Lectures 1 &2-CNS I & II Flashcards
State the mechanism of how Tyrosine turns into Dopamine .
Tyrosine–>DOPA–>Dopamine
True/ false: Dopamine is a stimulatory monamine neurotransmitter
True
Dopamine receptors on the postsynaptic membrane are?
G protein coupled receptors
After synthesis, dopamine is packaged into synaptic vesicles via the vesicular monoamine transporter _____ and stored there until its release into the synapse during neurotransmission.
VMAT2
Dopamine (DA) is removed from the synapse by the dopamine transporter (DAT). It can be destroyed inside the presynaptic neuron by ______. DA can be destroyed in the synapse by _____. (These can be targets of drugs).
monoamine oxidase (MAO) A/B;
catechol-o-methyltransferase (COMT)
State the 5 dopamine pathways in the brain & their general function:
Nigrastriatal- controls movement
Mesolimbic- controls reward and perception
Mesocortical -controls executive function
Tuberoinfundibular- controls pituitary prolactin function
Thalamic- ??
State the major functions of the nigrostriatal dopamine pathway.
(a) The nigrostriatal dopamine pathway, which projects from the substantia nigra to the basal ganglia or striatum, is part of the extrapyramidal nervous system and controls motor function and movement.
State the major functions of the mesolimbic dopamine pathway.
(b) The mesolimbic dopamine pathway projects from the midbrain ventral tegmental area to the nucleus accumbens, a part of the limbic system of the brain thought to be involved in many behaviors such as pleasurable sensations, the powerful euphoria of drugs of abuse, as well as delusions and hallucinations of psychosis.
State the major functions of the mesocortical dopamine pathway.
(c) A pathway related to the mesolimbic dopamine pathway is the mesocortical dopamine pathway. It also projects from the midbrain ventral tegmental area but sends its axons to areas of the prefrontal cortex, where they may have a role in mediating cognitive symptoms (dorsolateral prefrontal cortex, DLPFC) and affective symptoms (ventromedial prefrontal cortex, VMPFC) of schizophrenia.
State the major functions of the tuberoinfundibular dopamine pathway.
(d) The fourth dopamine pathway of interest, the tuberoinfundibular dopamine pathway, projects from the hypothalamus to the anterior pituitary gland and controls prolactin secretion.
Hyperfunctioning in the Mesolimbic pathway gives
addiction, hallucinations
Hyperfunctioning in the Mesocortical pathway gives
hypervigilance
Hyperfunctioning in the Nigrostriatal pathway gives
dyskinetic movement
Hyperfunctioning in the Tuberoinfundibular pathway gives
hypoprolactinemia
Hypofunctioning in the Mesolimbic pathway gives
amotivation, apathy
Hypofunctioning in the Mesocortical pathway gives
inattention
Hypofunctioning in the Nigrostriatal pathway gives
dyskinetic movement, parkinsonism
Hypofunctioning in the Tuberoinfundibular pathway gives
hyperprolactinemia
What is Levodopa? What disease is it used in? What happens if it is dosed too high?
A dopamine enhancing drug used in Parkinsons (low dopamine). Levodopa-
Is the precursor to DA and crosses blood-brain barrier (BBB).
Once in CNS it is converted to DA and can promote better movement by improving nigrostriatal functioning.
If dosed too high can create dyskinetic movement, hallucinations.
What is Carbidopa? What disease is it used in?
Carbidopa is an agent often combined with levodopa in Parkinson’s as it prevents peripheral dopamine activity and lowers fatigue, dizziness, nausea. It is an anti side effect drug.
State the side Effects of levodopa.
Overdosing = too much DA:
Psychosis, mania
Dyskinesia- abnormal, involuntary movements
Average side effects:
Hypotension, syncope
Nausea
Anxiety/agitation
Fatigue
What do l-methylfolate or s-adenosyl methionine do?
l-methylfolate & s-adenosyl methionine raise dopamine levels!
Some Depression is considered a low DA state where patients are amotivated and see no reward or enjoyment in life. By prescribing l-methylfolate or s-adenosyl methionine we can increase the 1 carbon cycle and allow DA neurons to make more DA, thus improving the patient’s apathy
l-methylfolate & s-adenosyl methionine side effects?
None, perhaps GI upset
What is bupropion(XL)?
A Norepinephrine-Dopamine Reuptake Inhibitor (NDRI)
It is an antidepressant
bupropion(XL) side effects?
Side effects include insomnia, jitteriness/hypervigilance, seizures all due to increased DA.
Any time we increase activity of norepinephrine via drugs-
think sympathetic stimulation like:
Fight flight = Insomnia, anxiety, agitation, nausea, dry mouth, sweating, palpitations, mild increases in blood pressure
Describe the pharmacological mechanism of Amphetamines and Methylphenidate products, and butropion.
Amphetamines like (dextroamphetamine, mixed amphetamine salts, lisdexamfetamine) block the DAT uptake and even reverse it so that the presynaptic neuron dumps out all of its DA.
Methylphenidate products block the DA transporter only, but way more agressivley than bupropion.
Stimulants like Amphetamines and Methylphenidate products are stronger stimulants than bupropion that only blocks DAT uptake .
Dextroamphetamine, mixed amphetamine salts, lisdexamfetamine are
Amphetamines
Side effects of Stimulants like Amphetamines or Methylphenidate products?
Fight flight = Insomnia, anxiety, agitation, nausea, dry mouth, sweating, palpitations, mild increases in blood pressure
Modafinil/Armodafinil has the most mechanisms of action and does ____ rely as heavily on the dopamine transporter, but still gives you a _____ effect (they are not true stimulants).
not; stimulant
______/_____ are approved for fatigue due to narcolepsy, apnea, shiftwork, but not ADHD.
Modafinil/Armodafinil
Modafinil/Armodafinil carry less severe but similar side effects to other stimulants and may increase (induce) _____ enzymes, _______ birth control effectiveness*
p450-3A4; lowering
Modafinil/Armodafinil mechanism of action:
Theoretically increases histamine activity in the ______ nucleus (TMN), thus activating ______ in the frontal cortex
Also, may increase _____ activity
Requires an operating DAT system and may block this reuptake pump…
May actually also manipulate noradrenergic receptors post synaptically
tuberomammilary; alertness; orexin;
Stimulant side effects:
As these drugs create more dopamine (DAT blockade etc) and norepinephrine (NET blockade) activity in the cortex (more so than bupropion) AND in the ______ pathways (reward center), ______ is now a problem
At super high doses, psychosis can occur
At moderate doses appetite and _____ loss can occur
At any dose, patients may get norepi and dopamine side effects
mesolimbic; addiction; weight
What is monoamine oxidase and what do MAO inhibitors do?
Monoamine Oxidase Enzymes (A and B) are responsible for breaking down Dopamine (and other monoamines like norepinephrine and serotonin).
MAO inhibitors are drugs that irreversibly inhibit MAO-A/B generally within the neuron allowing a build up of DA (serotonin and norepi too) because it cannot be broken down.
What is Selegiline? @ low dose what dose it inhibit/ what condition? @ high dose what does it inhibit/ what condition?
Selegiline (MAO-B inhibitor at low dose) for Parkinson’s or Depression (full MAO A+B inhibition at high dose)
What is Rasagiline & what does it inhibit/ what condition?
Rasagiline (MAO-B inhibitor) for Parkinson’s
NOTE: Selegiline & Rasagiline work primarily on MAO-B which is more relevant for DA
Isocarboxazid, phenelzine, tranylcypromine, selegiline (MAO A + B inhibition at high dose) treat what disease?
Depression
lisdexamfetamine is a prodrug that turns into ________.
lisdexamfetamine is a prodrug that turns into amphetamine.
Monoamine B is ________ enhancing only (what disease?) & monoamine A does ________.
Monoamine B is dopamine enhancing only (Parkinsons) & monoamine A does dopamine, seritonine, and norepi.
What are MAOi side effects (4)?
hypotension*, dizziness, insomnia, weight gain
How does someone taking an MAOi-A get a stroke or MI?
They eat something with tyramine in it.
What is a tyramine hypertensive crisis?
Adding any food source that contains tyramine to someoke taking an MAO-A inhibitor may cause an immediate release of NE stores, creating a hypertensive crisis that can result in heart attack or stroke.
What is the Serotonin Syndrome?
It occurs when someone taking an MAOi takes an aggressive serotonin drug, which amplifies the already high levels of serotonin.
Symotoms include: Tremor, muscle spasm, increasing or decreasing vitals, hyperthermia, delirium, coma, death.
What are the 2 COMT inhibitors (catechol-o-methyltransferase)? Side effects? What disease do they treat?
Entacapone- may cause nausea, fatigue side effects
Tolcapone- liver failure too
They treat Parkinsons.
Parkinsons meds have fatigue-like side effects
Bromocriptine, Pramipexole, Ropinerole, & Apomorphine injections are what kind of drugs? What are the side effects?
D2 receptor agonists
Nausea, fatigue, dizziness, mania typical side effects for all
Discus how you would use levodopa and D2 agonists together in treating a parkinsons patient.
So for Parkinsons, we do not want to treat with Levodopa right away because there will be problems in 10 yrs because the drug stops working and you get more dyskenesias.
We save Levodopa for last, best for last. Instead we give D2 receptor agonists until then, they turn on the dopamine 2 receptor, which allows a more constant background of dopamine activity. It delays the need for Levodopa.
What type of drug is Aripiprazole? What does it treat?
D3 partial & D2 partial agonist.
It treats schizophrenia & depression
What type of drug is Amantadine? What does it treat? Side effects?
It is a weak prodopaminergic, blocks DAT, and stimulate D2 receptors.
Is used to treat Parkinson’s and Influenza*
Nausea, dizziness, psychosis, insomnia, seizures are possible side effects
We would want to _______ DA activity in Parkinson’s, Depression, Restless Legs, Narcolepsy , ADHD in order to normalize these DA pathways
We would want to _____ DA activity in schizophrenia in the mesolimbic pathway to lower hallucinations and delusions.
increase; decrease
What does Reserpine do?
Is used for hypertension, it blocks VMAT so that vesicles with monoamines cannot be released into synapses. (opposite of stimulants perhaps). Thus, it decreasesdopamine. Can make people depressed & suicidal.
What does Tetrabenazine do? What disease does it treat?
Is used to for Huntington’s Chorea
newer VMAT inhibitor
By decreasing DA availability (VMATi) in the synapse, choreic movements lessen
First generation or ______ antipsychotics = FGA’s are D2 receptor antagonists.
2nd generation or _______ antipsychotics = SGA’s are D2 receptor antagonists.
Both treat ________.
typical; atypical; Schizophrenia
First generation (FGA) or typical antipsychotics are high potency and block the ____ receptor.
Blocking D2 in the mesolimbic pathway alleviates psychosis by returning this pathway from ______ DA activity back to normal.
Blocking D2 activity in the nigrostriatal pathway causes abnormally low DA activity and extrapyramidal side effects (EPS to occur)–This creates drug induced ________!
D2; high; PARKINSONISM
Describe the FGA High Potency Side Effects
***Extrapyramidal Syndromes (EPS) occurs when DA activity is forced too low: Akathisia = restlessness Dystonia = muscle spasm Parkinsonism= identical to Parkinson’s Disease but is reversible & Neuroleptic Malignant Syndrome (NMS): -Hyperthermia -Muscle rigidity -Vital sign instability -Rhabdomyolysis*/ renal failiure
Some of the oldest medications for Parkinson’s Disease are the cholinergic muscarinic receptor ________
Remember that inhibiting cholinergic tone in the basal ganglia ________ dopaminergic flow/tone in the nigrostriatal pathway- thus lowering Parkinson’s symptoms.
These drugs are somewhat effective in early Parkinson’s disease but very effective in Parkinsonism ________ Syndromes caused by the FGA/SGA, especially dystonias
antagonists (anticholinergics); improves; Extrapyramidal
What class of drugs are these: Benztropine, trihexyphenadyl, diphenhydramine? Side effects?
Anticholinergics
Anticholinergic side effects include: dry mouth, blurred vision, tachycardia (racing heart), constipation, confusion, delirium, hallucinations
What is tardive dyskenesia & what causes it?
Chronic D2 receptor antagonism may cause permanent movement disorder called TD due to “growth” of hypersensitive D2 receptors. This causes a permanent movement disorder.
Choreic Movements are fast, quirky in nature (especially around the face)
First generation high potency antipsychotics cause this.
High potency FGA hits D2 hard and give a lot of ____, low potency FGA hit D2 less hard but give more _____ side effects like fatigue (______), dry mouth and constipated (______), and orthostasis (a1 ______).
EPS; diverse; antihistamine; anticholinergic; a1 antagonist
Haloperidol, Fluphenazine, Thiothixine are _______ potency FGA antipsychotic drugs
high
Chlorpromazine & Thioridazine are _____ potency FGA antipsychotic drugs
low
The second generation antipsychotics also do D2 receptor antagonism which treats psychosis like FGAs, but the SGAs also block the Serotonin ___ receptor, which lessens ____ risks.
SGAs allow greater blocking of DA in the mesolimbic system, while allowing better transmission in all other DA pathways (improving selectivity compared to FGA). It keeps _____ DA in the nigrostriatal system.
2a; EPS; more
What are these? Side effects?
Risperidone Paliperidone Ziprasidone Iloperidone Lurasidone
SGA antipsychotics, called the “dones”; Possibly more EPS
What are these? Side effects?
Olanzapine
Quetiapine (XR)
Asenapine
Clozapine (Antagonizes D4 and D1 receptors too_
SGA antipsychotics, called the “dones”; More sedating due to more antihistamine activity & More metabolic syndrome (fattening) inducing as well
What is this? Side effects?
Aripiprazole
SGA antipsychotic, Actually is a partial agonist at D2 and D3 receptors
What are some SGA FDA Precautions/Boxed Warnings ?
Suicide risk in ages <25
Metabolic Syndrome
Diabetes, Hyperlipidemia, Hypertension, Obesity
TD/EPS
Stroke in dementia patients
What is Clozapine ? When is it used? What does it antagonize? What are the major side effects? What is the benefit of using Clozapine?
Clozapine is the original ‘atypical’ antipsychotic and used for refractory schizophrenia
Clozapine Antagonizes D2 and 5HT2a (setotonin 2a). Also antagonizes D1 and D4 (more DA blocking)
Clozapine is the most effective antipsychotic
Risk of agranulocytosis (Requires WBC and ANC monitoring)
Most metabolic risk of any agent
Little to zero EPS/TD
