ADHD

Question 1

impulsivity is hypothesized to be linked to?

Answer 1

Orbito-frontal Corte

Question 2

hyperactivity is hypothesized to be linked to?

Answer 2

supplementary motor cortex

Question 3

What is tonic firing?

Answer 3

baseline firing pattern

Question 4

What is the mechanism that causes ADHD

Answer 4

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

Question 5

What is phasic firing

Answer 5

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

Question 6

Modest levels of norepinepherine stimulate….

high levels of norepinepherine stimulate…. (which does what)

Answer 6

modest: alpha2A receptors

high levels: alpha1 and beta1 receptors -> this interferes with working memory

Question 7

Modest levels of dopamine stimulate….

high levels of dopamine stimulate….

Answer 7

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

Question 8

Is ADHD caused by too much DA and NE levels in the frontal lobe or not enough?

why?

Answer 8

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

Question 9

What is the argument for treating ADHD early?

Answer 9

to avoid secondary stress reactions caused by the symptoms

Question 10

What is the argument for treating ADHD early?

Answer 10

to avoid secondary stress reactions caused by the symptoms

Question 11

what happens if you enhance NE to the right level?

what about dopamine
?

Answer 11

increase the signal of information coming in from the environment to pyramidal cells

reduces noise/stimulation from the environment that isn’t releant

Question 12

What is typically used as first like treatment for ADHD in kids?

Adults?

Answer 12

Kids = stimulants

adults = non stimulants

Question 13

What are the 2 classes of drugs used to treat ADHD

Answer 13

Stimulants (methylphenidate and amphetamine)

NE increasing agents (atomoxetine and alpha-2A
adrenergic agonists)

Question 14

What is the mechanism of action of Methylphenidate?

Answer 14

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)

Question 15

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?

Answer 15

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

Question 16

What are important comorbidities to consider when prescribing drugs for ADHD?

Answer 16

tic disorders

anxiety

substance use

mania and/or psychosis

Question 17

What is the mechanism of action of Amphetamine (Adderall)?

what is problematic about this?

Answer 17

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

Question 18

What drug was created to prevent amphetamines from being abused?

how does it work?

Answer 18

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

Question 19

What is more important in stimulants: pharmacokinetics or pharmacodynamics?

Answer 19

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

Question 20

What type of drug is strattera?

How/why does it work

what is an advantage

Answer 20

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

Question 21

What is a second line drug treatment for ADHD

How/why does it work?

Answer 21

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

Question 22

What are the 2 main Alpha-2A adrenergic agonists

Answer 22

Two main drugs that are direct acting agonists:
– Guanfacine (Intunivtm)
– Clonidine (Cataprestm)

Question 23

What type of patients would benefit most from Alpha-2A adrenergic agonists

Answer 23

may be especially helpful for oppositional patients

Question 24

What were Alpha-2A adrenergic agonists initially developped to treat?

Answer 24

decrease blood pressure -> need to be careful