Flashcards in Unit 3 - CNS: Dopaminergic Drugs Deck (62):
how is dopamine produced?
tyr --> DA stored in vesicles by VMAT2
-tyr is taken up into DA nerve terminals via tyr transporter, and converted to DOPA by TOH (tyrosine hydroxylase), which is converted to DA by DDC (DOPA decarboxylase)
what are DA receptors?
G protein receptors that function to activate transcription factors to turn on or off other genes within a neuron
how is dopamine terminated?
DA is removed from synapse by the DAT
-destroyed in neuron by MAO A/B
-destroyed in synapse by COMT
what are the 5 dopamine pathways we should be aware about?
1. nigrastriatal (SN to striatum) controls movement
2. mesolimbic (tegmentum to nucleus accumbens) controls reward and perception
3. mesocortical (tegmentum to DLPFC and VMPFC) controls executive function
4. tuberoinfundibular (hypothalamus to pituitary) controls pituitary prolactin function
5. thalamic (midbrain to thalamus) controls unknown
describe the nigrastriatal dopamine pathway?
projects from SN to basal ganglia (striatum)
-part of extrapyramidal nervous system
-controls motor function and mvoement
describe the mesolimbic dopamine pathway?
projects from midbrain ventral tegmental area to nucleus accumbens
-involved in pleasurable sensations, powerful euphoria of drugs of abuse, and delusions and hallucinations of psychosis
describe the mesocortical dopamine pathway?
projects from midbrain ventral tegmental area to prefrontal cortex
-mediates cognitive symptoms via DLPFC (dorsolateral prefrontal cortex; hypoactive in schizophrenia)
-mediates affective symtoms via VMPFC (ventromedial prefrontal cortex; hyperactive in schizophrenia)
describe the tuberoinfundibular dopamine pathway?
projects from hypothalamus to anterior pituitary gland and controls PRL secretion
describe the thalamic dopamine pathway?
arises from multiple sites (periaqueductal gray, ventral mesencephalon, hypothalamic nuclei, lateral parabrachial nucleus) projecting to thalamus
-function not currently known
what does hyper VS hypofunctioning in the mesolimbic pathway cause?
hyper: addiction, hallucinations
hypo: amotivation, apathy
what does hyper VS hypofunctioning in the mesocortical pathway cause?
what does hyper VS hypofunctioning in the nigrostriatal pathway cause?
hyper: dyskinetic movement
hypo: dyskinetic movement, parkinsonism
what does hyper VS hypofunctioning in the tuberoinfundibular pathway cause?
what are the usual "extremes" of dopamine activity?
low = distractible (ADHD)
high = hypervigilant (PTSD)
what is levodopa? its dosing?
precursor for DA that can cross BBB
-promotes better movement of Parkinson's patients by improving nigrostriatal functioning
-if too low dose, won't work; if too high, can cause dyskinetic movement and hallucinations
-effect wears off in 15-30 years with even worse symptoms, so use as a last resort
what is carbidopa?
DA enhancer combined with levodopa to prevent peripheral dopamine activity (lowers side effects: fatigue, dizziness, nausea)
what are the side effects of levodopa?
at its worst (too much DA)
how can the 1 carbon cycle affect depression?
L-methylfolate and S-adenosyl methionine are metabolites of this cycle, cross the BBB, and allow DA neurons to make more DA
what are side effects of 1CC drugs? what about genetics? complimentary alternative medicine?
none, except maybe GI upset
-if you inherit TT alleles for MTHFR enzymes, you make less DA
-CAM can cause decreased effectiveness or purity
what is bupropion (XL) antidepressant? How does it work?
NE-D reuptake inhibitor (NDRI)
-blocks dopamine transporter (DAT; AKA dopamine reuptake inhibitor DRI)) to leave more DA in synapse, increasing mesocortical pathway
-not as addictive as stimulants, or as aggressive as levodopa
what are side effects of bupropion?
NE-related sympathetic stimulation: insomnia, jitteriness, hypervigilance, seizures, dry mouth, sweating, palpitations, mild increases in BP
what are amphetamines? how do they work?
stimulants to treat ADHD (dextroamphetamine, mixed amphetamine salts, disdexamfetamine)
-block DAT like bupropion, even reversing it
-increase vesicular monoamine transport (VMAT2), ejecting more DA from nerve terminals
what are methylphenidate products?
stimulants to treat ADHD
-block DA transporter
-more aggressive and more throughout the brain than bupropion
how do side effects compare between stimulants and bupropion NDRI?
stimulants are more addictive, but work better, and have greater DA and NE-releated side effects
what are modafinil and armodafinil? what are they used for? side effects?
isomer stimulants that have different mechanisms of action
-class IV addictive drugs, instead of normal class II
-approved for fatigue due to narcolepsy, apnea, shiftwork, but not ADHD
-carry less severe but similar side effects to other stimulants
--may increase p450-2A4 enzymes, thus lowering birth control effectiveness
mechansim of action of modafinil/armodafinil?
theoretically increase histamine activity in tuberomammilary nucleus (TMN), thus activating alertness in frontal cortex
-increase orexin activity (unique)
-requires operating DAT system and may block this reuptake pump
-may manipulate noradrenergic receptors post synaptically
what are side effects of stimulants?
create more DA and NE (via DAT and NET blockade) activity in cortex (moreso than NDRI) and in mesolimbic pathways (reward center; addiction problem)
-at super high doses, psychosis can occur
-at moderate doses, appetite and weight loss can occur
-at any dose, patients may get NE and D side effects
what do MAOi do generally?
irreversibly inhibit MAO A/B within neuron, allowing for DA, serotonin, and NE build-up
how does selegiline work?
MAO-B inhibitor at low dose (Parkinson's)
full MAO A/B inhibitor at high dose (depression)
how does rasagiline work?
MAO-B inhibitor for Parkinson's
which MAOi are selective MAO-B inhibitors? what do they treat?
selegiline (at low doses) and rasagiline treat Parkinson's
-more relevant for DA
which MAOi are non-selective MAO A/B inhibitors? what do they treat?
selegiline (full dose), isocarboxazid, phenelzine, tranylcypromine for depression
what are MAOi side effects?
cause hypotension, dizziness, insomnia, weight gain; stroke is very rare
-MAO-A inhibitors interfere with serotonin or NE breakdown, allowing for drug-drug interactions that may be life-threatening
what is the importance of Cg25 activity in depressed people?
there is increased activity, causing hyperactive sadness/depression
what is the hypertensive crisis?
usually, drugs that increase NE additively increase BP (but not crisis)
-adding any food source that contains tyramine may cause immediate release of NE stores, creating hypertensive crisis that can result in heart attack or stroke
-MAO-A is used to break down tyramine, which is in spoiled meat, marmite, pickled herring, peels, fava beans, smoked meats, aged cheese, tofu, etc
what is serotonin syndrome?
as MAOi inhibit breakdown of serotonin in CNS, adding aggressive serotonin drug (many antidepressants, narcotic pain meds, antihistamines) can create toxic levels of CNS serotonin
-tremor, muscle spasm, increased/decreased vitals, hyperthermia, delirium, coma, death
what are COMTi? where are they used? what are examples and side effects?
inhibitors of catechol-o-methyltransferase
-inhibition causes elevated DA and NE
-used to treat Parkinson's patients
-entacapone: cause nausea, fatigue
-tolcapone: cause liver failure
explain what phasic DA paths are? what do they treat? what are examples?
rapidly fluctuating (undulate instead of peaks/trough); after doing something that feels good and is rewarding (mesolimbic)
-D2 receptor agonism increases DA activity in treating Parkinson's or restless leg syndrome
-bromocriptine, pramipexole, ropinerole, apomorphine injections
--nausea, fatigue, dizziness, mania are typical side effects
explain what tonic DA paths are?
gradual DA fluctuations, usually through D3
-if D3 activity lowers, you get tired; if high, you are awake
what is aripiprazole?
antipsychotic for schizophrenia, but also approved to treat depression
-partial agonist at D3 (promotes alertness, energy) and D2
--30% activity when receptor is bound, so useful if own DA is low
what is amantadine?
antiviral used to treat Parkinson's and Influenza
-theorized to release DA from terminal vesicles, block DAT, and stimulate D2 receptors
-nausea, dizziness, psychosis, insomnia, and seizures are possible side effects
when would you want to increase DA activity versus decreasing it?
increase: Parkinson's, depression, restless leg syndrome, narcolepsy, ADHD
decrease: schizophrenia in mesolimbic pathway to lower hallucinations and delusions
what is reserpine? what is it used for? mechanism?
synapse depleter used for hypertension
-blocks VMAT so that vesicles with monoamines cannot be released into synapses (opposite of stimulants)
-less NE --> more depression, decreased BP
-less DA --> more depression, less psychosis
what is tetrabenazine? what is it used for? mechanism?
synapse depleter used for Huntington's chorea
-lowers DA availability (VMATi) in synapse to lessen choreic movements
what are D2 receptor antagonists?
-divided into first generation (typical) and 2nd generation (atypical) antipsychotics (FGAs and SGAs)
what are high potency FGAs? mechanism?
haloperidol, fluphenazine, thiothixine
-have high affinity for D2 receptor antagonism, and only require a few mg of drug to occupy 60% of D2 receptors to alleviate psychosis
-very selective and have few side effects outside of those from lowering D2 activity
-blocking D2 in mesolimbic pathway alleviates psychosis by returning this pathway from high DA activity back to normal
-blocking D2 activity in nigrostriatal pathway causes abnormally low DA acctivity and extrapyramidal side effects (EPS) to occur --> Parkinsonism
what are high potency FGA side effects?
1. extrapyramidal syndromes (EPS) occur when DA activity is forced too low
-akathisia = restlessness
-dystonia = muscle spasm
-Parkinsonism = identical to Parkinson's, but is reversible
-neuroleptic malignant syndrome (NMS)
define what FGAs are and their potency?
first generation antipsychotics (D2 receptor antagonism)
-high potency agents and low potency agents
what is neuroleptic malignant syndrome (NMS)?
-vital sign instability
how are anticholinergic drugs used in Parkinson's disease?
inhibiting cholinergic tone in the basal ganglia improves dopaminergic flow in the nigrostriatal pathway, thus lowering Parkinson's symptoms
-somewhat effective in early disease, but very effective in Parkinsonism EPS caused by FGA/SGA
what are anticholinergic drugs you can use in Parkinson's disease or parkinsonism? side effects?
benztropine, trihexyphenadyl, diphenhydramine
-ASE: dry mouth, blurred vision, tachycardia, constipation, confusion, delirium, hallucinations
what is tardive dyskinesia?
chronic D2 receptor antagonism may cause permanent movement disorder of the face
-choreic movements are fast, quirky
-athetotic movements are slow, writhing
--pushing DA too high (with levodopa) or too low causes dyskinesia
what are low potency FGAs? mechanism?
-low affinity for D2 antagonism and require more mg of drug to provide antipsychotic effects
-antagonize D2, but are "messy" or "multifactorial" as they also manipulate other receptors associated with side effects
what are side effects of low potency FGA?
1. D2 receptor antagonism --> EPS
2. histamine 1 receptor antagonism
-fatigue and increased appetite/weight
3. anticholinergic muscarinic antagonism
-dry mouth, blurred vision, constipation
4. a1 receptor antagonism
between high and low potency FGA drugs, which are more prone to EPS?
high potency are more prone to EPS, while low potency are more prone to anticholinergics
what are SGA mechanisms of action?
-D2 receptor antagonism --> improves psychosis, mania (in bipolar), aggression (n autism)
-5HT2c/3/7 antagonism, SRI and NRI properties --> help depression
-5HT2a antagonism --> lessens EPS risks
--greater blocking of DA in mesolimbic system while allowing better transmission in all other DA pathways (improving selectivity compared to FGA
-5HT1a antagonism --> help anxiety
what are the classes of SGA drugs?
'dones --> risperidone, paliperidone, ziprasidone, iloperidone, lurasidone
'rips --> aripiprazole (actually is partial agonist at D2/3 receptors)
'pines --> olanzapine, quetiapine (XR), asenapine, clozapine (antagonizes D1/4 receptors too)
what are the general side effects for the "dones" class of SGA drugs?
possibly more EPS, but less metabolic side effects (as opposed to pines)
what are the general side effects for the "pines" class of SGA drugs?
-more sedating due to more antihistamine activity
-more metabolic syndrome inducing, so cannot give to diabetic or overweight patients
what are side effects for SGA?
each SGA has a very unique pharmacodynamic profile
-D2 antagonism, anticholinergic properties, H1 antagonism, a1 antagonism = same side effects as FGA
-5HT2c antagonism: slow metabolism, desensitize leptin system allowing weight gain, increase cholesterol and blood glucose
-5HT1a partial agonism, 5HT3/7 antagonism: serotonin activity --> headaches, GI problems, insomnia, anxiety
-SRI/NRI properties --> lesser, but similar to SSRI antidepressants = headache, GI problems, insomnia, anxiety
what are the precautions and boxed warnings of SGA?
-suicide risk in ages < 25
-metabolic syndrome (diabetes, hyperlipidemia, hypertension, obesity)
-stroke in dementia (esp. Alzheimer's) patients