Pharm: Dopaminergic Agents Flashcards
What are the ways in which dopamine’s action is terminated?
1) Destruction by MAO A or B
2) Destruction by COMT
3) Recycled by DAT
What does the nigrastriatal pathway do?
Controls movement
Hyperfunctioning: dyskinetic movement
Hypofunctioning: dyskinetic movement, parkinsonism
Mesolimbic pathway
Controls reward and perception
Hyperfunctioning: addiction, hallucinations
Hypofunctioning: amotivation, apathy
Mesocortical
Controls executive function
Hyperfunctioning: hypervigilance
Hypofunctioning: inattention
Tuberoinfundibular
Controls pituitary prolactin function
Hyperfunctioning: hypoprolactinemia
Hypofunctioning: hyperprolactinemia
Dopamine enhancing drugs
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
Side effects of levodopa
Too much DA –> psychosis, mania, dyskinesia
Average dose –> hypotension/syncope, nausea, anxiety/agitation, fatigue
What can we use to treat depression caused by a low dopaminergic state?
L-methylfolate or s-adenosyl methionine
Increases 1 carbon cycle and allows DA neurons to make more DA
What drug increases DA in the synapse?
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
Amphetamines
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
Modafinil/Armodafinil
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
Stimulant side effects
- creates more DA and NE not only in cortex but also mesolimbic pathway –> ADDICTION
- high doses –> psychosis
- moderate doses –> no appetite, weight loss
What enzyme is responsible for breaking down dopamine?
Monoamine oxidase A and B
What do MAOIs do?
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
MAOI side effects
Hypotension, dizziness, insomnia, weight gain
Hypertensive Crisis
- 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)
Serotonin Syndrome
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
COMTI
COMT inhibitors
- COMT degrades monoamines. Inhibiting it –> increased dopamine, norepi
- treats Parkinson’s patients (Entacapone, Tolcapone)
D2 receptor agonists
Increase DA activity in treating Parkinsons or Restless Leg Syndrome
- Bromocriptine
- Pramipexole
- Ropinerole
- Apomorphine injections
D3 receptor agonist
Aripiprazole - antipsychotic for schizophrenia, depression
- partial agonist at D3 and D2
- if DA is low, binding of the partial agonist –> net increase in DA
Amantadine
Used to treat Parkinsons and influenza
- releases DA from terminal vesicles, blocks DAT, D2 agonist
DA synapse depleters
Reserpine - used for hypertension, blocks VMAT so vesicles with monoamines can't be released into synapses Tetrabenazine - used for Huntington's chorea - VMATI
High potency FGAs
- 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
Extrapyramidal Syndrome (EPS)
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
