L-methylfolate or s-adenosyl methionine:
None, maybe GI upset
- What does an NDRI do and give an example? Side effects
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)
- For ADHD, what drugs can be used and what are their mechanisms?
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
- Random fact about lisdexamfetamine:
PRODRUG!!
- Classification of modafinil/armodafinil:
- Stimulant class of medications (pseudostimulants?)
- Class IV addictive (less addicting)
- Good for fatigue due to narcolepsy, apnea, shifwork (NAS)
- Less severe but similar SE’s to other stimulants and might increase p450-3A4
- Modafinil/armodafinil mech:
- Increase histamine activity in tuberomammillary nucleus (TMN), activating alertness in frontal cortex
- Could increase OREXIN activity
- Requires operating DAT system and might block this pump, akin to DRI
- Could actually manipulate NE receptors post-synaptically
- With stimulants, what SE’s are we looking at?
- Addiction now an issue
- Super high doses: psychosis
- Moderate doses: appetite and weight loss
- Any dose: NE and DA side effects
- What do MAOi’s do? Give examples; SE’s of these guys?
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
- In which case can you have a hypertensive crisis?
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!!
- MAOi leads to less breakdown of ___, leading to ____ syndrome; what drugs shouldn’t be given in this case and what are SE’s?
serotonin; serotonin;
think antidepressants, narcotic pain meds, antihistamines;
SE’s: tremor, muscle spasm, inc/dec vitals, hyperthermia, delirium, coma, death (
- Entacapone, tolcapone: what do they try to do, SE’s
Inhibit COMT, which could help degrade dopamine or NE otherwise; use for PARKINSON patients;
Enta: nausea, fatigue, diarrhea, dyskinesias
Tol: Also has liver failure
- D2 receptor agonism: what does phasic mean and what can this treat? Examples of drugs? SE’s
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
- D3 receptor agonism: what does tonic mean? example of drug,
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
- Amantadine: therapeutic, mech, SE’s
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
- What can deplete the synapse of dopamine?
- Reserpine: blocks VMAT and used for hypertension, but less NE and DA means more depression, and less BP and maybe less psychosis, respectively
- Tetrabenazine: used to treat Huntington’s chorea (VMATi to help lessen movements)
- FGA Mech of Action and where do the high potency agents work?
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)
- FGA High potency SE’s:
If DA activity is too low
- Akathisia (restlessness)
- Dystonia (muscle spasm)
- Parkinsonism (potentially reversible)
- Neuroleptic Malignant Syndrome (hyperthermia, muscle rigidity, vital sign instability, rhabdo)
- How do anti-Ch drugs relate to Parkinson’s? Examples? SE’s
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
- Chronic D2 receptor antagonism could cause
permanent movement disorder called tardive dyskinesia
- For the low potency FGA’s,
there is low affinity for D2 antagonism and they also deal with other receptors:
- H1 receptor antagonism: fatigue and increased appetite/weight
- Anti-Ch: dry mouth, blurry vision, constipation
- Alpha 1 receptor antagonism (orthostasis
- D2 receptor antagonism chronically: EPS
- Examples of high potency FGA drugs are; low potency FGA drugs are
High potency: Haloperidol, fluphenazine, thiothixine;
Low potency: chlorpromazine, thioridazine
- SGA mech of action; how is it improved over FGA’s?:
- D2 receptor antagonism (improve psychosis, mania, aggression: PAM)
- Serotonin 2a antagonism (lessen EPS risk);
IMPROVED SELECTIVITY since the blocking is going on primarily in the mesolimbic system (where psychosis reigns)
- Dones main SE; Pines main SE’s
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)
- SGA SE’s besides those listed for the dones and pines?
Think suicide risk <25 and stroke in dementia patients!!
- Clozipine: thera, mech, SE’s, misc
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
