Exam 5

Question 1

Is ADHD due to genetic or non-genetic factors? What are some examples of each?

Answer 1

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.

Question 2

When looking at adults with and without ADHD, which MRI will show more brain activity?

Answer 2

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).

Question 3

What clinical presentation is associated with ADHD? (5) What is the possible circuitry mechanism for this presentation?

Answer 3

• 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.

Question 4

What is the MOA of methylxanthines? What are some examples of methylxanthines?

Answer 4

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

Question 5

What are the differences between adenosine receptors?

Answer 5

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.

Question 6

What is cocaine’s MOA? What is it used for?

Answer 6

Cocaine - Indirect-acting sympathomimetic agent. It inhibits (blocks) monoamine transporters (NE, 5HT, and lots of DA).

Use - Local anesthetic

*highly rewarding and addictive

Question 7

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?

Answer 7

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

Question 8

What are 5 non-stimulants that are used for ADHD?

Answer 8

Atomoxetine - NET inhibitor
Bupropion
Clonidine
Guanfacine
TCAs

*modafinil is a stimulant that is used for narcolepsy, not ADHD

Question 9

How does solriamfetol, modafinil, and pitolisant work for narcolepsy? What are the 2 other agents that are used in narcolepsy?

Answer 9

solfiamfetol - NET and DAT inhibitor

modafinil - DAT

pitolisant - histamine 3 (H3) receptor antagonist/inverse agonist

antidepressants
Xyrem (GHB)

Question 10

What proportion of children with ADHD will carry that diagnosis in adulthood? What diseases are at an increased risk if ADHD is left untreated?

Answer 10

• 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

Question 11

What is the diagnostic criteria of ADHD? (4)

Answer 11

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

Question 12

What are the symptoms in the Inattention domain (9)? How many and for how long do these symptoms need to persist?

Answer 12

*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

Question 13

What are the symptoms in the Hyperactivity and Impulsivity domain (9)? How many and for how long do these symptoms need to persist?

Answer 13

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

Question 14

Stimulants for ADHD - do we use weight based dosing in pediatrics? When is IR preferred? Can we use two different stimulants at once?

Answer 14

• 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

Question 15

What are the special considerations with Mydayis, Daytrana, Vyvanse, and Jornay PM?

Answer 15

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.

Question 16

What are some common adverse effects from stimulants? (11)

Answer 16

• 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)

Question 17

What is the important uncommon side effect of stimulants? How do we mitigate this risk?

Answer 17

Risk for sudden cardiac death - assess the risk of cardiac structural abnormality and family history. If concerned, do cardiac ECHO

Question 18

How can we manage these stimulant side effects: reduced appetite/weight loss, stomach ache, insomnia, headache, rebound symptoms, irritability/jitteriness

Answer 18

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

Question 19

What 7 things do we need to monitor while a patient is on a stimulant?

Answer 19

• appeptite
• behavior
• blood pressure
• growth rate
• heart rate
• sleep
• ECG (only in some patients with cardiac risks/meds)

Question 20

What 2 α2 agonists are used in ADHD? What metabolism interaction is important? What adverse effects are associated with them (6)?

Answer 20

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

Question 21

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)?

Answer 21

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)

Question 22

What 7 things do we need to monitor when patients are taking non-stimulants for ADHD?

Answer 22

• appetite
• behavior
• blood pressure
• growth rate (atomoxetine)
• heart rate
• LFTs (atomoxetine)
• sleep

Question 23

Is bupropion FDA approved in ADHD?

Answer 23

No–Bupropion is not FDA approved for ADHD
- May be considered if there’s concerns with medication misuse or side effects to a stimulamts

Question 24

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?

Answer 24

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

Question 25

What are the AAP ADHD treatment guidelines for preschool, elementary/middle-school, and adolescents?

Answer 25

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

Question 26

What are the NICE ADHD guidelines for adults? (step-wise treatment)

Answer 26

1. Methylphenidate (short or long) OR lisdexamfetamine (switch if no response to one or the other) 2. Dextroamphetamine (if unable to tolerate lisdexamfetamine long half life) 3. Atomoxetine (if no symptoms response to above agents)

Question 27

What is the impact of living situation and environment on the development and exacerbation of pediatric psychiatric disorders?

Answer 27

Kids in foster care are 3-4.5x more likely to be on psychotropic mediations. - Increased trauma leading to behaviorial dysregulation?

Question 28

Who has a higher risk of adverse effects from medications, adults or kids?

Answer 28

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

Question 29

What is the DSM-5 criteria for Tic disorders?

Answer 29

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

Question 30

What percent of pts with tic disorders also have ADHD or OCD? What is the rule of thirds?

Answer 30

~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)

Question 31

How do we treat tics?

Answer 31

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!!

Question 32

What is our drug of choice when using antipsychotics for tic disorder?

Answer 32

- Aripiprazole (FDA approved for 6-17 years old) (also have risperidone, haloperidol, Orap (pimozide), etc.)

Question 33

What is the risk of using stimulants for Tourette's?

Answer 33

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

Question 34

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?

Answer 34

- 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

Question 35

What is the DSM-5 criteria for conduct disorder? How do we specify between childhood vs. adolescent onset?

Answer 35

- 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

Question 36

When should pharmacotherapy be used for ODD & CD? What medications do we use when pharmacotherapy is appropriate?

Answer 36

- 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

Question 37

How can we treat separation anxiety disorder?

Answer 37

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.

Question 38

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?

Answer 38

- 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

Question 39

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?

Answer 39

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

Question 40

How do we treat repetitive behaviors/ADHD/sleep problems in ASD?

Answer 40

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

Question 41

What is the DSM-5 criteria with disruptive mood dysregulation disorder (DMDD)?

Answer 41

- 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

Question 42

How do we treat DMDD?

Answer 42

- 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)

Question 43

What are the main differences in depression between children and adolescents?

Answer 43

- 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)

Question 44

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?

Answer 44

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

Question 45

What is first line for bipolar I with and without psychosis and bipolar-depression in peds?

Answer 45

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

Question 46

What is first line in the treatment of PTSD in pediatrics?

Answer 46

- 1st line is trauma-focused psychotherapy - SSRIs is the first line pharmacologic treatment

Question 47

In childhood-onset schizophrenia, what symptom is more common when compared to adults and at what age do the symptoms begin?

Answer 47

- 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%

Question 48

At what ages are atypical antipsychotics approved to treat pediatric patients?

Answer 48

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

Question 49

How does pain sensitization develop?

Answer 49

1. Tissue injury 2. Local release of active factors like (PG, BK, K) 3. Persistent activation/sensitization of Aδ/C - Peripheral sensitization 5. Activity in ascending pathways + spinal facilitation 6. Exaggerated output for given stimulus input - Central sensitization 8. Ongoing pain + hyperalgesia

Question 50

What are the types of pain fibers (Aβ, Aδ, C), what are their roles in pain transduction, and what are their functions?

Answer 50

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

Question 51

How can you estimate the type of pain someone is experiencing based on their description of pain?

Answer 51

Inflammatory - Throbbing, pulsating Neuropathic - Stabbing, shooting, burning, tingling Visceral - Squeezing

Question 52

How will pain travel through the CNS and what receptors will be involved along the way?

Answer 52

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.

Question 53

How are substance P and NMDA/AMPA receptors involved in central and peripheral sensitization?

Answer 53

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.

Question 54

Which opioids are phenanthrenes, non-phenanthrenes, or benzylisoquinolines?

Answer 54

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

Question 55

What is the difference between opiates and opioids?

Answer 55

Opiates are only opioids that are naturally occurring - Opioids is the overarching term

Question 56

What is the metabolism and excretion of morphine/phenanthrenes? What 3 opioids are prodrugs?

Answer 56

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

Question 57

What is the role of each opioid receptor type? What is each of their respective endogenous opioids?

Answer 57

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

Question 58

What are the adverse effects of targeting the mu and delta receptor?

Answer 58

mu receptor: - AEs: respiratory depression, constipation, pruritus (side effect), addiction, urinary retention, N/V, miosis delta receptor: - AEs: seizures

Question 59

What is the difference between tolerance and hyperalgesia?

Answer 59

Tolerance - need increased dose of opioid to produce an equivalent effect due to receptor adaptation Hyperalgesia - Altered excitability of target neurons by NMDA, Cholecystokinin, dynorphin, and substance P to increase the sense of pain. Increasing the dose of the drug won't help in this case.

Question 60

What opioids are used for these non-analgesic purposes: Cough/antitussive (2), anti-diarrheal (3)

Answer 60

Cough/antitussive: - Codeine - Dextromethorphan (limited opioid activity, so not scheduled) Antidiarrheal: - diphenoxylate with atropine (schedule V) - loperamide (strong pgp substrate, so low BBB penetration, OTC) - eluxodaline (mu/kappa agonist, delta antagonist, schedule V)

Question 61

Which opioids (mu) agonists are used surrounding hospital procedures (6 drugs/groups)?

Answer 61

Sufentanil, remifentanil, Alfentanil - For anesthesia/sedation. Broken down by plasma esterases due to ester linkages (short acing) Fentanyl Hydromorphone, oxymorphine - no active metabolite Morphine - has extended release form, used in PCA Hydrocodone - lots of formulations with APAP Oxycodone - in formulations with APAP

Question 62

What are the 2 non-phenanthrene opioids that we focus on and what are they used for?

Answer 62

Tramadol - mild opiate analgesic - Has SNRI properties - Used as a painkiller when you don't want to have to use a stronger opioid Meperidine - - Has toxic metabolite (normeperidine) - Used to treat rigors (shivering) - renally excreted, not recommended for use without good justification

Question 63

What is methadone's MOA? What is it primarily used for?

Answer 63

Methadone - blocks NMDA receptors to disrupt the pain transmission signal, also mu agonist - primarily used for opioid dependence as MAT - may prolong QTc

Question 64

What are the MOAs of these agents: pentazocine and butorphanol, nalbuphine, and buprenorphine

Answer 64

Pentazocine, butorphanol - kappa agonist, partial agonist/antagonism at mu receptor - side effects: less dysphoria, hallucinations, increases BP and HR Nalbuphine - full agonist at kappa, antagonist at mu - the antagonism produces withdrawal Buprenorphine - partial mu agonist, weak kappa agonist, and delta antagonist - primarily used in opioid replacement therapy

Question 65

What are the roles of COX-1 and COX-2 enzymes in the formation of specific prostanoids and their function and how does NSAIDs inhibition of COX enzymes produce therapeutic and adverse effects?

Answer 65

COX-1 leads to formation of TXA2, which is needed for platelet aggregation. Also protective in the stomach lining. Blocking COX-1 can lead to GI bleeding/ulcer. COX-2 leads to formation of prostaglandins, which are important for pain transmission and will block platelet aggregation. Blocking COX-2 can lead to clotting.

Question 66

What are the differences and similarities between reversible NSAIDs, irreversible NSAIDs (aspirin), COX-2 selective inhibitors and APAP in terms of side effects, overdose symptoms/MOA, and clinical utility?

Answer 66

Reversible NSAIDs - Used for analgesic effects, anti-inflammatory, antipyretic. Competitive (reversible) inhibitors of COX1/2. Some can also inhibit leukotriene synthesis, which contributes to anti-inflammatory effects. Big adverse effect is renal function. Also risk of bleeding, inhibition of uterine motility, and GI distress/ulceration Aspirin - Used prophylactically as an anti-platelet. It irreversibly inhibits COX1/2 (low dose only COX1). Big adverse effect is Reye's syndrome. Also vertigo & tinnitus. Severe effects include respiratory alkalosis, metabolic acidosis, N/V, etc. COX-2 selective - Less GI bleeds/ulcers, but more risk of CV events (blood clots, strokes, and heart-attacks) APAP - Used as analgesic and antipyretic. Big risk is liver damage (dose-dependent, NAPQI toxin, needs GSH conjugation)! Also some renal toxicity.

Question 67

How do you treat an aspirin and APAP overdose?

Answer 67

Aspirin - Reduce salicylate load: increase urinary excretion by using dextrose or sodium bicarb - Treat by correcting metabolic imbalance Acetaminophen - Administer n-acetylcysteine to detoxify NAPQI

Question 68

What are the contraindications and warnings of using NSAIDs?

Answer 68

- CKD - Peptic ulcer disease - Hx of GI bleed *NSAIDs have CV risk (highest risk with diclofenac, lowest with naproxen) **all NSAIDs can interfere with bone healing ***can cause asthma exacerbations

Question 69

what is the MOA of sodium channel blockers as painkiller and what is the connection with anti-depressant activity, including the role of norepinephrine?

Answer 69

Sodium channels are involved in pain transmission. Local anesthetics - Lidocaine, bupivacaine, benzocaine Anticonvulsants - Lamotrigine, carbamezapine Tricyclic antidepressants - Amitriptyline SNRIs increase norepinephrine levels by acting on α2A receptors in the spinal cord, which produces analgesia. - Ex. Duloxetine, venlafaxine (milnacipran and tapentadol do not have sodium channel activity)

Question 70

How are calcium channel blockers (ex. gabapentin, pregabalin, ziconotide, keppra) used in chronic pain treatment and how are their MOAs?

Answer 70

CCBs for pain work to disrupt glutamate signaling by disrupting glutamate release Ex. Gabapentin, pregabalin, ziconotide, levetiracetam

Question 71

How does the DEA classify controlled substances?

Answer 71

Schedule I - No medical use & high abuse potential. Safety is not guaranteed. Ex. Heroin, marijuana, THC, LSD, etc. Schedule II - There is medical use, but high abuse potential and large risk of dependence. Ex. morphine, fentanyl, cocaine, PCP, oxycodone, etc. Schedule III - Medical use, moderate abuse and dependence. Ex. marinol (THC in oil capsule), ketamine, etc. Schedule IV - Medical use, low abuse and dependence. Ex. benzodiazepines Schedule V - Lower risk relative to schedule IV. Ex. cough suppressants with a small amount of codeine, lomotil

Question 72

Which drugs are stimulants (6), depressants (5), or psychedelics (5)?

Answer 72

Stimulants - cocaine, amphetamine, meth, bath salts, ecstasy, nicotine Depressants - opioids, alcohol, cannabis, GHB, inhalants Psychedelics - LSD, psilocybin, PCP, mescaline, ketamine

Question 73

What drugs work on mu receptors, serotonin receptors, cannabinoid receptors, GABA-b, adenosine receptors

Answer 73

Mu receptors - opioids (heroin, prescription meds) Serotonin receptor (5-HT) - LSD, mushrooms Cannabinoid receptors (CB1) - Marijuana, K2, spice GABA-B - GHB Adenosine - caffeine

Question 74

What drugs work on dopamine transporters, monoamine transporters, Ach receptors, NMDA receptors, and GABA-a receptors

Answer 74

Dopamine transporter - cocaine, amphetamine Monoamine transporters - MDMA/ecstacy ACh receptors - nicotine (agonist) NMDA receptor - PCP, ketamine (antagonists) GABA-A - benzos, barbiturates (Positive allosteric modulators)

Question 75

What are the roles of dopamine and glutamate in substance abuse?

Answer 75

Pleasure comes from the nucleus accumbens. There are also progressions into the frontal cortex, where decision making occurs, and to the hippocampus, where memory is formed. From the VTA, there is a dopamine neuron that projects towards the nucleus accumbens. There are also opioid neurons, glutamate inputs, GABA neurons, GABA neurons. All of these drugs influence the nucleus accumbens & dopamine in some way. Dopamine is important for assigning value to reward prediction. Dopamine does not encode liking, but it makes reward predictions. (ex. thinking something will result in a reward) Glutamate can increase DA activity in the nucleus accumbens. DA controls glutamate activity in the amygdala After a while, there will be a change in neuronal levels, called long term potentiation.

Question 76

What do these terms mean: incentive salience, synaptic strength, plasticity, physiological dependence, psychological dependence, positive and negative reinforcement

Answer 76

incentive salience - state or quality of an item that stands out relative to neighboring items. Ex. I want the red apple because it's better than the green apples. synaptic strength - how strong the signal between neurons are plasticity - the ability of a neuron to modify itself in response to a stimulus physiological dependence - body needs more drug (tolerance) due to cellular adaptations. The body withdrawals without the drug psychological dependence - mental urge to take the drug to function (addiction), compulsive need/craving, present even in absence of withdrawal positive reinforcement - the user feels pleasure/satisfaction when using negative reinforcement - trying to escape the negative effects of NOT using (using to avoid withdrawal)

Question 77

How can you distinguish between mild, moderate, and severe substance use disorder? How can you tell if the patient's withdrawal signs are emotional, physical, and/or life threatening?

Answer 77

Mild (2-3); Moderate (4-5), Severe (>6); based on # of symptoms/behaviors the pt displays Emotional - anxiety, depression, restlessness, insomnia, irritability, headaches, poor concentration Physical - sweating, racing heart, goose bumps, muscle spasms, tremors, N/V/D Life threatening - grand mal seizures, heart attacks, strokes, hallucinations, delirium tremens

Question 78

What is the pharmacologic stepwise treatment approach for non-malignant pain?

Answer 78

Step 1 - non-opioid, +/- adjuvant analgesic Step 2 - opioid for mild-moderate pain + non-opioid, +/- adjuvant analgesic Step 3 - opioid for moderate-severe pain, + non-opioid, +/- adjuvant analgesic *never get rid of non-opioid **step up if pain is persisting or increasing, step down if pain is resolving or toxicity occurs

Question 79

How do we classify and assess pain?

Answer 79

Assess: subjectively - PQRST(U); objective - look at behavioral or physiological changes (dilated pupils, paleness, sweating, etc.) P - palliative or precipitating factors Q - quality of pain R - region of pain location S - severity T - time-related nature (ex. only at bed time) U - impact of pain on you Intensity - use intensity scales (ex. 1-10, no pain to worst possible pain, wong-baker faces) Classify: - Acute (<3 months) or Chronic (>3 months) - Nociceptive (tissue), neuropathic (nerve), mixed (tissue and nerve)

Question 80

What are the goals of therapy when treating pain?

Answer 80

Correct - correct underlying cause of pain (if possible) Minimize - minimize pain and symptoms from pain/injury (may not be possible to be free of pain) Improve - improve quality of life (QOL) and activities of daily living (ADLs) Limit - limit pharmacotherapy side effects

Question 81

What pharmacological classes and agents within each class are used to treat non-malignant pain?

Answer 81

non-opioids - acetaminophen, NSAIDs adjuvant therapies - gabapentanoids, SNRIs, TCAs, skeletal muscle relaxants, antiepileptics, topical agents

Question 82

Which medications to treat non-malignant pain are on the Beer's Criteria? (12 drugs/classes, but can use 2 types with caution)

Answer 82

- COX non-selective NSAIDs - Indomethacin, ketorolac - Skeletal muscle relaxants - TCAs - Carbamazepine (last line, but could use) - Gabapentin/pregabalin (use with caution) - Duloxetine (can use) - Combining opioids + gabapentinoids - Anticholinergics - Antidepressants - Opioids + benzos

Question 83

How can we develop a patient specific plan to treat acute and/or chronic non-malignant pain?

Answer 83

For elderly: acetaminophen, topicals (lidocaine, diclofenac, capsaicin), SNRIs (caution), gabapentinoids (caution) Stepwise therapy - 1. Step 1 - non-opioid, +/- adjuvant analgesic 2. Step 2 - opioid for mild-moderate pain + non-opioid, +/- adjuvant analgesic 3. Step 3 - opioid for moderate-severe pain, + non-opioid, +/- adjuvant analgesic

Question 84

Which opioids are weak agonists? What is the one opioid antagonist?

Answer 84

Weak agonists - codeine, tramadol Antagonist - Naloxone (full agonists - morphine, hydrocodone, hydromorphone, oxycodone, meperidine, fentanyl, methadone)

Question 85

What are the differences between dependence and withdrawal?

Answer 85

Dependence - - Sedation/decreased level of consciousness (LOC) - Pinpoint pupils - Decreased respiratory rate - Bradycardia - Hypotension - Pale, clammy skin Withdrawal - - Indomnia/Agitation - Dilated pupils - Increased respiratory rate - Tachycardia - Hypertension - Sweating

Question 86

How can we treat opioid overdose?

Answer 86

Naloxone (Narcan) - can use IV or nasal spray *puts pt into withdrawal **should be prescribed with opioids in pts at risk for overdose Prescribe especially if pt has hx of overdose or SUD, on higher opioid dosages, or if concurrent benzodiazepine use

Question 87

What are the onsets of withdrawal for short vs. long acting opioids? How can we treat opioid withdrawal?

Answer 87

Onset of withdrawal for short-acting opioids occurs 8-24 hours after last use and the duration is 4-10 days. Onset of withdrawal for long-acting opioids (methadone) occurs 12-48 hours after last use and the duration is for 10-20 days. Treatment - - Clonidine (helps with symptoms of withdrawal such as HTN, sweating, vomiting, anxiety) - Buprenorphine - Methadone

Question 88

What are the uses, side effects, and pearls for opioids?

Answer 88

Opioids - Used for acute and chronic pain - SEs: antitussive, constipation, nausea & vomiting, itching, orthostatic hypotension, urinary retention, sedation, RESPIRATORY DESPRESSION - May need to start a stool softener and/or stimulant laxative - There is a potential for tolerance, dependence, and addiction - These are all schedule II, except for tramadol or codeine

Question 89

What are some counseling points for patients using the fentanyl patch? (3)

Answer 89

- One patch every 72 hours (3 days) - Can apply patch to chest, back, flank, or upper arm - Do not let the patch get too warm while wearing, or else body will absorb too much medication

Question 90

What are the allergic cross reactions between opioids?

Answer 90

Natural opiates - Morphine and Codeine: YES Avoid in patient with allergy to other natural opiates and semi synthetic opioids Semi synthetic opioids - Hydromorphone, Oxycodone, Oxymorphone, Hydrocodone, Buprenorphine: YES avoid in pts with allergy to other semi synthetic opioids and natural opiates Synthetic opioids - Fentanyl, Methadone, Meperedine: NO, these CAN be used if a pt has an allergy to another synthetic opioid, semi synthetic opioids, or natural opiate. **allergy is something like anaphylaxis or hives all over the body, not itching or nausea

Question 91

How do you convert one dose of opioid to another?

Answer 91

- Calculate the daily consumption for each opioid - Convert each opioid to oral morphine - Add morphine doses together to get total daily oral morphine dose - Reduce the equal analgesic dose by 25-50% - Split the total daily dose into appropriate dosing intervals based on the opioid selected

Question 92

What 3 disease states are PCAs commonly used for?

Answer 92

Used for severe acute non-malignant pain - Post-operative - Pancreatitis - Sickle cell crisis

Question 93

What should we monitor for a patient on analgesic therapy in order to adjust medications when necessary ?

Answer 93

- Evaluate patient 1 month after initiating the opioid, then reassess dose/risks/benefits, then evaluate every 3 months after that *make sure patient is not on opioids + benzos

Question 94

What is the recommended treatment for low back pain?

Answer 94

- Self-care & education. Pt should remain active if possible - Non-pharm treatment: exercise, CBT, interdisciplinary rehab Medications: - 1st line: acetaminophen and NSAIDs - 2nd line: SNRIs, TCAs *notice opioids not recommended

Question 95

What is the recommended treatment for osteoarthritis?

Answer 95

- Non pharm: exercise, weight loss, patient education Medications - 1st line: APAP, oral or topical NSAIDs - 2nd line: intra-articular hyaluronic acid, capsaicin

Question 96

What is the recommended treatment for fibromyalgia?

Answer 96

-Non pharm: low-inpact aerobic exercise, CBT, biofeedback, interdisciplinary rehabilitation Medications: - FDA approved: pregabalin, duloxetine - Other options, not FDA approved, but could be helpful: TCAs, gabapentin, venlafaxine

Question 97

What is the recommended treatment for neuropathic pain?

Answer 97

1st line: SNRIs, gabapentin/pregabalin 2nd line: Topical lidocaine, TCAs

Question 98

How can you reduce/taper opioids?

Answer 98

Tapering depends on low long they've been on opioids. - Patient taking opioids for more than a year: decrease by 10% per month - patient taking opioids for less than a year: decrease by 10% per week *once lowest available dose has been reached, the interval between doses can be extended (QD -> QOD) **if discontinuing opioids, they can be stopped once patient is taking them less than once per day

Question 99

What are 4 main things we want to treat in hospice patients?

Answer 99

Pain relief - ex. morphine Anxiety/Agitation - ex. lorazepam Nausea/Vomiting - ex. promethazine Secretions - ex. hyoscyamine *can stop everything else, unless they want it for comfort

Question 100

What are the opioid prescribing laws?

Answer 100

2014 Chronic Pain Law - any pt who is routinely taking opioids (w/ exception of palliative/hospice/nursing home/terminal), practitioners are required to assess risk vs. benefit/evaluation 2017 Opioid 7 Day Prescribing Limit - a physician prescribing an initial opioid prescription for patient may not prescribe more than a 7 day supply (exception of cancer, MAT for SUD, palliative care, professional judgment) 2019 INSPECT requirement - must check INSPECT each time before prescribing an opioid or benzodiazepine to any patient. There is no exception. If pt is on a pain management contract, can check every 90 days.

Question 101

What are the current trends in stimulant overdose deaths?

Answer 101

There has been an increase of deaths. This is predominantly due to fentanyl. However, psychostimulant overdoses are on the rise, as well. In summary, psychostimulants play a major role in drug overdose. *remember theres usually more than 1 drug in the patient's system if they overdose

Question 102

What are the different psychostimulants based on the neurotransmitter that's effected by their administration?

Answer 102

Nicotine - activates nicotinic acetylcholinergic receptor. Na+ enters the cell and K+ exits the cell, which is what makes up the action potential. This receptor has at least 12 different subunits. Nicotine is not degraded by acetylcholinesterase, so it has longer duration than ACh. Nicotine binding to receptor on dopamine neuron causes release of DA. Cocaine - Atagonist of amine transporters, such as DAT, SERT, and NERT. DAT ≥ SERT > NERT. This prevents reuptake of monoamines, and thus increases DA concentration and increases duration of DA action. Methamphetamine, Ecstasy, Bath salts - Block DA reuptake, push DA out of vesicles, and activates TAAR1, which phosphoylates DAT to turn it into a reverse transporter, which pushes more DA into the synapse. Cathinones - Derived from the Khat plant. Cause mild euphoria, similar to strong coffee. These are very easy to manipulate.

Question 103

What are the primary clinical effects of psychostimulants as their doses increase? (neurological, psych, ENT, cardiovascular, skin)

Answer 103

Neurologic - Delirium, tremor Psych - Anxiety, paranoia, hallucinations, delusions, repetitive behavior ENT - Profuse dental decay Cardiovascular - Tachycardia, HTN/vasospasm Skin - Diaphoresis (sweating)

Question 104

What is the effect of chronic psychostimulant use on the CNS dopaminergic system?

Answer 104

Stimulants usually work at the DA neuron synapse, then DA goes on to stimulate the nucleus accumbens. DA receptor downregulation in the brain can occur from chronic psychostimulant use. However, recovery can occur after stopping the drug. Addition is not fully linked to an increase in dopamine. Studies have shown that it's much more complex that just dopamine.

Question 105

Why is pseudoephedrine regulated to reduce methamphetamine use?

Answer 105

If you take away one oxygen from pseudoephedrine, you can make Methamphetamine. It's relatively easy to do. (Phenylephrine has an additional hydroxyl group, which prevents it from being converted to meth. However, it's a worthless oral decongestant)

Question 106

What are the primary manifestations of sympathomimetic toxidrome?

Answer 106

MATHS M - Mydriasis (blown-out pupils) A - Agitation, arrhythmia, angina T - Tachycardia H - Hypertension, hyperthermia S - Seizure, sweating Management: 1. Treat agitation, HTN, and seizures with benzodiazepines 2. Avoid pure β-blockers due to unopposed alpha agonism *HTN usually responds to sedation, hyperthermia denotes a poor prognosis, aggression and paranoia are often seen

Question 107

What is the legal status of natural and synthetic cannabinoids?

Answer 107

1937 - Marijuana Tax Act 1996 - California became the first legal medical marijuana state 2013 - "hands-off" policy for legal medical marijuana states. Essentially just follow state laws. 2018 - Hemp and hemp derived products are legal; Delta-8 THC is legal *Cannabis is still Schedule I under Federal Controlled Substance Ace

Question 108

What are the differences between hemp and marijuana based on THC content?

Answer 108

Hemp - 0.3% or less of THC *legal Marijuana - 15-20% of THC

Question 109

What are the clinical effects associated with cannabis and cannabinoids? (perceptual, affective, cognitive, physical)

Answer 109

Perceptual - temporal slowing of time, illusions Affective - euphoria, disinhibition, anxiety Cognitive - suspiciousness or paranoid ideation, impaired judgement/reaction time/attention Physical - tachycardia, postural hypotension, dry mouth

Question 110

What is the endocannabinoid system and what are the effects of key cannabinoids (THC and CBD) on this system? (4 key components, how endocannabinoids & phytocannabinoids work)

Answer 110

4 key components: - Receptors: CB1 (psychoactive) and CB2 (immune regulation); Brain has more CB1, brainstem doesn't, so respiratory depression risk is low! CB2 is present in periphery, which enhances migration of immune cells into inflammatory site. - Ligands (anandamide [AEA] and 2-AG): synthesized on demand - Transporter (EMT) - Enzymes that synthesize and degrade *we do not have THC like compounds endogenously. We have compounds that work in the ECS (endocannabinoid system), but not THC-like compounds. Endocannabinoids & phytocannabinoids are retrograde regulators, which means they are formed post-synaptically, are released into the clept, and then work pre-synaptically. They block the release of GABA and glutamate at CB1R. - THC is a partial agonist at CB1R, which synthetic cannabinoids are full agonists.

Question 111

What is the abuse potential of cannabis and what is its association with mental health disorders?

Answer 111

about 10% of cannabis users will develop cannabis use disorder (need at least 2 criteria) *the risk of developing CUD is the cumulative effect of many factors, making it impossible to predict who will move from experimentation to regular use to CUD It's difficult to prove is cannabis use is associated with mental health disorders. There is growing evidence for an association, but association ≠ causation. - Age and use onset and potency appear to be key determinants in whether or not cannabis can lead to psychosis

Question 112

What are the symptoms and management of cannabinoid hyperemesis syndrome?

Answer 112

Cannabinoid Hyperemesis Syndrome - - Cyclic vomiting/abdominal pain that occurs after prolonged, excessive use. - Relief is achieved by sustained cessation. - May be associated with pathological bathing, where taking a hot shower makes them feel better. Treatment: - Cannabis cessation - Benzodiazepines - Haloperidol - Capsaicin cream

Question 113

What are the 3 FDA approved cannabinoid drugs?

Answer 113

Marinol (Dronabinol) - synthetic Δ9-THC in sesame oil - Schedule III - Used to counter loss of appetite Nabilone (Cesamet) - THC mimetic - Schedule II - Used as an anti-emetic and off label for chronic pain (fibromyalgia, MS) Cannabidiol (CBD) - may antagonize THC @CB1 - FDA approved for seizure disorders (Dravet Syndrome, Lennox-Gastaut Syndrome), but most commonly used for pain

Question 114

What are the differences between delusions, hallucinations, and illusion? Which ones are most commonly caused by psychedelic drugs?

Answer 114

Delusions - Fixed, false belief unresponsive to logic. Paranoia is a common manifestation Hallucinations - A false perception arising from internal stimuli. Creates a false reality. Ex. Nothing is there, but the brain thinks something is there Illusion - A misperception of external stimuli. It distorts reality. Ex. Something is there, but the brain perceives it wrong. *i think illusions are most common, but it doesn't exactly say

Question 115

What are the differences between classical psychedelics and dissociative psychedelics based on their MOAs and clinical effects?

Answer 115

Classical - Most are agonists of 5-HT2A receptors (exception of MDMA, which stimulates 5-HT release) - Derivatives of phenethylamine: Mescaline, MDMA; Lowest potency, long lasting, and has cross tolerance to LSD - Derivatives of tyramine: LSD, DMT - Psilocybin (pro-drug) Dissociative - NMDA receptor antagonists (inhibition of GABA release and disinhibition of glutamate release). These induce anesthesia AND analgesia. - Phencyclidine (PCP): More potent than ketamine, also is D2 receptor agonist. Can cause severe dissociation and analgesia, leading to self-mutilation without recognition. - Ketamine: Esketamine FDA approved in treatment resistant depression. Also used in opioid tolerant patients for chronic pain. - Muscimol: agonist of GABA-A that can induce dissociatie psychedelic effects. - Dextromethorphan: Abused in high schoolers

Question 116

What are the acute and long-term/psychological adverse effects of psychedelic drug use?

Answer 116

Short-term physiologic - Tachycardia, hypertension, tremors, dry mouth, nausea, hyperthermia Acute dysphoric reaction - Terrifying thoughts, fear of insanity, fear of losing control, fear of death Psychological - Flashbacks, enduring changes in personality, exacerbate underlying psychotic disorder, instigate prolonged psychotic disorder *rate of psychosis after LSD is 1-5%

Question 117

What is the current interest in psychedelics as psychotherapeutics?

Answer 117

- Cancer-related psychological distress - PTSD - Depression - Substance Use Disorder (alcohol) So far, clinical trials have had small sample size, lack of or inadequate controls, selection bias, etc. All of this just means it's hard to apply this to the real world. *more than 90% of volunteers are excluded from most clinical trials of psilocybin

Question 118

What are the primary psychoactive inhalants and what are their MOAs?

Answer 118

Alkyl nitrites - Produce nitric acid. Commonly called 'poppers'. NO release causes relaxation of anal sphincter, enhanced erections, euphoria. Consequence is decreased oxygen due to methemoglobinemia. Volatile solvents - Liquid at RT and evaporate readily when exposed to air. Toluene acts on many channels, but the important one is GABA-A. Causes euphoria and locomotor stimulation. Can cause CNS depression and slurred speech at high doses. - Toluene (model glues, spray paints), Acetone (nail polish remover, rubber cements), Benzene (cleaning fluids, rubber cements), Butane (cigarette lighters, hair spray, spray paint) *Highest frequency of use among adolescents, especially in isolated communities

Question 119

What are the adverse effects of psychoactive inhalant misuse?

Answer 119

- Asphyxiation: from repeated inhalations that lead to high concentrations of inhaled fumes - Suffocation - Convulsions or seizures - Coma - Choking: due to vomiting - Fatal injury: from intoxication - Neurotoxicity/degeneration - Sudden sniffing death syndrome: Development of fatal arrhythmias within minutes of inhalation. *probably 100-200 deaths per year from these

Question 120

What are the kinetics and enzymes involved in alcohol metabolism?

Answer 120

Alcohol is 90% metabolized by the liver. - At lower levels, ADH (alcohol dehydrogenase) metabolizes the liver - At higher levels, MEOS (involves CYP2E1) metabolizes alcohol. CYP2E1 has a low affinity for alcohol, so it only works at higher levels. If alcohol levels are persistently high, our body will make more CYP2E1, which will impact drugs if they are metabolized by CYP2E1. - ALDH metabolizes acetaldehyde to acetate: ALDH1B1 and ALDH2 (only 50% of asians have ALDH2). If homozygous for ALDH2*2, the person cannot tolerate alcohol. Heterzygous for ALDH2*2 means reduced metabolic activity, but can still drink (asian glow).

Question 121

What are the effects of alcohol at low, intermediate, and high levels.

Answer 121

low levels: (30-60mg/dL) euphoria, disinhibition, talkative, analgesia intermediate levels: (80-120mg/dL) CNS stimulation (mood swings, aggression), CNS depression (slurred speech, ataxia, sedation, irrational dehavior) high/fatal levels: (300-500mg/dL) respiratory paralysis

Question 122

What are the CV, physiological, and long-term adverse effects and drug-drug interactions of acute and chronic alcohol use, taking into account the dose and persons gender?

Answer 122

*alcohol is a dirty drug. We especially know that it acts on GABA-A and the opioid receptor. Cardiovascular - vasodilation (warm, flushed, reduced BP, increase HR); with moderate use, there is a reduced risk of coronary disease; with heavy use, can affect the heart by causing cardiomyopathy, arrhythmias, HTN, hemostasis Physiological - Hypothermia, secretagogue (increases HCl secretion and can cause chronic gastritis in alcoholics) appetite stimulant at low dose, appetite depressant at high dose Long-term - Cirrhosis, anemia, cancer Drug-drug interactions - - CNS depressants (opioids, antipsychotics, antihistamines) - ALDH inhibitors (disulfiram, antimicrobials, sulfonylureas) - APAP - ASA

Question 123

What are the MOAs of the different pharmacological treatments for alcohol use disorders (both FDA approved and off-label)

Answer 123

Fomepizole (Antizole) - ADH inhibitor. Used in cases of poisoning by ethylene glycol (MeOH). This will slow formation of formaldehyde and toxic metabolites, so the liver has more time to metabolize them. Disulfiram (Antabuse) - FDA approved. irreversible inhibitor of ALDH2. The effects persist up to 14 days. This inhibits the metabolism of acetaldehyde, which essentially throws the person into hangover symptoms. Acamprosate (Campral) - FDA approved. NMDA antagonist/GABA agonist. Reduces relapse and prolongs abstinence Naltrexone (Revia) - FDA approved. Opioid receptor antagonist. Prevents relapse and the people who do relapse are in better control. Topiramate (Topamax) - Not FDA approved. Inhibits glutamate, enhances GABA. Similar to acamprosate, which reduces relapse and prolongs abstinence. Balcofen - Simulates GABA-B receptors. It reduces anxiety and craving, and at high doses have been shown to reduce drinking. Varenicline (Chantix) - Nicotinic acetylcholine receptor partial agonist. Approved for smoking cessation and tests are underway to see its effectiveness for alcoholism

Question 124

How do polymorphisms in ALDH and mu opioid receptors play a role in alcohol users' ability to consume alcohol and be treated for it?

Answer 124

Acetaldehyde is metabolized by ALDH1B1 and ALDH2 (only 50% of asians have ALDH2). If homozygous for ALDH2*2, the person cannot tolerate alcohol. Heterozygous for ALDH2*2 means reduced metabolic activity, but can still drink (asian glow). 118G mutation in the mu receptor causes patients to respond better to naltrexone

Question 125

What is the difference between morphine and heroin? How is heroin synthesized and metabolized? What are the risks associated with kratom and fentanyl/acetylfentanyl mixed herion?

Answer 125

Heroin is a pro-drug that gets metabolized into morphine. - Metabolized by esterases. - Rapidly crosses BBB due to high lipid solubility. Kratom - weak mu opioid agonist. It's legal and used as a natural pain remedy, but it may be just as addictive as heroin. It doesn't cause as much respiratory depression as herion due to being derived from mitragynine and being a biased agonist. Acetylfentanyl is 5-15x more potent than morphine. (carfentanil is 10,000x more potent than morphine.) When added to herion, the potency is higher. It can mask a weak heroin batch.

Question 126

What are the treatments of opioid dependence and what are their MOAs and limitations?

Answer 126

Methadone - full mu opioid agonist and NMDA antagonist (helps w/ pain). It's slow acting (long half life) and provides relief from withdrawal. Buprenorphine - mu opioid partial agonist. Blocks the full agonist effect, but provides some activation to prevent withdrawal. However, Subutex has abuse potential. Suboxone has naloxone in it to prevent IV high. Naltrexone - Full antagonist. Decent oral bioavailability, but better IM. Will cause withdrawal. Naltrexone is NOT naloxone! Naloxone is IM/intranasal, naltrexone can be given PO. Naltrexone is for medication assisted therapy, naloxone is a rescue drug.

Question 127

What are the benefits and limitations of narcan used to treat opioid overdose?

Answer 127

Naloxone (Narcan) is the rescue drug. It may require multiple doses. (Repeat every 2-5 mins if pt is not conscious.)

Question 128

What effect can these drugs have on the fetus: Amphetamines/marijuana/nicotine, cocaine, alcohol

Answer 128

Amphetamines, marijuana, nicotine - Low birth weight, premature birth, higher risk of stillbirth Cocaine - Lower IQ, poor growth Alcohol - fetal alcohol syndrome (problems of head and face, heart defects, mental problems)

Question 129

What is neonatal abstinence syndrome and how can it be treated?

Answer 129

Neonatal abstinence syndrome - Symptoms may begin 24-48hours after birth or as late as 5-10 days. Symptoms include tremors, yawning, poor feeding, and sweating. *babies cannot exhibit psychological dependence **heroin and other opiates, including methadone, can cause serious withdrawal that can last for up to 4-6 months. Also may cause seizures. Treatment: - Non-pharm: supportive care, such as swaddling, hypercaloric feeding, rehydration, etc. - Pharm: morphine, sublingual buprenorphine, or methadone (morphine and buprenorphine are better than methadone). Also maybe clonidine.

Question 130

What is the MOA of benzodiazepines and what are the risks associated with chronic use? What drug is a reversal agent for benzos?

Answer 130

Benzos are a positive allosteric modulator at the GABA-A receptor Risks with chronic use: - abuse and drug dependence - BZD withdrawal syndrome, which includes seizures, hallucinations, depression *flumazenil can be used for reversal

Question 131

What is the DSM-5 criteria for substance use disorders? (11)

Answer 131

Substance Use Disorders - problematic pattern of substance use leading to clinically significant impairment or distress, as manifested by 2 of the following, occurring in a 12 month period: - Taken in large amounts or over a longer period than intended - Persistent desire or unsuccessful efforts to cut down or control use - Great deal of time spent in activities necessary to obtain substance or recover from use - Craving, strong desire, or urge to use - Recurrent use results in failure to fulfill major role obligations - Continued use despite consistent or recurrent social or interpersonal problems caused or exacerbated by use or effects of use - Important activities are given up or reduced - Recurrent use in situations in which it is physically hazardous - Continued use despite knowledge of having a persistent or recurrent physical or psychological problem related to use - Tolerance - Withdrawal

Question 132

How do we use benzodiazepines and antiseizure drugs in the treatment of alcohol withdrawal? How does that change in concomitant organ dysfunction? What does the evidence say about using anticonvulsants (carbamazepine, valproic acid, phenytoin) to prevent/treat alcohol withdrawal related seizures?

Answer 132

There is prophylaxis/Fixed dosing that we use for people with a history of DTs or if they have a high CIWA score: - BZD: Ex. Chlordiazepoxide 25mg TID x2 days, BID x2 days, daily x2 days, then d/c - PRN lorazepam to supplement Individualized: lowers amount of benzo pts get & reduces treatment duration - CIWA <8-10: nonpharm treatment - CIWA 8-15: Medicate - CIWA > 15: Medicate with benzo, there's a risk of complication if untreated *if liver function, use lorazepam/oxazepam **carbamazepine may be effective for mild/mod symptoms, valproic acid may reduce severity of withdrawal symptoms, including seizures, phenytoin is NOT effective to treat withdrawal seizures

Question 133

What are the stages of alcohol withdrawal, including time frame for potential onset of delirium tremens? What are the risk factors for developing DTs?

Answer 133

Stage I: ~6-8 hours; Moderate autonomic hyperactivity (anxiety, tremulousness, tachycardia, insomnia, nausea, vomiting, diaphoresis) and a craving for alcohol Stage II: ~24 hours; Autonomic hyperactivity with auditory or visual hallucinations lasting ~1-3 days (most remain lucid and oriented) Stage III: ~1-2 days; ~4% develop grand mal seizures ~7-48 hours after the drop in BAC Stage IV: 3-5 days; DTs in ~5% of patients (confusion, illusions, hallucinations, agitation, tachycardia, hyperthermia). 5-15% mortality associated with DTs due to arrhythmias, shock, infection, trauma, or aspiration

Question 134

What are the risk factors for delirium tremens?

Answer 134

- Prior history of DTs (this is the #1 predictor of DTs) - Number of detoxifications - Consuming equivalent of 1 pint of whiskey per day for 10 of 14 days prior to administration - Early symptoms of withdrawal - Hepatic dysfunction

Question 135

What vitamin supplements do we use when treating alcohol withdrawal and dependence?

Answer 135

Thiamine - Always recommend if there's any suspicion of alcohol use

Question 136

What is Wernicke's encephalopathy and Korsakoff's psychosis? How do we treat these conditions?

Answer 136

Wernicke's encephalopathy - Results from thiamine deficiency. Give thiamine before dextrose-containing fluids, since dextrose can increase the risk of Wernicke's encephalopathy. Thiamine is a co-factor in glucose metabolism, and Wernicke's can be precipitated by high glucose loads Korsakoff's psychosis - Chronic condition, treat with antipsychotics

Question 137

What medications are used for alcohol use disorder? What are their pros and cons, side effects, monitoring parameters, and drug interactions?

Answer 137

Disulfiram - - Potential for CV collapse, death - Must have a highly motivated person - Monitor LFTs - The disulfiram reaction will be present for up to 14 days after discontinuation--caution with alcohol Acamprosate - increases abstinence - renally eliminated, need renal dose adjustment (avoid in severe renal impairment) - side effects: diarrhea, nausea, depression, anxiety - suicidality warning - monitor renal function Naltrexone - decreases binge drinking, helps increase time between drinking days - warning for injection site reactions (need to know if pt experiences signs of infection) - monitor LFTs at baseline and routinely - routinely monitor pain management needs *risk of opioid overdose if pt discontinues this and keeps drinking

Question 138

How do we treat the symptoms of opioid withdrawal? (5 symptom groups to treat)

Answer 138

Muscle aches/tension -> APAP or NSAID Agitation/Anxiety/Insomnia -> Hydroxyzine and BZDs (only use BZD if inpatient, not outpatient) Abdominal cramping/N/V -> Ondansetron Diarrhea -> Loperamide Autonomic effects (sweating/yawning/increased tearing/runny nose) -> clonidine (preferred from IN medicaid) or lofexidine (FDA approved)

Question 139

What are the ASAM Focused Update 2020 guidelines for the treatment of opioid use disorder?

Answer 139

**Treat withdrawal symptoms (~7 day time frame, individualized) - Use medications FIRST (buprenorphine, methodone) - Psychotherapy should be offered - Pregnant women should be screened for OUD in prenatal care, then be offered buprenorphine or methadone - Incarcerated people need to be screened and treated - Combo treatment with opioids + benzos is NOT recommended

Question 140

What is important about treatment of OUD with methadone 2) or buprenorphine (4)?

Answer 140

Methadone - must be given in a licensed treatment program - Serious concern for QTc prolongation Buprenorphine - Usually given in combo with naloxone (SL tab, film strip). This has poor bioavailability when swallowed, so must be dissolved. - Initiate therapy when there are clear signs of withdrawal (to avoid precipitating withdrawal), administer in divided doses on day 1 - Monitor LFTs, watch out for serotonin syndrome - Risk of respiratory depression in overdose is much less common than with opioids including methadone (due to partial agonist effect) *ask patient which one they want to do & think about access

Question 141

What is Sublocade? When do we use it and what should we monitor for?

Answer 141

Extended-release injection of buprenorphine - Use for moderate to severe opioid use disorder - Pts need to be initiated on SL buprenorphine for at least 7 days prior to the first injection - Monitor for serotonergic syndrome

Question 142

When was Narcan FDA approved OTC?

Answer 142

Naloxone kits - in March of 2023, FDA approved OTC nasal spray

Question 143

What P450 interactions should we be aware of in the treatment of SUDs?

Answer 143

Methadone - - P450 2B6, 3A4(!!!!), 2C19, 2D6 Buprenorphine - - P450 3A4!!!