Exam 5 Flashcards
Is ADHD due to genetic or non-genetic factors? What are some examples of each?
ADHD is due to genetic AND non-genetic factors.
Genetic - Some systems that are implicated include the dopamine transporter, COMT, cholinergic receptors, cholesterol metabolism, CNS development, and glutamate receptors.
non-genetic - low birth weight, smoking, lead, etc.
When looking at adults with and without ADHD, which MRI will show more brain activity?
People with ADHD have lower brain activity. This is just a hypothesis, but it suggests that ADHD is a problem with low neuronal activity (opposite of epilepsy, which is about over-excitability).
What clinical presentation is associated with ADHD? (5) What is the possible circuitry mechanism for this presentation?
- symptoms at ages 5-9 years old (generally diagnosed before 12yo)
- 6 or more symptoms must be present (inattention, hyperactivity, impulsivity)
- significant impairment in two or more settings (home vs. school)
- symptoms documented by parent, teacher, and clinician
- Interferes with functioning and development
Proposed circuitry mechanism - Medical prefrontal cortex (mPFC) control might not be fully functional. mPRF inhibition inhibits us from doing these impulsive outward behaviors.
What is the MOA of methylxanthines? What are some examples of methylxanthines?
MOA - Antagonize adenosine receptors. Adenosine has a lot of functions, but mainly it’s used to reduce activity (lower HR, lower neuronal activity). Inhibiting adenosine increases activity. Methylxanthines also inhibits phosphodiesterases, which increases cAMP. Methylxanthines also increase activity of ryanodine receptors, thus increasing intracellular Ca2+.
Effects - Increase alertness, decrease fatigue. (also vasoconstriction, smooth muscle relaxation, mild cortical arousal, etc.)
Ex. Caffeine, theophylline
What are the differences between adenosine receptors?
A1 - Gi linked, has inhibitory modulation of many neurotransmitters. In the CNS, it causes sedation, anxiolysis, anticonvulsant activity. In the periphery, it can cause decreased heart rate.
A2 - Gs linked. In the vasculature, it causes vasodilation.
A2b - Gs-linked, mostly on glial cells with unknown function
A3 - Gq linked. It’s only activated in states of excessive catabolism, such as during seizures, hypoglycemia, stroke. It’s not antagonized by methylxanthines.
What is cocaine’s MOA? What is it used for?
Cocaine - Indirect-acting sympathomimetic agent. It inhibits (blocks) monoamine transporters (NE, 5HT, and lots of DA).
Use - Local anesthetic
*highly rewarding and addictive
How do amphetamines work? Which monoamine is MDMA more selective for? What are their effects (3) and what are they used for (3)? What are some examples of amphetamines?
Amphetamines - non-selective activation of monoamines
*MDMA (molly) is more selective for 5-HT
Effects - Wakefulness, alertness, increased ability to concentrate
Use - narcolepsy, anorexiant/weight loss, ADHD
Ex. dextroamphetamine, lisdexamfetamine, methylphenidate, dexmethylphenidate, Adderall
What are 5 non-stimulants that are used for ADHD?
Atomoxetine - NET inhibitor
Bupropion
Clonidine
Guanfacine
TCAs
*modafinil is a stimulant that is used for narcolepsy, not ADHD
How does solriamfetol, modafinil, and pitolisant work for narcolepsy? What are the 2 other agents that are used in narcolepsy?
solfiamfetol - NET and DAT inhibitor
modafinil - DAT
pitolisant - histamine 3 (H3) receptor antagonist/inverse agonist
antidepressants
Xyrem (GHB)
What proportion of children with ADHD will carry that diagnosis in adulthood? What diseases are at an increased risk if ADHD is left untreated?
- 1/3 of children with ADHD will have the diagnosis in adulthood
- increased risk of substance use and antisocial personality disorder if ADHD is left untreated
What is the diagnostic criteria of ADHD? (4)
Symptom domain - must have at least 6 symptoms present
Adults (17years+) - at least 5 symptoms are required for either of the two specifiers
Prior to age 12 - several inattentive or hyperactive symptoms must be present (starts in childhood, even if pt is an adult presenting)
Settings - Symptoms must be present in at least 2 settings
What are the symptoms in the Inattention domain (9)? How many and for how long do these symptoms need to persist?
*6 or more symptoms for 6 or more months
**inconsistent with developmental level and negatively impacting daily function
- fails to give close attention to details, makes careless mistakes
- difficulty sustaining attention in tasks or play activities
- doesn’t listen when spoken to directly
- doesn’t follow through on instructions/chores/homework
- difficulty organizing tasks and activities
- avoids, dislikes, reluctant to engage in tasks that require sustained mental effort
- loses things necessary for tasks/activities
- easily distracted by extraneous stimuli
- forgetful in daily activities
What are the symptoms in the Hyperactivity and Impulsivity domain (9)? How many and for how long do these symptoms need to persist?
6 or more symptoms for 6 or more months
**inconsistent with developmental level and negatively impacting daily function
**these tend to go down as the pt gets older
- fidgets with hands/feet
- leaves seat in situations when remaining seated is expected
- runs/climbs in inappropriate situations
- unable to play or engage in leisure activities quietly
- “on the go”
- talks excessively
- blurts out an answer before a question is completed
- difficulty waiting their turn
- interrupts or intrudes on others
Stimulants for ADHD - do we use weight based dosing in pediatrics? When is IR preferred? Can we use two different stimulants at once?
- Weight based dosing is not found to be helpful. We should treat them for what they need.
- IR preferred in pts <16kg due to limited low-dose availability of long-acting stimulants
- Don’t use two different stimulants at once
What are the special considerations with Mydayis, Daytrana, Vyvanse, and Jornay PM?
Mydayis - (mixed amphetamine salts) Max dose is 25mg/day for adults OR 12.5mg/day for ages 13-17 or if CrCL is 15-30mL/min
Daytrana - (methylphenidate patch) Will only work if pt responded to methylphenidate and would benefit from the patch. Apply patch to outside of hip 2 hours prior to needed effects, then remove after 9 hours
Vyvanse - (lisdexamfetamine) prodrug, converted to dextroamphetamine via first-pass metabolism. Must be swallowed whole. Not useful if pt didn’t respond to dextroamphetamine
Jornay PM - (methylphenidate HCl) take dose in the evening between 6:30-9:30pm. Must titrate at first, can’t switch 1:1 from IR methylphenidate.
What are some common adverse effects from stimulants? (11)
- appetite loss
- abdominal pain
- headaches
- sleep disturbances
- decreased growth
- hallucinations or other psychotic symptoms (rare)
- increased blood pressure
- increased heart rate
- sudden cardiac death (rare)
- priapism
- peripheral vasculopathy (Raynaud’s)
What is the important uncommon side effect of stimulants? How do we mitigate this risk?
Risk for sudden cardiac death - assess the risk of cardiac structural abnormality and family history. If concerned, do cardiac ECHO
How can we manage these stimulant side effects: reduced appetite/weight loss, stomach ache, insomnia, headache, rebound symptoms, irritability/jitteriness
Reduced appetite/weight loss - high calorie meal when stimulant effects are low (breakfast, dinner)
Stomach ache - give on full stomach, lower dose is possible
Insomnia - dose earlier in day, lower last dose of the day or give it earlier, consider a sedating med at bedtime
Headache - divide dose, give with food, give analgesics
Rebound symptoms - longer-acting stimulant trial, atomoxetine, antidepressant
Irritability/jitteriness - assess for co-morbid condition, reduce dose, consider mood stabilizer or atypical antipsychotic
What 7 things do we need to monitor while a patient is on a stimulant?
- appeptite
- behavior
- blood pressure
- growth rate
- heart rate
- sleep
- ECG (only in some patients with cardiac risks/meds)
What 2 α2 agonists are used in ADHD? What metabolism interaction is important? What adverse effects are associated with them (6)?
Intuniv (guanfacine ER) - 3A4 substrate!! dose adjustments needed with strong 3A4 inhibitors/inducers
Kapvay (clonidine ER)
AEs: decreased HR and BP, orthostasis, somnolence, dizziness, rebound HTN if abrupt discontinuation
What norepinephrine reuptake inhibitors are used for ADHD? What metabolism interactions are there? Do either of them require weight based dosing? What happens if you can’t swallow the capsules? What adverse effects are associated with them (3)?
atomoxetine (Strattera) - 2D6 substrate. Weight based dosing
viloxazine (Qelbree) - 2D6/UGT substrate, strong 1A2 inhibitor. Capsules can be swallowed whole or put in applesauce
AEs: increased HR and BP, increased suicidal thinking (black boxed warning)
What 7 things do we need to monitor when patients are taking non-stimulants for ADHD?
- appetite
- behavior
- blood pressure
- growth rate (atomoxetine)
- heart rate
- LFTs (atomoxetine)
- sleep
Is bupropion FDA approved in ADHD?
No–Bupropion is not FDA approved for ADHD
- May be considered if there’s concerns with medication misuse or side effects to a stimulamts
How does the effectiveness of TCAs compare to that of methylphenidate? What is the big concern that we have when using TCAs?
Do we use mood stabilizers for ADHD?
TCAs:
- LESS effective than methylphenidate
- Cardiac concerns - sudden cardiac death in children (can be lethal)!!
Mood stabilizers (atypical antipsychotics) -
- may be useful if there is comorbid bipolar disorder, conduct disorder, or intermittent explosive disorder
- do NOT use atypical antipsychotics as monotherapy
What are the AAP ADHD treatment guidelines for preschool, elementary/middle-school, and adolescents?
preschool: first line is parent training in behavior management (PTBM); second line is PTBM + FDA-approved medication
elementary/middle school: first line if FDA-approved medication + PTBM
adolescents: first line is FDA-approved medication + may offer PTBM
What are the NICE ADHD guidelines for adults? (step-wise treatment)
- Methylphenidate (short or long) OR lisdexamfetamine (switch if no response to one or the other)
- Dextroamphetamine (if unable to tolerate lisdexamfetamine long half life)
- Atomoxetine (if no symptoms response to above agents)
What is the impact of living situation and environment on the development and exacerbation of pediatric psychiatric disorders?
Kids in foster care are 3-4.5x more likely to be on psychotropic mediations.
- Increased trauma leading to behaviorial dysregulation?
Who has a higher risk of adverse effects from medications, adults or kids?
Kids! Metabolism is different in kids along with many other changes.
Ex. aripiprazole adds 20 ADDITIONAL pounds for kids on top of the 40lbs it already adds to adults
What is the DSM-5 criteria for Tic disorders?
Tourette’s - multiple motor and vocal tics present, onset before 18 years old, tics may wax and wane, but they must have been present for more than 1 year
Persistent (Chronic) motor or vocal tic disorder - either motor or vocal tics
Provisional tic disorder - symptoms for less than 1 year
What percent of pts with tic disorders also have ADHD or OCD? What is the rule of thirds?
~75% also have ADHD
~50% also have OCD
Rule of Thirds - about medication
1/3 resolve
1/3 improve
1/3 stay the same
(~10% have persistent symptoms as adults)
How do we treat tics?
1st line - α2 agonists (also good for ADHD)
- reduces symptoms by ~30%
- ex. clonidine, guanfacine, ER guanfacine
2nd line - atypical antipsychotics
- reduces symptoms by 30-60%
- ex. Aripiprazole, risperidone
- will see some weight gain, increases in blood sugar, increased prolactin
3rd line - typical antipsychotics
- reduces symptoms by 80%
- ex. Haloperidol, pimozide
- remember EPS!!
What is our drug of choice when using antipsychotics for tic disorder?
- Aripiprazole (FDA approved for 6-17 years old)
(also have risperidone, haloperidol, Orap (pimozide), etc.)
What is the risk of using stimulants for Tourette’s?
amphetamine based stimulants can exacerbate motor and vocal tic symptoms. However, ADHD is a common co-morbidity in Tourette’s, so we have to treat both. We can d/c the amphetamine stimulant and try to use atomoxetine or a TCA; If that doesn’t work, we can resume the amphetamine stimulant and adjust the antipsychotic to better control Tourette’s symptoms
What is the DSM-5 criteria for oppositional defiant disorder? What is different depending on if the child is more or less than 5 years old?
- Pattern of angry/irritable mood, argumentative/defiant behavior, and vindictivness for at least 6 months
- If less than 5 years old, the behavior should occur on most days for at least 6 months
- If over 5 years old, the behavior has to be at least once weekly for 6 months
What is the DSM-5 criteria for conduct disorder? How do we specify between childhood vs. adolescent onset?
- Repetitive and persistent pattern of behavior in which the rights of others or societal norms or rules are violated with at least three of these criteria in the past year: aggression to people and animals, destruction of property, deceitfulness or theft, and serious violations of rules.
Childhood-onset - started less than 10 years old
Adolescent-onset - started when they were over 10 years old
When should pharmacotherapy be used for ODD & CD? What medications do we use when pharmacotherapy is appropriate?
- pharmacotherapy is used as adjunct on top of therapy if other interventions have not worked
- treat underlying conditions (ADHD, depression/anxiety)
- drugs of choice: stimulants and clonidine/guanfacine BEFORE atypical antipsychotics
- atypical antipsychotics may be used to treat severe behaviors of aggression and defiance
- Usually will see a combo is a stimulant and α-agonist if pt has ADHD with impulsivity or if they need sedation for sleep
How can we treat separation anxiety disorder?
1st line for mild anxiety - psychotherapy
- if moderate-severe anxiety, do psychotherapy + combo therapy
SSRIs are drug of choice for drug therapy
*be sure to treat co-morbidities like depression, ADHD, bipolar, etc.
What is the DSM-5 criteria for autism spectrum disorder (ASD)? What are the hallmark signs & symptoms of ASD? What medical problems are associated with ASD?
- Persistent deficits in social communication and social interaction across multiple contexts
- Restricted, repetitive patterns of behavior, interests, and activities
Hallmark symptoms:
- aggression
- hyperactivity
- inattention
- irritablity
- mood instablity
- poor frustration tolerance
- self-harm
- severe temper tantrum
- OCD symptoms
- sleep disturbances
- hypersensitivity
*no medications have shown efficacy in treating the core ASD symptoms
**ASD is associated with seizure disorder (up to 30% have at least one seizure by age 20) and GI disorders
How can we treat disruptive behaviors in ASD? What do we use typical and atypical antipsychotics for in ASD? How effective are mood stabilizers, divalproex, and lamotrigine/levetiracetam for ASD?
1st line treatment - behavioral interventions (applied behavioral analysis)
Typical antipsychotics: haloperidol reduces social isolation & improves anger-related behaviors, hyperactivity, etc.
Atypical antipsychotics: apripiprazole (6-17yo) and risperidone (5-16yo) FDA approved for managment of irritablity/aggression. These are considered FIRST LINE! Can help with stereotypy and hyperactivity
Mood stabilizers: inconsistent for treating irritability or aggression
*divalproex has a modest effect, lamotrigine/levetiracetam have no significant effect on irritability
**many pts have co-morbid seizure disorders, so are receiving anticonvulsants
How do we treat repetitive behaviors/ADHD/sleep problems in ASD?
Repetitive behaviors - SSRIs, antipsychotics (haloperidol, risperidone, aripiprazole; watch out for 2D6 interactions with risperidone and aripiprazole), divalproex
- fluoxetine and paroxetine are 2D6 inhibitors
ADHD - stimulants (methylphenidate)
Sleep - sleep hygiene and medication, such as melatonin
What is the DSM-5 criteria with disruptive mood dysregulation disorder (DMDD)?
- Severe recurrent temper outbursts manifested verbally that are out of proportion with the intensity/duration of the situation
- Present in at least 2 of 3 settings (home, school, with peers) and is severe in at least one of these
- Diagnosis should not be made before age 6 or after age 18
How do we treat DMDD?
- First line are SSRIs and stimulants
- DMDD is more similar to depression, ADHD, or anxiety compared to bipolar, so we use antidepressants
- Need to differentiate from bipolar disorder (both for using antidepressants as well as evaluating the need for mood stabilizers)
What are the main differences in depression between children and adolescents?
- SIGECAPS also applies here, also one of the two of losing interest in what they used to enjoy and depressed mood most of the day
Children: physical complaints, irritability, conduct problems, can have suicidal ideation
Adolescents: express feelings of depression and suicidal behaviors more than younger children
*these symptoms are chronic (not episodic)
What is first line when treating depression in peds? What ages can fluoxetine and escitalopram be used? What SSRI should be avoided due to suicidal thinking risk?
First line is non-pharm treatment. The support of family/caregiver is necessary for success.
- CBT early enough can result in remission rates of 70%!!
- Fluoxetine is the only antidepressant that is FDA approved for kids down to 8 years old
- Escitalopram can be used in 12-17 year olds
*Avoid paroxetine in kids!!! It’s the 1st antidepressant with suicidal thinking warning
What is first line for bipolar I with and without psychosis and bipolar-depression in peds?
Bipolar I without psychosis - lithium is first choice, also valproate, carbamazepine, olanzapine, risperidone, quetiapine; may add 2nd agent if needed after 4 weeks
Bipolar I with psychosis - lithium is first choice, also valproate, carbamazepine WITH any atypical antipsychotic (mood stabilizer)
Bipolar depression - Lithium is first choice, then SSRI/bupropion as adjunct to lithium
What is first line in the treatment of PTSD in pediatrics?
- 1st line is trauma-focused psychotherapy
- SSRIs is the first line pharmacologic treatment
In childhood-onset schizophrenia, what symptom is more common when compared to adults and at what age do the symptoms begin?
- visual hallucinations more common than in adults
- onset of symptoms before age 13
*this is rare in children, adolescent prevalence is around adult prevalence of 0.5-1%
At what ages are atypical antipsychotics approved to treat pediatric patients?
For schizophrenia - Can use down to 13 years old
*paliperidone is approved down to age 12 for schizophrenia
- Ex. Aripiprazole, brexpiprazole, lurasidone, olanzapine, paliperidone, quetiapine, risperidone
For bipolar - Can use down to 10 years old
*olanzapine is only down to 13 years old
- Ex. aripiprazole, asenapine, lurasidone, olanzapine, olanzapine/fluoxetine, quetiapine, risperidone
How does pain sensitization develop?
- Tissue injury
- Local release of active factors like (PG, BK, K)
- Persistent activation/sensitization of Aδ/C
- Peripheral sensitization - Activity in ascending pathways + spinal facilitation
- Exaggerated output for given stimulus input
- Central sensitization - Ongoing pain + hyperalgesia
What are the types of pain fibers (Aβ, Aδ, C), what are their roles in pain transduction, and what are their functions?
Aβ - non-noxious (touch, pressure); innervates the skin; faster transduction of pain
Aδ - pain, cold; these are myelinated; fast transduction, has the reflex arc when something is sharp or really cold
C - pain, temp, touch, pressure, itch; these are unmyelinated; tranduce signal slowly
How can you estimate the type of pain someone is experiencing based on their description of pain?
Inflammatory - Throbbing, pulsating
Neuropathic - Stabbing, shooting, burning, tingling
Visceral - Squeezing
How will pain travel through the CNS and what receptors will be involved along the way?
Trauma occurs - Peripheral nociceptors on peripheral nerves receive the signal and that signal travels through the spinal cord, then through the spinothalamic tract to the brain. Also, the trauma activates the peripheral nervous system, which transmits the signal to activate the CNS at the spinal cord. This signal makes its way to the brain.
- There are temperature (TRP), acid (ASIC), and chemical irritant sensitive peripheral receptors that are involved in pain signaling
- the nerve transmission from periphery to the spinal cord involves many different ion channels.
There is a high expression of opioid receptors in the brain stem along the descending pathway.
How are substance P and NMDA/AMPA receptors involved in central and peripheral sensitization?
NMDA/AMPA - In the spinal cord, glutamate is released to transmit the pain signal. The pain signal then travels further up the path to the brain. These receptors increase expression and sensitivity during neuropathic pain sensitization
Substance P - Plays an important role in heightening pain responding. Causes vasodilation, degranulation of mast cells, release of histamine, and inflammation and prostaglandins.
Which opioids are phenanthrenes, non-phenanthrenes, or benzylisoquinolines?
Opium has 2 types of alkaloids (phenanthrenes, benzylisoquinolines)
- Phenanthrene - morphine, codeine, thebaine; these have 3 rings connected
- Non-phenanthrene - tramadol, meperidine, fentanyl
- Benzylisoquinolines - noscapine, papaverine; these have rings that aren’t fully connecting
What is the difference between opiates and opioids?
Opiates are only opioids that are naturally occurring
- Opioids is the overarching term
What is the metabolism and excretion of morphine/phenanthrenes? What 3 opioids are prodrugs?
Metabolism:
- Morphine/phenanthrenes go through first pass metabolism (morphine has 25% bioavailability) and are then metabolized by CYP2D6 and CYP3A4.
- CYP3A4 is creating an inactive ‘nor’ metabolite
- CYP2D6 is what creates most of the active metabolites
Excretion:
- Morphine/phenanthrenes go through glomerular filtration and are mostly excreted within the first 24 hours
Codeine - prodrug -> morphine
Heroine - prodrug
Tramadol - prodrug
What is the role of each opioid receptor type? What is each of their respective endogenous opioids?
GPCRs - family A are peptide receptors, can be Gi coupled to inhibit cAMP production, can open GIRK K+ channels, can close calcium channels
Mu - morphine; endogenous opioid is endorphin
- targeted for analgesia (but is not as effective for chronic pain), sedation, and as an antitussive (suppresses cough center in medulla oblongata), also as an anti-diarrheal
Kappa - ketocyclazocine; endogenous opioid is dynorphin
- activation leads to dysphoric feelings (aversive), so could potentially use as a treatment of addiction due to reducing dopamine release
Delta - deferens; endogenous opioid is enkephalin
- play a role in hypoxia/ischemia/stroke
- can reduce anxiety, depression, treat alcoholism, relieve hyperalgesia/chronic pain
- big side effect is seizures, so there’s no FDA approved delta opioids
Nociceptin/Orphanin FQ - endogenous opioid is nociceptin
- endogenous opioids are natural processes to relieve pain
