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Pharmacology of ADHD
Terms in this set (30)
What is the suggested neurobiological basis for ADHD?
Structural changes in the basal ganglia, reduction in number and volume of dopaminergic receptors, and/or reduced functioning in the pre-frontal cortex and limbic regions.
To which receptor do drugs that treat ADHD by increasing levels of NE bind?
α2A, in the pre-frontal cortex
To which receptor do drugs that treat ADHD by increasing levels of dopamine bind?
D1, in the pre-frontal cortex
The balanced increase in neurotransmitters that is the goal of ADHD pharmacotherapy achieves what?
To improve the "signal to noise" ratio and improve communication between the pre-frontal cortex and the basal ganglia, which is thought to underlie executive function, attention and the ability to exercise inhibition.
What type of drugs are the DOC for school aged children and adolescents with ADHD?
Stimulants. They stimulate the CNS and the sympathetic division of the ANS.
What are the main stimulants used to treat ADHD?
l-amphetamine, d-amphetamine (Adderall)
Methylphenidate (Ritalin immediate release)
-Metadata and Concerta (once daily)
How do stimulants work?
-Stimulants of the CNS and sympathetic branch of ANS
-Orally active and cross BBB
Main action is to increase the synaptic concentrations of NE and/or DA
-Increases of NE and DA at therapeutic doses (subeuphoric) in the pre-frontal cortex improve cognition
-65-75% effective at improving hyperactivity, inattentiveness, and impulsivity in children
What is the ideal dosing regimen for stimulants?
To increase tonic NE and DA in the PFC, which involves having a
sub-saturating concentrations (targeting α2A and D1 receptors)
over an extended period of time, while
avoiding higher concentrations in the nucleus accumbens (D2 receptors)
* which can contribute to abuse.
What are the amphetamines and how do they work?
Amphetamine, Dextroamphetamine (Adderall), lisdexamphetamine (Vyvanse)
Work by increasing the
release of DA and NE
via 2 mechanisms:
1) Reduced reuptake
2) Increased non-vesicular release through the plasma membrane transporters (reverse transport)
Amphetamines bind competitively to the norepinephrine transporter (NET) and the dopamine transporter (DAT), and serotonin transporter to a lesser extent, resulting in
decreased reuptake of endogenous DA and NE
"No, you can't have my catecholamines back! I neeeeeed them!"
What is the relationship between amphetamines and MAO?
Amphetamines compete for binding to MAO, therefore inhibiting the degradation of NE and DA. The accumulation of DA and NE causes the vesicular monoamine transporters (VMATs) to work in the opposite direction, pumping DA and NE out of the cell and into the synapse (reverse transport).
If I had more time to care, I would think that this is cool as shit.
What underlies the addictive properties of amphetamines?
The actions on DA terminals in the nucleus accumbens (D2) --> euphoria.
The d-isomer (dextroamphetamine, Dexedrine) is 3-4 times more potent for what transporter?
Is the l-isomer of amphetamine more potent for DAT or NET?
Neither, it is equipotent and has no preference. It's "meh".
How is Lisdexamfetamine different from dextroamphetamine?
Vyvanse is a
prodrug that is converted to dextroamphetamine
. It is taken once daily. The idea is to increase the therapeutic window and reduce adverse effects.
The stimulant effects of amphetamines differ how in the CNS vs the periphery?
CNS --> effects due to increased dopaminergic activity
Periphery --> effects due to increased NE release (adrenergic activity)
What are the peripheral (sympathetic) effects of amphetamines?
Increased systolic and diastolic blood pressure which can cause a reflex reduction in heart rate.
Can amphetamines be given with MAOIs?
NO! This will result in massive increases of peripheral norepinephrine which could cause hypertensive crisis and death.
How do methylphenidate and dexmethylphenidate differ from amphetamines?
They block reuptake of dopamine and norepinephrine at central synapses primarily in the brainstem arousal system and the cerebral cortex. They bind
allosterically (non-competitively) to DAT and NET and inhibit its function
so DA and NE are not taken up into the presynaptic terminal which leads to an increase in synaptic concentrations.
Methylphenidate is also used for narcolepsy.
Methylphenidate is recommended for which age group, over amphetamines?
Preschool aged children. Best not to give them the crack too young.
Does methylphenidate have the same peripheral effects as amphetamines?
No. While it causes the same degree of CNS stimulation, it does not increase motor activity and does not increase peripheral catecholamines, so it is less likely to cause cardiovascular stimulation (another reason it is preferred over amphetamines in preschool aged children).
What is dexmethylphenidate?
Focalin is the d-isomer of methylphenidate, which is more potent and requires a lower dose with potentially fewer side effects.
What are the adverse effects of stimulants?
Insomnia, ab pain, anorexia, headache, sadness and irritability.
Growth suppression and the precipitation or exacerbation of tics, tachycardia and changes in blood pressure.
Why is there a risk of worsening pre-existing psychosis in a patient taking stimulants?
Because of the dopaminergic actions of stimulants. Remember the dopamine theory of psychosis...oh, you don't? Yeah me neither after Monday.
How do NSRIs work?
selective blockade of NETs without affecting serotonin selective transporters
. They also increase DA, because DA is indiscriminate and will bind to NE receptors. These drugs have minimal affinity for other receptors like histamine or muscarinic receptors, so they have the potential to have better side effect profiles.
First non-stimulant approved for ADHD. Increases NE and DA in the PFC. Less effective than stimulants, therefore it is
reserved for use in pts who are intolerant/refractive to stimulants, or in pts with hx of addictive tendencies.
Why does Atomaxetine (Strattera) have no potential for abuse?
Because there are very few NETs in the nucleus accumbens, so this drug does not affect NE or DA levels there.
block the reuptake of NE and serotonin
and are less effective than stimulants for treating ADHD. The disadvantage is that they have significant antimuscarinic, antiadrenergic and antihistaminic side effects. Not first line treatments.
What are the 2 tricyclic antidepressants used to treat ADHD?
1) Imipramine (Tofranil)
2) Desipramine (Norpramin)
Desipramine is a major active metabolic of Imipramine and has higher selectivity for the NET than the serotonin transporter and is indicated for ADHD in pts refractive to stimulant therapy.
A unique antidepressant in that it
blocks the reuptake of dopamine
. It is not approved for ADHD but due to its dopaminergic profile, may be of use. It is a weak antihistaminic drug but tends to have significant convulsant effects.
α2A receptor agonist
* that is approved for once daily use for treatment of ADHD. By stimulating the α2A receptor in the PFC it improves the signal to noise ratio. It has lower efficacy and is reserved for refractory pts. Less significant hypotensive and sedative effects than are seen in other α2A receptor agonists such as clonidine.
Beneficial in patients with comorbid tic disorders bc it has no DA action.
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