Block 4 Lecture 2 -- ADHD Flashcards
What have been the most significant developments for ADHD drugs in the past 10 years?
drug formulation (LA, ER)
How do males and females differ in ADHD presentation, referral, diagnosis?
males:
- 6-10x more likely to be referred
- more externalizing behaviors
- 3x more likely to be diagnosed
- more likely to have co-morbid neuropsychiatric issues
What CNS “pathways” are involved in attention?
1) Alerting pathways
2) orienting pathways
3) working memory pathways
4) executive control pathways
What regions are involved in CNS alerting pathways?
1) locus coeruleus
2) HT
3) PFc
4) parietal cx
5) reticular activating system in the brainstem
What regions are involved in CNS orienting pathways?
1) parietal cx
2) visual cx
3) auditory cx
What is the function of the locus coeruleus?
- NE synthesis
- ANS control center
involved in the CNS alerting pathways
What regions are involved in the CNS executive control pathways?
1) PFc
2) limbic area
3) basal ganglia
4) cerebellum
What regions are involved in the CNS working memory pathways?
1) PFc
2) cingulate cx
3) entorhinal cx
4) hippocampus
5) Amygdala
What is the function of CNS orienting pathways?
1) tune spatiotemporal representation of relevant sensory stimuli
2) increase focus on a specific stimulus
What is the function of CNS working memory pathways?
process and focus info about sensory stimuli or tasks
– over seconds to mins
What is the function of the executive control CNS pathways?
integration and organization of information
What genes are HYPOTHESIZED (not proven) to be mutated/involved in ADHD?
1) DAT
2) D4/D5 DAr
- - exon 3 7-repeat allele yields blunted response to DA
3) DBH
What are the theories for ADHD pathology?
1) genetic
2) DA deficiency hypothesis
What is the basis for the DA deficiency hypothesis?
1) stimulants work for 80% of pts
2) some imaging studies show DA/DAr deficits
3) animal studies support DA’s role in motor control, attention, and impulsivity
What is the basis for the genetic theories of ADHD?
one of the most heritable neuropsychiatric conditions!
– 3-8x higher incidence if a parent has ADHD
What are the weaknesses of the DA deficiency hypothesis?
1) literature doesn’t support one theory for ALL parts of ADHD
2) literature doesn’t support co-morbidities solely due to DA deficit
What are risk factors for ADHD?
1) heredity
- - most significant!
2) labor/delivery complications
3) sub-optimal family environment
4) in utero tobacco smoke or lead exposure
5) developmental drug/alcohol exposure
- - NOT directly caused by bad parenting, tv, etc.
What are co-morbidities of ADHD?
1) cigarette smoking
2) conduct disorder
3) bipolar disease
4) depression, anxiety, OCD
5) learning disabilities
6) tourettes
7) sleep disturbances
8) sensory dysfunction
9) pervasive disorders (Asbergers)
What are the most common co-morbidities of ADHD?
1) learning disabilities! (40%)
2) conduct disorder (25%)
- - males much more than females
3) bipolar (10%)
tourettes (40-80% of tourettes pts have ADHD)
cigarette smoking is 2-3x the age-adjusted rate
– as symptoms increase, more likely to smoke
What are the 3 presentations of ADHD?
1) primary inattention
2) primary hyperactivity/impulsivity
3) combined inattention and hyperactivity/impulsivity
What are the possible diagnoses for a patient with symptoms?
- mild, moderate, or severe
- primary inattention, primary hyperactivity/impulsivity, or combined
– +/- autism spectrum disorder
presentation can vary across years
How did DSM-IV differ from the current DSM-V?
1) presentations called “subtypes”
2) sxs had to appear before 6 yo
3) no mild/mod/severe
4) no ASD co-diagnosis
5) no differences for older patients
What is the Vanderbilt ADHD diagnostic parent rating scale?
a tool that differentiates oppositional-defiant disorder, conduct disorder, and anxiety/depression from ADHD
MoA of methylphenidate:
blocks DAT and NET
– DAT moreso than NET
What kind of system is methylin ER? What are counseling points?
methylcellulose polymer / wax matrix;
- 8 hour release
- swallow whole
- may still require BID admin
(same as ritalin SR)
What kind of system is ritalin SR? What are counseling points?
intermediate-acting
methylcellulose polymer / wax matrix;
- 8 hour release
- swallow whole
- may still require BID admin
(same as methylin ER)
What kind of system is Metadate CD/ER? What are counseling points?
intermediate-acting
IR/ER bead mixture
- CD is caps, ER is tabs
- can open and sprinkle on food
What kind of system is Ritalin LA? What are counseling points?
intermediate-acting
IR/ER beads formulated in SODAS
What are the short-acting forms of MPH?
1) MPH – Ritalin, Methylin
2) Dex-MPH – Focalin
What are the intermediate-acting forms of MPH?
1) Methylin ER, Ritalin SR
- - methylcellulose/wax polymer matrix
2) Metadate ER, Metadate CD
- - ir/er beads
3) Ritalin LA
- - sodas
What are the long-acting forms of MPH?
1) Concerta
- - OROS
2) Focalin XR
- - sodas
3) Daytrana TD patch
4) quillivant XR
- - ER liquid MPH
What is SODAS?
spheroidal oral drug absorption system
- outer polymer dissolves, holes form
- GI fluid enters
- drug solubilizes and escapes
What is OROS?
osmotic-release oral system
- outer immediate release core
- water enters thru semi-permeable membrane
- osmotic pressure pushes layers of ensuing ER drug solution out of laser-drilled hole
Describe ER liquid used in quillivant XR.
20% true soln; 80% ionic exchange resin suspension
What kind of system is concerta? Counseling points?
OROS
- 12 hour release
- QD dosing
What kind of system is Focalin XR?
SODAS
What kind of system is Quillivant XR? Counseling Points?
ER liquid ion exchange resin
– QD dosing
What is the MoA of amphetamines?
1) act on VMAT to reverse DAT
2) decrease MAO activity
- - DA affected moreso than NE
What are the short-acting amphetamines?
1) Dextroamphetamine and amphetamine salts (Adderall)
2) Dextroamphetamine (Dexedrine, Dextrostat)
What are the long-acting amphetamines?
1) Dexedrine spansule
2) Adderall XR
3) Lisdexamfetamine (Vyvanse)
What kind of system is Dexedrine spansule?
IR/ER bead mixture
What are the considerations for short-acting amphetamines?
1) best for initial treatment!
2) 2-3 x/day dosing :(
3) approved for kids 3+
What are the considerations for long-acting amphetamines?
worse effects on:
- evening appetite
- sleep
- growth stunting
What are the considerations for Vyvanse (also a long-acting amphetamine)?
1) delayed onset in therapeutic action
2) less abuse and diversion potential
Describe PK of lisdexamfetamine.
- hydrolyzed to d-amphetamine during first pass
- — in intestines or liver
- — Lys is cleaved
- rate-limited biotransformation
Describe PK of MPH.
t1/2 = 3-4 hr
BID dosing
How does dexmethylphenidate compare to methylphenidate?
lower dosage
In what ages are short-acting MPH and amphetamines approved?
MPH: 6+
amphetamines: 3+
You’re starting an ADHD patient on psychostimulant therapy. How do you do this?
1) titrate slow
- - want efficacy at lowest possible dose to avoid ADRs
2) don’t pick an SR form
- - difficult for titration
- - variable PK
- - variable time to max efficacy
When are psychostimulants contraindicated?
1) bipolar disorder
2) schizophrenia
3) aggression
- - more DA worsens manic-depressive switching, and schizo and aggressiveness
4) h/o drug/EtOH abuse
What are ADRs of psychostimulants?
1) black box: sudden death in children
2) diminished appetite, weight loss
3) delayed sleep onset / insomnia
4) late-day “wear off”
5) increased HR and BP
6) irritability, obsessiveness, social withdrawal
How to manage appetite and sleep effects of psychostimulants?
appetite/weight loss -- wears off over time -- time meals to correlate with minimal med effect insomnia -- change dose/formulation -- follow sleep hygiene
What is the MoA of atomoxetine?
selective NET inhibitor
What are ADRs of atomoxetine?
1) dry mouth
2) constipation
3) n/v
4) insomnia
5) sympathomimetic ADRs limit use
When is atomoxetine used in ADHD?
1) substance abuse
2) stimulant failure or severe ADRs
3) need a 24h solution
- - ex: behavior problems in the am
- - ex: sleep disruption is a problem
Why is atomoxetine not first line?
lower efficacy than stimulants
What a2-adrenergic agonists are available for use in ADHD?
1) clonidine (IR/XR)
2) guanfacine (IR/XR)
What is the MoA of clondine IR/XR?
probably POST-synaptic a2-adrenergic receptors in prefrontal cortex
When are a2-adrenergic agonists used for ADHD?
NOT first line
1) best for hyperactive/aggressive patients
2) substance abuse
3) severe tics
4) seizure disorders
5) sleep disturbances
6) psychostimulant failure
How is clonidine/guanfacine administered for ADHD?
1) ER formulations more useful, but still BID
2) can be adjunct to stimulants
What are ADRs of clonidine/guanfacine
sedation (IR worst)
dry mouth
hypotension
What antidepressants are used for ADHD treatment?
1) bupropion
2) duloxetine
3) venlafaxine
4) TCAs: imipramine and nortriptyline
NO SSRIs alone, not effective
MoA of bupropion:
DAT/NET
– also lowers seizure threshold
MoA of duloxetine:
SERT/NET
MoA of Venlafaxine:
SERT/NET
MoA of TCAs:
DAT/NET/SERT
When are antidepressants used for ADHD?
maybe for ADHD + depression
– off-label
What are the drug classes used for ADHD?
1) psychostimulants
2) selective NET inhibitors
3) a2-adrenergic agonists
4) antidepressants
What are the effects of pharmacotherapy in ADHD?
How does it compare to counseling vs. the combination?
1) lessens sxs, sets stage for CBT benefits
2) continuous improvements
3) may slightly DELAY growth
4) no increase in substance abuse/diversion
– better than counseling; no obvious advantage with the combo
What are the non-drug treatments of ADHD?
1) personal and family education
2) lifestyle changes
3) assistance in educational settings
4) improving interpersonal relationships
5) improving health habits
- - sleep, exercise, eating
What are the DSM-V requirements for ADHD diagnosis in kids?
6 signs of inattention or hyperactivity for ≥ 6 mos
- must appear before age 12
- 2 settings
- 2 independent evaluators
What are the DSM-V requirements for ADHD diagnosis in adults?
5 signs of inattention or hyperactivity for ≥ 6 mos
- child-onset, persistent, and current sxs
- usually have significant sxs
- 2 settings, 2 evaluators
How does ADHD change with age?
decreased hyperactivity and impulsivity
persisting inattention
What is DA’s supposed role in ADHD treatment?
decreasing inappropriate system “noise”
What is NE’s supposed role in ADHD treatment?
increasing appropriate signaling
What things lead to sudden onset disorders resembling ADHD?
1) head trauma
2) stroke
3) prefrontal cortex damage
What is the thought for pathophysiology behind ADHD?
defects in one of the brain attention pathways
– specific neurochemical deficits are difficult to identify
How is impulsivity studied?
delayed discounting
– presence of impulsive choice associated with gambling, risky behaviors, etc.
What is the underlying pathophys of impulsivity?
damage to PFc DA system
