PHRM845 Exam 4 (Ott)

Question 1

Overview of ADHD

Answer 1

-ADHD is more frequent in males than females (14.5% vs. 8%)
-Higher rate in white children and adolescents (greater healthcare access)
-Higher rate if diagnosed in a first-degree relative (~ 50% of children with a parent diagnosed with ADHD will also have
ADHD)
-6 in 10 children will have another mental health, emotional, or conduct disorder
-Etiology is multifactorial (environmental, genetics, physiological)–ex: smoking tobacco during pregnancy

*Hypersensitivity doesn’t necessarily stick with the patient into adulthood
**Overdiagnosed in white children; underdiagnosed in children of color (some populations of color try to avoid healthcare)

Question 2

Clinical course of ADHD

Answer 2

• Median age of diagnosis: 6 years old
  ~Diagnosis can be as young as 3 years old (diagnostic criteria down to this age)
   ~More severe cases diagnosed earlier
• Preschool: mainly manifests as hyperactivity
• Elementary: mainly manifests as inattentiveness
• One-third of children with ADHD will have the diagnosis in adulthood
• Co-morbid conditions:
   -10% risk of bipolar disorder
   -8 – 11% will have a mild tic
  - Increased risk of substance use and
  antisocial personality disorder if ADHD
  is left untreated (get on stimulant and methamphetamine)

Question 3

Which stimulant is FDA-approved for 3+ y/o

Answer 3

Adderall

Question 4

Potential impact of ADHD

Answer 4

1. Poor academic performance
2. Low self-esteem (can’t focus/handle classes and get held back)
3. Poor interpersonal relationships
4. Employment difficulties

Question 5

ADHD diagnostic criteria

Answer 5

-A pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development, characterized by inattention and/or hyperactivity and impulsivity
-For each symptom domain, must have at least 6 symptoms present
-For older adolescents and adults (17 years and older), at least 5 symptoms are required for either of the two specifiers
-Several inattentive or hyperactive symptoms must be present prior to age 12 years
-Several inattentive or hyperactive-impulsive symptoms are present in two or more settings

**If only happening in one setting, there might be something going on in that environment
**After age 12, only need 5 symptoms, but must explain S/Sx of ADHD in childhood

Question 6

Types of ADHD

Answer 6

-Combined: criteria met for both inattention and hyperactivity (common in children; can be removed as the child gets older)
-Predominantly inattentive presentation: criteria met for inattention, but not hyperactivity
-Predominantly hyperactive/impulsive presentation: criteria met for hyperactivity/impulsivity but not inattention

Question 7

Inattention (Six or more of the following symptoms persisting for at least 6 months; inconsistent with developmental level
and negatively impacting daily functioning)

Answer 7

-Fails to give close attention to details, makes careless mistakes
-Difficulty sustaining attention in tasks or play activities (kids can sit and game for 6h and still have ADHD–based on interests)
-Doesn’t seem to listen when spoken to directly
-Doesn’t follow through on instructions, fails to finish homework, chores, duties in the workplace
-Difficulty organizing tasks and activities (long to-do lists; look at it and think they can’t get it done)
-Avoids, dislikes, reluctant to engage in tasks that require sustained mental effort
-Loses things necessary for tasks/activities (misplacing)
-Easily distracted by extraneous stimuli
-Forgetful in daily activities

Question 8

Hyperactivity and impulsivity (Six or more of the following symptoms persisting for at least 6 months; inconsistent with developmental level and negatively impacting daily functioning)

Answer 8

-Fidgets with or taps hands/feet, squirms in seat
-Leaves seat in situations when remaining seated is expected
-Runs about or climbs in inappropriate situations
-Unable to play or engage in leisure activities quietly
-“On the go”, acting as if “driven by a motor”
-Talks excessively
-Blurts out an answer before a question is completed
-Difficulty waiting their turn
-Interrupts or intrudes on others (not meant to be rude)

Question 9

Non-pharmacologic tx of ADHD

Answer 9

Behavioral therapy and psychosocial treatment
-Training for both adults (parents/guardians) and child/adolescent
-Learn how to respond to behaviors and improve behaviors in a specific setting

Training interventions
-Target skill development
-Repeated practice in behaviors with feedback (not just in one setting)

Question 10

Pharmacological tx options

Answer 10

-Stimulant (amphetamine or methylphenidate-based) **stimulants increase dopamine and NE to help focus and concentrate; limits hyperactivity

-Non-stimulants
*Atomoxetine
*Viloxazine
*Clonidine ER (preferred non-stimulant agent)
*Guanfacine ER (preferred non-stimulant agent)
*Atypical antipsychotics
*Bupropion
*Imipramine
*Modafinil/Armodafinil
*Mood stabilizers

Question 11

Stimulant MOA

Answer 11

Inhibition of DAT-1 and NET
→ Inhibition of reuptake→Increased amount of dopamine and norepinephrine in synapse
* Inhibition of monoamine oxidase (amphetamines are more potent)
* Additional mechanism of amphetamines: ability to enter the presynaptic terminal and cause release of neurotransmitters

Question 12

MOA of guanfacine and clonidine

Answer 12

• Selective α2A-adrenergic agonist
• Theorized that use in ADHD is related to binding of receptors in the pre-frontal cortex

Question 13

MOA of atomoxetine and viloxazine

Answer 13

Selective NE reuptake inhibitor

Question 14

Stimulant dosing

Answer 14

-Low-dose immediate release or controlled release used initially
-Dose-response effects seen in a short period of time (do not need to wait weeks to see impact)
-Can titrate in a short amount of time (7 days, 3
days if urgent)
-Start low in dosing
-Calculating a dose in pediatric patients based
on mg/kg not found to be helpful as variations in dosing not found to be due to height or weight
-IR dosage forms given at least twice daily
-IR preferred for patients weighing < 16 kg due to limited low-dose availability of long-acting stimulants
-Avoid giving dose too late in the day, may give an after-school dose
-Late afternoon symptoms may require longer-acting formulation
-Don’t use two different stimulants
-Can use two different dosage forms of the same stimulant
-Combo of stimulant/atomoxetine common; not good clinical evidence of efficacy

Question 15

Special considerations for stimulants

Answer 15

-Mydayis (mixed amphetamine salts)
*Max dose = 25 mg/day (adults) or 12.5 mg (age 13-17) if CrCl
< 30 to 15 mL/min
-Daytrana (methylphenidate)
**If PO methylphenidate did not work, do NOT try patch
*Apply patch to outside of hip 2 hours prior to needed effects, remove after 9 hours (alternate hip daily)
*Reserved for those who respond to methylphenidate and would benefit from patch
-Vyvanse (lisdexamfetamine)
*Prodrug covalently linked to l-lysine; converted to dextroamphetamine via first-pass metabolism/hepatic metabolism–takes a while for conversion
*Must be swallowed whole even though it is not SR
*Not useful if no response to dextroamphetamine
Misuse if beads are crushed up and then injected
-Jornay PM (methylphenidate hydrochloride)
*Take dose in the evening between 6:30 pm and 9:30 pm **give at bedtime; will not keep patient awake
*Must start with titration for dosing, do not switch mg per mg if patient already on IR methylphenidate

Question 16

Adverse Stimulant Effects

Answer 16

-Appetite loss
-Abdominal pain (if stomach is upset, then eat first; will delay absorption, but they will still get same amount)
-Headaches
-Sleep disturbances
-Decreased growth (1 to 2 cm, diminished after 3rd year of treatment)–rare and kids will eventually catch up
-Hallucinations or other psychotic symptoms (rare)
-Increased blood pressure (1 to 4 mmHg)
-Increased heart rate (1 to 2 bpm)
-Sudden cardiac death (rare)–studies show no difference in those on stimulants vs. those without.
-Priapism–necrotic if not fixed; elongated erection
-Peripheral vasculopathy (Raynaud’s)–bluing in fingertips

Question 17

Stimulant monitoring

Answer 17

-Appetite
-Behavior
-Blood pressure
-Growth rate (height/weight)
-Heart rate
-Sleep
-ECG may be considered based on cardiac risk

Question 18

Alpha 2 agonists

Answer 18

Intuniv (guanfacine ER)
Kapvay (Clonidine ER)
**These are staples
**Stimulant during day and alpha-2 at night; if very hyper throughout day, can use alpha-2 agonist during the day too.

Question 19

What is guanfacine ER?

Answer 19

• Onset of action is ~ 4 weeks
• Dosed once daily
  *3A4 substrate – dose adjustments with strong 3A4 inhibitors or inducers–>post-marketing warning for CYP 3A4 inducers/inhibitors

Question 20

Clonidine ER

Answer 20

• Onset of action is ~ 4 weeks
• Dosed twice daily

Question 21

Importance of tapering alpha-2 agonists

Answer 21

Must be tapered if discontinued to avoid rebound hypertension

Question 22

Atomoxetine (strattera)

Answer 22

• Approved for ages 6 and older
  *2D6 substrate; dose adjustment with strong 2D6 inhibitor or poor 2D6 metabolizer–2D6 inhibitors can increase atomoxetine concentration
  *Weight-based dosing if pt less than 70 kg

Question 22

NE reuptake inhibitors (non-stimulant)

Answer 22

Atomoxetine and Viloxazine

Question 23

Viloxazine (Qelbree)

Answer 23

• Approved for ages 6 – 17
• 6 – 11 years = 100 mg
• 12 – 17 years = 200 mg
• Capsules – swallow whole or put in
  applesauce
• 2D6/UGT substrate; strong 1A2 inhibitor,
  weak 2D6/3A4 inhibitor

*Not any better than atomoxetine, but is much newer

Question 24

Atomoxetine and Viloxazine SE

Answer 24

• Increased HR and BP
• Somnolence
• GI symptoms
• Decreased appetite
• Diminished growth
• Increase in suicidal thinking (boxed warning)–if they develop this, they are coming off of the drug
• Hepatitis (rare) (atomoxetine only)

Question 25

Clonidine and Guanfacine SE

Answer 25

• Decreased HR and BP, orthostasis
• Somnolence
• Dry mouth
• Dizziness
• Irritability
• Headache
• Abdominal pain
• Rebound hypertension if abrupt
  discontinuation

Question 26

Monitoring for non-stimulants

Answer 26

-Appetite
-Behavior
-Blood pressure
-Growth rate (height and weight) (atomoxetine)
-Heart rate
-LFTs (atomoxetine)-hepatotoxicity is rare
-Sleep

Question 27

Bupropion

Answer 27

**Increases NE and DA
-Not FDA-approved for ADHD
-Not as effective as stimulants/atomoxetine
-May be considered if concerns with medication misuse or side effects to a stimulant
-2B6 major substrate
-2D6 inhibitor
-Contraindicated in seizure disorders and
eating disorders
*monitor BP especially if taken with atomoxetine because they both increase BP

Question 28

Modafinil

Answer 28

-FDA-approved for narcolepsy, obstructive
sleep apnea, shift work sleep disorder
-Current studies for ADHD only compare
to placebo
-C-IV – risk of misuse
-Adverse effects:
* Headache, decreased appetite
* GI intolerance, warning for SJS/TEN

Question 29

Tricyclic Antidepressants (TCAs)

Answer 29

*Increase NE
*Long-term drugs
-Less effective than methylphenidate
-Use is limited by lack of data and concerns with adverse effects
-Cardiac concerns-sudden cardiac death in children; lethal in OD because they cause arrhythmias

Question 30

Mood stabilizers (atypical antipsychotics)

Answer 30

**Do NOT treat ADHD
-May be useful if there is comorbid bipolar disorder, conduct disorder, intermittent explosive disorder
-More data with carbamazepine, but often see valproate used
-Lithium ineffective for ADHD
-Should not use atypical antipsychotics as
monotherapy
**SE burden is too high

Question 31

American Academy of Pediatrics (AAP) ADHD tx guidelines

Answer 31

*Medications as first line as well as CBT and family tx if needed
-Preschool age:
* First-line: parent training in behavior
management (PTBM)
* Second-line: PTBM plus FDA-approved
medication
-Elementary and middle-school age:
* First-line: FDA-approved medication plus
PTBM
-Adolescents (age 12-18):
* First-line: FDA-approved medication, may
offer PTBM

Question 32

AAP medication recommendation for preschool age

Answer 32

• First-line: Methylphenidate
• Non-stimulant medications are not FDA-approved for this age

*at really young age, we think about meds, especially methylphenidate

Question 33

AAP medication recommendation for elementary/middle school/adolescent

Answer 33

• First-line: Stimulants
• Second-line: Atomoxetine, Guanfacine ER, Clonidine ER

Question 34

Adjunctive tx

Answer 34

• May be considered if stimulant is not fully effective or limited by side effects
• Only guanfacine ER and clonidine ER have evidence as adjuncts to stimulants
  *Can also add an alpha-2 agonist in evening for when med wears off or morning for when kid is super hyper

Question 35

National Institute for Health and Care Excellence (NICE)

Answer 35

1st line: methylphenidate or lisdexamfetamine
2nd line: dextroamphetamine, atomoxetine, or guanfacine

Question 36

NICE ADHD guideline for adults

Answer 36

Methylphenidate (short- or long-acting)
OR Lisdexamfetamine (if no response to one, switch to the other)

Dextroamphetamine
(If unable to tolerate lisdexamfetamine long half-life)

Atomoxetine
(if no symptom response to above agents)

**Nothing in guidelines for Qelbree yet
**Adults can take meds QD or PRN

Question 37

what is CADDRA?

Answer 37

The Canadian ADHD guidelines

Question 38

Medication selection

Answer 38

Patient-related factors
* Age and individual variations
* Duration of effect needed (ex: for school day and that’s it?)
* Concurrent psychiatric and medical issues
* Physician, family, patient attitudes

Medication-related factors
* Active ingredient, doses/dosage forms, cost
* Onset and duration of action

Other
* Combining medications
* Potential for misuse or diversion–who picked it up for the pt; think about misuse if pt seems to not have effect from med even with increasing dosage.

*Be careful with how much we are expecting child to take (regimen)