Stimulants and "Non-Stimulants" for ADHD

stimulants

a substance that increases CNS activity aka psychostimulants or uppers (caffeine, amphetamine, cocaine)

sypathomimetic

Many prescription stimulants are ___________ meaning they increase fight or flight response

-increased alertness

-increased attention

-energy

What are the effects of prescription stimulants?

anorexiants

drugs with CNS activity that suppress appetite (hypothalamus and limbic system)

-dangerously high body temperature

-an irregular heartbeat

-heart failure

-seizures

What happens to your body when you take high doses of prescription stimulants?

stimulant indications

-ADHD

-narcolepsy

-weight management

attention deficit hyperactivity disorder Dx

≥ 6 symptoms of inattention and/or hyperactivity-impulsivity for ≥ 6 months for children up to age 16 years,

OR

≥ 5 symptoms of inattention and/or hyperactivity-impulsivity for ≥ 6 months for ages 17 and older

inattention

-Lack of attention to details

-Trouble holding attention on tasks or play activities.

-Does not seem to listen when spoken to directly.

-Does not follow through on instructions and fails to finish work

-Trouble organizing tasks and activities.

-Avoids, dislikes, or is reluctant to do tasks that require mental effort over a long period of time

-Loses things necessary for tasks and activities

-Is often easily distracted

-Is often forgetful in daily activities

Hyperactivity and Impulsivity

-Fidgets with or taps hands or feet, or squirms in seat

-Leaves seat in situations when seating is expected

-Runs about or climbs in situations where it is not appropriate

-Unable to play or take part in leisure activities quietly.

-"on the go" acting as if "driven by a motor".

-Talks excessively.

-Blurts out an answer before a question has been completed.

-Has trouble waiting their turn.

-Interrupts or intrudes on others

boys

Historically ADHD is thought to be more prevalent in ________

females with ADHD

-inattentive symptoms more likely

-'internalizing' disorders (anxiety, depression, eating disorders)

males with ADHD

-hyperactivity and impulsivity symptoms more likely

-'externalizing' disorders (SUD, conduct disorders)

childhood

ADHD is historically thought to be a __________ disorder.

women

ADHD is more likely to persist in ________

patho and etiology of ADHD

-changes in brain architecture

-changes in functional activity in particular brain regions imp to mood and "resting state maintenance"

-medical prefrontal cortex, posterior cingulate

risk of ADHD

-large genetic component 40-90% based on cholinergic signaling, metabotropic glutamate signaling, and other neuronal genes

-developmental toxicity based on FAS and lead poisoning and meningitis

behavioral, educational, dietary interventions

What are the non-pharn tx for ADHD?

stimulants and non-stimulants

What are the pharmacotherapies for treating ADHD?

antidepressants, anti-psychotics, omega 3 fatty acid supplementation

What are the off label pharmacotherapies for treating ADHD?

stimulant

a drug designed to enhance or "stimulate" the nervous system

MOA of stimulants

increase NE and DA signaling

Amphetamine

increase DA and NE release with some proposed inhibition of NET and DAT and SERT and even MAO inhibition

Methylphenidate

inhibit NET and DAT with some proposed increase in DA and NE release and even MAO inhibition

amphetamines

-Amphetamine (Adzenys ER and XR-ODT, Dyanavel, Evekeo)

-Dextroamphetamine (Dexedrine, Zenzedi, Procentra)

-Mixed amphetamine salts (Adderall, Adderall XR, Mydayis)

-Lisdexamfetamine (Vyvanse)

Methylphenidates

-Methylphenidate (Ritalin, Concerta, Quillichew, etc)

-Dexmethylphenidate (Focalin)

-Serdexmethylphenidate/dexmethylphenidate (Azstarys)

sympathomimetic agents

-mimic actions of sympathetic amines

-particularly NE and DA

reduces attack by MAO (branching usually CH3)

Why is the branching in chain at alpha position important in stimulant chemistry?

decreases

Increasing chain length in stimulants _________ activity

CNS activity

Why is aromaticity important for stimulant chemistry?

sympathomimetic nature

Stimulant AEs are all due to their ____________

stimulant AEs

-Headache

-Insomnia

-Reduced appetite, weight loss

-Irritability/jitteriness

-Stomachache

-Risk of dependence

-Rarer adverse effects

• Priapism (mechanism poorly understood)

• Hallucinations (DA effects)

• Skin discoloration with methylphenidate patches

abuse, misuse and addiction

What is the box warning of stimulants?

Amphetamine (Adzenys, Dyanavel, Evekeo)

racemic about 50:50 R-amphetamine sulfate (levo) and S-amphetamine sulfate (dextro)

mixed amphetamine salts (Adderall, Adderall XR, Mydyasis)

varying ratio mixtures of racemic amphetamine and dextroamphetamine

Dextroamphetamine (Dexedrine, Zenzedi, Procentra)

S-amphetamine, most active (3-4x more potent)

Lisdexamfetamine (Vyvanse) MOA

-Prodrug of dextroamphetamine, promotes presynaptic release of DA and NE

• Also inhibitor of DAT, NET, and SERT

first pass metabolism in the liver

Lisdexamfetamine is converted in __________ to dextroamphetamine and L-lysine via hydrolysis of amide.

amphetamine-like stimulants used for obesity and eating disorders

-Diethylpropion

-Benzphetamine

-Phentermine

-Phendimetrazine

MOA of other amphetamine like stimulants used for obesity and some eating disorders

promote presynaptic release of DA and NE

Methylphenidate (Concerta, Aptensio, Quilichew, Ritalin)

racemic mixture

Dexmethylphenidate (Focalin)

single enantiomer of methylphenidate (more potent)

Serdexmethylphenidate

prodrug of dexmethylphenidate (conversion in the gut via unclear mechanism)

Dexmethylphenidate

potent d-threo-enantiomer of methylphenidate

Alpha 2 AR agonists and NET inhibitors

may or may not increase NE and DA signaling

Alpha-2 AR agonists

-Guanfacine (Intuiv)

-Clonidine

NET Inhibitors

-Atomoxetine (Straterra)

-Viloxazine (Qelbree)

Guanfacine (Intuiv)

-AE: Sedation, dizziness, heart block, constipation, headache, upper abdominal pain

-Less sedation than clonidine

Clonidine

AEs: sedation, dizziness, heart block, constipation, HA, upper abdominal pain

proposed to involve alpha-2 AR in the prefrontal cortex rather than brainstem

How does alpha-2 AR agonism lead to ADHD symptom relief?

Atomoxetine (Straterra) MOA

selectively inhibits NET

chemistry of Atomoxetine

marketed as R-enantiomer

CYP2D6 and CYP2C19

Atomoxetine is metabolized by _________ to active metabolite 4-hydroxyatomoxetine.

AEs of Atomoxetine

increased HR and BP, aggression/hostility, mania, growth retardation, HA, N, insomnia, dry mouth

Viloxazine (Qelbree) MOA

inhibits NET and may modulate some 5-HT receptors as well

AEs of Viloxazine (Qelbree)

increased HR and BP, HA, insomnia/lethargy, N

methamphetamine MOA

promotes presynaptic release of DA and NE also inhibits DAT, NET and SERT

Methamphetamine

-stimulant

-indicated for ADHD

-racemic mixture

CYP2D6

Methamphetamine is metabolized by ________ then N-demethylation to active amphetamine.

no

Is there an antidote for stimulant overdose?

stimulant toxicity

-aka "overamping"

-CNS response: anxiety, panic, irritability, dizziness, confusion, hallucinations, psychosis

-Cardiac: increased BP and HR, arrhythmia, chest pains, tightness

-Rapid breathing

-Nausea or vomiting

-Dilated pupils, tremors

-Overheating / excessive sweating