ADHD Flashcards
impulsivity is hypothesized to be linked to?
Orbito-frontal Corte
hyperactivity is hypothesized to be linked to?
supplementary motor cortex
What is tonic firing?
baseline firing pattern
What is the mechanism that causes ADHD
it is the result of inefficient activation of various prefrontal areas
- there is supposed to be a baseline level of tonic firing, but this is not happening as it should be because it requires a certain level of norepinepherine and dopamine
What is phasic firing
A type of firing that occurs on top of the basline tonic firing, so it’s a type of increase in firing that can promote learning and reward
Modest levels of norepinepherine stimulate….
high levels of norepinepherine stimulate…. (which does what)
modest: alpha2A receptors
high levels: alpha1 and beta1 receptors -> this interferes with working memory
Modest levels of dopamine stimulate….
high levels of dopamine stimulate….
modest: D1 and D3 receptors
high: overstimulate D1 and recruit D2 receptors in the frontal lobe
- > results in too much phasic firing and compulsive types of behaviours
Is ADHD caused by too much DA and NE levels in the frontal lobe or not enough?
why?
Too low in childhood (tonic too low)
Too high in adolescence and adulthood (increase in phasic due to stress, phasic is too high)
Beacuse ADHD symptoms are stressful for kids which leads to an over release of DA and NE -> which results in over stimulation later on
What is the argument for treating ADHD early?
to avoid secondary stress reactions caused by the symptoms
What is the argument for treating ADHD early?
to avoid secondary stress reactions caused by the symptoms
what happens if you enhance NE to the right level?
what about dopamine
?
increase the signal of information coming in from the environment to pyramidal cells
reduces noise/stimulation from the environment that isn’t releant
What is typically used as first like treatment for ADHD in kids?
Adults?
Kids = stimulants
adults = non stimulants
What are the 2 classes of drugs used to treat ADHD
Stimulants (methylphenidate and amphetamine)
NE increasing agents (atomoxetine and alpha-2A
adrenergic agonists)
What is the mechanism of action of Methylphenidate?
Blocks reuptake transporters for NE and DA (NET and DAT)
through Allosteric binding
(meaning it binds at a site other than the active site and changes the shape/affinity of the receptor, this meants that no drug is taken up in to presynaptic neuron)
If it is hypothesized that in adulthood ADHD results from a high level PHASIC of DA and NE due to stress, why do we prescribe drugs that increase DA and NE?
In childhood the low NE and DA is low tonic firing, this results in stress which results in high levels of phasic firing and high levels of NE and DA
- they then become depleted and it’s harder to replace them, so the stimulant medications returns the baseline tonic functining to normal
- which prevents the overrelease and depletion of NE and DA with phasic firing
What are important comorbidities to consider when prescribing drugs for ADHD?
tic disorders
anxiety
substance use
mania and/or psychosis
What is the mechanism of action of Amphetamine (Adderall)?
what is problematic about this?
Competitively inhibits the transporters for NE and DA (NET and DAT)
*Main activity is through dopamine
meaning it binds at the same site as NE and DA
it also inhibits the vassicular monamine transporter so NE and DA can’t be repackaged, which displaces dopamine and can result in a LOT more in the synapse
if you take it in very high doses (or though a different route e.g., smoking it) would
result in very high levels of DA (result in phasic firing) which can make it a drug of abuse
What drug was created to prevent amphetamines from being abused?
how does it work?
Vyvanse
The drug is bonded to l-lysine and NEEDS oral administration to result in the drug effect, if you snort it or put it into the blood stream it won’t be effective because it needs to go through first pass metabolism first
What is more important in stimulants: pharmacokinetics or pharmacodynamics?
Pharmacokinetics (what the body does to the drug) is almost more important pharmacodynamics
issue is you want a slow steady release of the effective dose, incomplete saturation and long lasting
What type of drug is strattera?
How/why does it work
what is an advantage
SNRI
blocks reuptake of NE
BUT there actually aren’t a lot of DA transporters in the prefrontal cortext so often the NE transporters will also do reuptake of DA, so if we block NET we end up with both more NE and more DA in the synapse
there are few NE neurons nucleus accumbens (reward center) which reduces the potential for abuse
AND
because it was originally put on the market for people with depression it might also help with comorbid mood disorders or stress
easier to take because has longer dutation of action
BUT you need to take it for a while (several weeks) before you get the effect
What is a second line drug treatment for ADHD
How/why does it work?
Alpha-2A-adrenergic agonists
Alpha-2A receptors are highly concentrated in locus coeruleus and cortex (but low in the nucleus accumbens)
these receptors mediate the effects of NE on prefrontal cortex
Low to moderate concentrations of NE will stimulate alpha-2A receptors resulting in improved cognition
What are the 2 main Alpha-2A adrenergic agonists
Two main drugs that are direct acting agonists:
– Guanfacine (Intunivtm)
– Clonidine (Cataprestm)
What type of patients would benefit most from Alpha-2A adrenergic agonists
may be especially helpful for oppositional patients
What were Alpha-2A adrenergic agonists initially developped to treat?
decrease blood pressure -> need to be careful
