4.7 Pathophysiology of ADHD, pharmacology of stimulants Flashcards
What causes the majority of ADHD?
Heritable (genetics)
What are the implicated systems in ADHD?
- DA transporter, COMT, cholinergic receptors
- Cholesterol metabolism, CNS development, glutamate receptors
What are clinical presentations of ADHD?
- Sxs at ages 5-9 yo (generally before 12 for diagnosis)
- 6 or more sxs must be present
- Significant impairment in 2 or more settings
- Sxs documented by parent, teacher, and clinician
- Interferes w functioning and development
What are the clinical sxs of ADHD?
- Inattention: difficulty organizing tasks, easily distracted
- Hyperactivity
- Impulsivity
What is the possible circuity mechanism as to why the sxs of ADHD are what they are?
Medial prefrontal cortex (mPFC) control might not be fully functional
What type of stimulant is methylxanthines?
Indirect acting sympathomimetics
What are indirect acting sympathomimetics?
Stimulant compounds that mimic the effect of endogenous agonists of sympathetic nervous system
What do methylxanthines do?
- Antagonize adenosine receptors
- Inhibit phosphodiesterases: increase cAMP (potentiate Gs linked receptors)
- Increase activity of ryanodine receptors, increasing intracellular Ca2+
What is the A1 (adenosine) receptor linked to?
Gi/o linked
What does the A1 receptor do?
Inhibitory modulation of many neurotransmitters
Where are A1 receptors located?
Cerebral cortex, hippocampus, cerebellum, thalamus, brain stem, spinal cord
Activation of A1 receptors in the CNS can cause:
Sedation, anxiolysis, anticonvulsant activity
Activation of A1 receptors in the periphery can cause:
Decreased HR
What is A2a receptor linked to?
Gs linked
Where are A2a receptors located?
Cerebral vasculature, striatum
What are A2a receptors responsible for?
Vasodilation
Which adenosine receptors are heterodimers of A1 and D2 receptors?
- A2b
- A3
What is the A2b receptor linked to (hint: same as A2a)?
Gs linked
Where are A2b receptors located and what is its function?
- Glial cells
- Function unknown
What is the A3 receptor linked to?
Gq linked
Where are A3 receptors located?
Hippocampus and thalamus
When are A3 receptors activated?
Only activated in states of excessive catabolism (e.g. seizures, hypoglycemia, stroke)
Are A3 receptors antagonized by methylxanthines?
No
What is the effect of methylxanthines?
- Increased alertness
- Decreased fatigue
What are monoamines?
DA, NE, 5HT
What type of stimulant is cocaine?
Indirect acting sympathomimetics
What is the MOA of cocaine?
Inhibit (blockade only) monoamine transporters (NE, 5HT, DA)
What is cocaine used clinically?
Local anesthetic
What type of stimulant are amphetamines?
Indirect acting sympathomimetics
What is the MOA of amphetamines?
Non-selective activation of monoamines
What is the one exception to amphetamines MOA?
Ecstasy, which is more selective for 5HT
What are effects of amphetamines?
Wakefulness, alertness, increased ability to concentrate
High doses of amphetamines can cause what?
High doses can elicit psychotic behaviors
What drugs are amphetamines?
- Dextroamphetamine (dexedrine), lisdexamfetamine (vyvanse)
- Methylphenidate
- Adderall
- Mydayis
What are amphetamines used for?
Narcolepsy, anorexiant/weight loss, ADHD
What are the non-stimulants for ADHD?
- Atomoxetine (stratterera): a NET inhibitor for adult
- TCAs (tricyclic antidepressants)
- Bupropion (wellbutrin)
- Clonidine (catapres)/guanfacine (tenex)
What are alternative therapies for ADHD?
- Elim artificial food additives, colors, preservatives
- EEG biofeedback
- Essential FA supp
- Yoga/massage
- Green outdoor spaces
What is narcolepsy?
- Excessive daytime sleepiness
- Cataplexy/weakening of muscles
- Poor quality of sleep
- Sleep paralysis
- Hypnogogic hallucinations
What are txs for narcolepsy?
Stimulants for sleepiness:
- Solriamfetol (sunosi): MOA on NET and DAT
- Modafinil (provigil)
- Antidepressants
- Xyrem (GHB)
- Pitolisant: histamine3 receptor antagonist
