Pharm: Dopaminergic Agents

Question 1

What are the ways in which dopamine’s action is terminated?

Answer 1

1) Destruction by MAO A or B
2) Destruction by COMT
3) Recycled by DAT

Question 2

What does the nigrastriatal pathway do?

Answer 2

Controls movement
Hyperfunctioning: dyskinetic movement
Hypofunctioning: dyskinetic movement, parkinsonism

Question 3

Mesolimbic pathway

Answer 3

Controls reward and perception
Hyperfunctioning: addiction, hallucinations
Hypofunctioning: amotivation, apathy

Question 4

Mesocortical

Answer 4

Controls executive function
Hyperfunctioning: hypervigilance
Hypofunctioning: inattention

Question 5

Tuberoinfundibular

Answer 5

Controls pituitary prolactin function
Hyperfunctioning: hypoprolactinemia
Hypofunctioning: hyperprolactinemia

Question 6

Dopamine enhancing drugs

Answer 6

Used to treat low DA states like Parkinson’s

Levodopa: the precursor to DA, crosses BBB

• in CNS converted to DA, promotes better movement by improving nigrostriatal functioning
• too high of a dose –> dyskinetic movement, hallucinations

Carbidopa: often combined with levodopa, prevents peripheral dopamine activity and lowers fatigue, dizziness, nausea

Question 7

Side effects of levodopa

Answer 7

Too much DA –> psychosis, mania, dyskinesia

Average dose –> hypotension/syncope, nausea, anxiety/agitation, fatigue

Question 8

What can we use to treat depression caused by a low dopaminergic state?

Answer 8

L-methylfolate or s-adenosyl methionine

Increases 1 carbon cycle and allows DA neurons to make more DA

Question 9

What drug increases DA in the synapse?

Answer 9

Norepi-DA reuptake inhibitors like bupropion XL:

• blocks DAT–> more DA in synapse to increase DA activity in the mesocortical pathway
• side effects: insomnia, jitteriness/hypervigilance, seizures

Question 10

Amphetamines

Answer 10

Dextroamphetamine, mixed amphetamine salta, lisdexamfetamine
- block DAT like bupropion, may even reverse it. Increases VMAT2, ejecting more DA from nerve terminals

Methylphenidate products
- block DAT

Question 11

Modafinil/Armodafinil

Answer 11

Stimulants approved for fatigue due to narcolepsy, apnea, shiftwork, NOT ADHD

• may increase p450-3A4 enzymes
• increases histamine activity in TMN, activating alertness in frontal cortex
• increases orexin
• requires an operating DAT system and may block this reuptake pump

Question 12

Stimulant side effects

Answer 12

• creates more DA and NE not only in cortex but also mesolimbic pathway –> ADDICTION
• high doses –> psychosis
• moderate doses –> no appetite, weight loss

Question 13

What enzyme is responsible for breaking down dopamine?

Answer 13

Monoamine oxidase A and B

Question 14

What do MAOIs do?

Answer 14

Irreversible inhibit MAO-A/B, generally within the neuron, allowing a build up of DA (also 5HT and norepi) because it can’t be broken down

Question 15

MAOI side effects

Answer 15

Hypotension, dizziness, insomnia, weight gain

Question 16

Hypertensive Crisis

Answer 16

• can be caused by adding MAOIs and any drug that raises norepi
• adding any food source that contains tyramine may cause an immediate release of NE stores, creating a hypertensive crisis –> MI, stroke
• MAO-A breaks down tyramine (spoiled meat/fish, marmite, pickled herring, banana peel, fava beans, smoked meats, aged cheese, tofu)

Question 17

Serotonin Syndrome

Answer 17

MAOIs decrease breakdown of 5HT in CNS
- adding an aggressive serotonin drug may create toxic levels of CNS 5HT –> tremor, muscle spasm, ind/dec vitals, hyperthermia, delirium, coma, death

Question 18

COMTI

Answer 18

COMT inhibitors

• COMT degrades monoamines. Inhibiting it –> increased dopamine, norepi
• treats Parkinson’s patients (Entacapone, Tolcapone)

Question 19

D2 receptor agonists

Answer 19

Increase DA activity in treating Parkinsons or Restless Leg Syndrome

• Bromocriptine
• Pramipexole
• Ropinerole
• Apomorphine injections

Question 20

D3 receptor agonist

Answer 20

Aripiprazole - antipsychotic for schizophrenia, depression

• partial agonist at D3 and D2
• if DA is low, binding of the partial agonist –> net increase in DA

Question 21

Amantadine

Answer 21

Used to treat Parkinsons and influenza

- releases DA from terminal vesicles, blocks DAT, D2 agonist

Question 22

DA synapse depleters

Answer 22

Reserpine 
- used for hypertension, blocks VMAT so vesicles with monoamines can't be released into synapses
Tetrabenazine
- used for Huntington's chorea
- VMATI

Question 23

High potency FGAs

Answer 23

• High affinity for D2 receptor
• Very selective
• Blocking D2 in mesolimbic pathway alleviates psychosis by returning pathway from high DA back to normal
• blocking D2 in nigrostriatal pathway causes abnormally low DA activity and EPS –> parkinsonism

Haloperidol, Fluphenazine, Thiothixine

Question 24

Extrapyramidal Syndrome (EPS)

Answer 24

Occurs when DA activity is forced too low

• Akathsia: restlessness
• Dystonia: muscle spasm
• Parkinsonism: like Parkinsons but reversible
• Neuroleptic Malignant Syndrome: hyperthermia, muscle rigidity, vital sign instability, rhabdo

Question 25

Anticholinergics for Parkinson's Disease

Answer 25

- inhibiting cholinergic tone in basal ganglia improves dopaminergic tone in nigrostriatal pathway, lowering Parkinson's symptoms - effective in early Parkinsons but not for Parkinsonian EPS - Benztropine, trihexyphenadyl, diphenhydramine

Question 26

Tardive dyskinesia

Answer 26

Chronic D2 receptor antagonism may cause this permanent movement disorder - Choreic movements: fast, quirky - Athetotic movements: slow, writhing

Question 27

Low Potency FGAs

Answer 27

Have low affinity for D2 antagonism, requires more mg of drug to provide antipsychotic effects - antagonist D2 but are "messy" --> manipulate other receptors, causing side effects Chlorpromazine, Thioridazine

Question 28

FGA low potency side effects

Answer 28

D2 antagonism--> EPS Histamine 1 antagonism --> fatigue, increased appetite Anticholingergic muscarinic --> dry mouth, blurred vision, constipation Noradrenergic alpha-1 antagonism --> orthostasis

Question 29

SGA mechanism

Answer 29

D2 receptor antagonist improves psychosis, mania, aggression 5HT2A antagonist lessens EPS risk - allows greater blocking of DA in mesolimbic system while allowing better transmission in all other DA pathways (better selectivity)

Question 30

SGA drugs

Answer 30

Dones, Rips and Pines Dones: Risperidone, Paliperidone, Zipasidone, Iloperidone, Lurasidone Rips: Aripiprazole (partial agonist at D2, D3) Pines: Olanzapine, Quetiapine, Asenapine, Clozapine (antagonizes D4, D1 also)

Question 31

SGA side effects

Answer 31

Dones: possibly more EPS Pines: more sedating due to more antihistamine activity, more metabolic syndrome inducing

Question 32

Side effects of 5HT2c antagonism

Answer 32

Slow metabolism, desensitize leptin system allowing weight gain, increased cholesterol and blood glucose

Question 33

Side effects of 5HT1a partial agonism, 5HT3, 7 antagonism

Answer 33

Promotes serotonin activity --> headaches, GI probs, insomnia, anxiety

Question 34

SGA FDA box warnings

Answer 34

Suicide risk ages

Question 35

Clozapine

Answer 35

The original 'atypical' antipsychotic used for refractory schizophrenia - antagonizes D2, 5HT2a - also antagonizes D1, D4 - Risk of agranulocytosis (requires WBC and ANC monitoring) - Most metabolic risk of any agent - Little to zero EPS/TD