IP7 Exam 3

Which of the below are monoamines? (select all that apply)

a) Dopamine

b) Norepinephrine

c) Acetylcholine

d) Glutamate

e) Serotonin

a) Dopamine

b) Norepinephrine

e) Serotonin

What is the major receptor type at the autonomic ganglia and neuromuscular junctions?

a) Nicotinic acetylcholine receptor (cation channel)

b) Muscarinic acetylcholine receptor (metabotropic)

c) Metabotropic glutamate receptor (mGluR)

d) Alpha adrenergic receptors

a) Nicotinic acetylcholine receptor (cation channel)

Select the best description of alpha2 adrenergic receptors:

a) Excitatory action, increasing PLC activity via Gq to increase sympathetic outflow

b) Excitatory action, increasing cAMP production via Gs

c) Inhibitory action - reduce sympathetic outflow from the vasomotor center

d) Inhibitory action, increasing cAMP production via gi

c) Inhibitory action - reduce sympathetic outflow from the vasomotor center

Where is the concentration of Ca2+ the highest in a normal muscle cell?

a) Cytoplasm

b) Cell wall

c) Sarcoplasmic reticulum

d) Golgi

e) Nucleus

c) Sarcoplasmic reticulum

Select the best description of the role of RyRs (ryanodine receptors) in a muscle cell:

a) Sodium-induced potassium release from the SR

b) Calcium-induced potassium release from the SR

c) sodium-induced calcium release from the SR

d) calcium-induced calcium release from the SR

d) calcium-induced calcium release from the SR

What is spasticity?

- upper motor neuron disorder: MS, cerebral palsy, spinal cord injury, brain injury (central dysfunction)

- stiffness, hypertonicity

What is a spasm?

- involuntary contraction (twitch, cramp)

- commonly associated with skeletal muscle pain (acute and chronic)

What are the anti-spasticity drugs?

- baclofen

- dantrolene

- diazepam

- tizanidine

which antispastics have activity in the CNS?

- baclofen

- diazepam

- tizanidine

Which antispastics have activity peripherally only?

- dantrolene

- botulinum toxin

What is the mechanism of action of baclofen?

GABA-B agonist (action in the spinal cord - centrally acting)

Activation of GABA-B results in hyperpolarization by three distinct actions

1 - closure of presynaptic calcium channels

2 - increased postsynaptic K+ conductance

3 - inhibition of dendritic calcium influx channels

What are the potential adverse effects of baclofen?

- dizziness

- confusion

- respiratory depression

- withdrawal (hallucinations seizure)

What is the mechanism of action of tizanidine?

alpha-2 agonist (presynaptic inhibition in the spinal cord)

What are the potential adverse effects of tizanidine?

- asthenia (weakness)

- drowsiness

- dry mouth

- hypotension

- hepatotoxicity

- withdrawal symptoms with abrupt discontinuation

What is the mechanism of action of diazepam?

increase GABA-A opening frequency

What is diazepam used for (as a skeletal muscle relaxant)?

Adjunct for the relief of skeletal muscle spasm and spasticity (used for BOTH spasm and spasticity)

In which patient populations should diazepam be avoided?

avoid in renal/hepatic impairment

What are the potential adverse effects of diazepam?

- sedation higher than others in this group

- withdrawal risks

What is the mechanism of action of dantrolene?

inhibits calcium release from the sarcoplasmic reticulum (RyR1 inhibitor)

What are the potential adverse effects of dantrolene?

- hepatotoxicity

- weakness

- less sedation than diazepam & baclofen

What are the antispasmodics?

- carisoprodol

- chlorzoxazone

- *cyclobenzaprine*

- metaxalone

- methocarbamol

- orphenadrine

What is the mechanism of action for cyclobenzaprine?

reduces tonic somatic motor activity (MOA not well known)

What is the therapeutic use of cyclobenzaprine?

- short-term use in muscle spasm (2-3 weeks)

- used as an adjunct with rest and physical activity

What are the potential side effects of cyclobenzaprine?

- confusion and visual hallucinations

- similar ADEs to TCAs because of similar structure (anticholinergic effects - pupillary dilation, dizziness, confusion, urine retention, constipation)

In which patient populations should cyclobenzaprine be avoided?

- avoid in older patients (anticholinergic effects - fall risk)

- use caution in those with cardiac conduction/arrhythmias

- avoid use in closed angle glaucoma (increases intraocular pressure)

What is the mechanism of action of succinylcholine?

Agonist at nicotinic (n) AchR (sustained local muscle endplate depolarization)

- voltage-gated sodium channel in a prolonged inactivation state (desensitization)

- binds at Ach binding site (opening channel and holding it open to prevent repolarization)

What enzyme metabolizes succinylcholine in the liver and plasma?

butyrylcholinesterase (BCHE)

What warnings are associated with succinylcholine?

- pediatric: acute rhabdomyolysis with hyperkalemia (K+ efflux from extrajunctional receptors)

- genetic variation: extended action, malignant hyperthermia (uncontrolled calcium release from RyR)

What are the characteristics of malignant hyperthermia?

- triggered by succinylcholine or volatile anesthetics

- calcium release from the skeletal muscle sarcoplasmic reticulum

- hyperkalemia (acute K+ release)

- rapid CO2 increase, tachycardia, tachypnea, muscle rigidity

- rhabdomyolysis -> acute kidney injury

How does the mechanism of succinylcholine differ from the other antispasmodics (unique characteristics)?

There is an initial contraction before the paralysis of the muscle (still contracts once, but then blocks to prevent repolarization). Because of this, there is an additional risk of transient increase in intraocular pressure, gastric pressure (regurgitation risk) and myalgia (less common in non-ambulatory patients).

This drug is also fast on and fast off (depending on the plasma acetylcholinesterase concentrations).

What are the non-depolarizing neuromuscular blockers?

- tubo*cur*anine

- ro*cur*onium

- ve*cur*onium

- pan*cur*onium

- cisatra*cur*ium

- atra*cur*ium

all contain "cur"

What is the pharmacological class of succinylcholine?

depolarizing neuromuscular blocker

What is the mechanism of action of the non-depolarizing neuromuscular blockers?

- compete with Ach (prevent cations from entering = no contraction)

- reversed by increasing Ach (cholinesterase inhibitors such as neostigmine or pyridostigmine

What must be done for patients who are on non-depolarizing neuromuscular blockers?

These patients MUST be ventilated (it will paralyze the diaphragm - aspiration risk)

What is the mechanism of action of botulinum toxin?

blocks presynaptic Ach release (persistent)

What is botulinum toxin indicated for?

spasticity

What are the potential adverse effects of botulinum toxin?

- may spread from the area of injection

- asthenia

- muscle weakness

- urinary incontinence

- breathing difficulties

These are only a concern if the toxin spreads out to the whole body (overdose), and are not commonly seen with local action.

What are the phytocannabinoids?

synthesized from the natural plant (leaves, flowers, seeds, etc.) - mixed but can be purified

Includes:

- delta-9-tetrahydrocannabinol (THC)

- cannabidiol (CBD)

What is the mechanism of action of THC?

partial agonist at CB1 and CB2

Has both euphoric and psychoactive effects.

What is the mechanism of action of cannabidiol (CBD)?

- agonist at 5HT1A receptors (anxiolytic effect)

- may non-competitive inverse agonism/antagonist at CB1/CB2 (much is unknown)

Is there a psychoactive effect associated with CBD use?

NO!

CBD is NOT an agonist at CB1 or CB2

What is Epidolex (cannabidiol) used for?

- seizures caused by Lennox-Gestaut syndrome and Dravet syndrome

- seizures associated with tuberous sclerosis complex

- very high dosage relative to non-prescription CBD products (2.5-12.5mg/kg twice daily)

What is the mechanism of action of Epidolex?

MOA is mixed/not well understood

- agonist at TRPV1

- inhibits presynaptic Ca2+ via GPR55

- agonist at 5HT1A

What are the potential ADRs of Epidolex?

- appetite suppression

- somnolence

- diarrhea

What interactions are important to note about Epidolex?

- clobazam levels major increase (and others) due to CYP3A4 and CYP2C19 inhibition

- elevated hepatic transaminase (especially with valproate)

What are the synthetic CB1 agonists?

- CPP-55

- ACPA

What are the synthetic CB2 agonists?

- JWH-133

- NMP7

- AM1241

What are the synthetic CB1/CB2 nonselective agonists?

- CP55940

- ajulemic acid (AJA)

- nabuilone

- dronabinol

Nabulone and dronabilol have very similar effects to THC (synthetic THC)

What are the approved uses of dronabinol and nabilone?

- anorexia in patients with AIDs, CINV (chemotherapy-induced nausea/vomiting)

- analgesic, antiemetic (CINV)

nabilone is NOT available in the US

What are the adverse effects of dronabinol and nabilone?

- exacerbation of depression, amnia, or schizophrenia

- confusion, altered mental state

- xerostomia (dry mouth)

- ataxia

- depression, drowsiness

- vertigo

mood elevation (psychological high)

- risk of hyperemesis with misuse

What interactions are important to be aware of with dronabinol and nabilone?

- substrate of CYP3A4 and CYP2C9

- clearance reduced and more ADR risk in patients with CYP2C9 3/3 genotype (diminished function)

What are the endogenous cannabinoids?

Compounds made by our own neurons

- anandamide (AEA)

- 2-arachidonoyl glycerol (2-AG)

What is the mechanism of action of anandamide (AEA)?

Partial agonist at CB1/CB2 (same as THC - psychoactive effects)

Also has activity at TRPV1 (transient potential pain receptors - not fully understood)

What is the mechanism of action of 2-arachidonoylglycerol (2-AG)?

Full agonist at CB1/CB2

What is 2-AG derived from?

arachidonic acid

What are the actions of CB1 receptors?

- inhibitory GPCRs (inhibit adenylyl cyclase, inhibit VGCA2+ channels, open K+ channels)

- expressed in cortical GABAergic interneruons, pain afferents, PAG (periaqueductal gray) - similar to where opioid receptors are expressed

*found in the neurons*

What are the actions of CB2 receptors?

Inhibitory GPCRs (inhibit adenylyl cyclase, inhibit VGCA2+ channels, inhibit release of proinflammatory cytokines)

*expressed in immune cells* (microglia, t-cells, monocytes, NK cells, macrophages)

Antiemetic & appetite stimulant MOAs of cannabinoid products

Action via CB1

- inhibitory effect on chemoreceptor trigger zone (CBZ, inhibits N/V signaling)

- appetite stimulation via hypothalamus (not long-term effects)

Other effects

- central sympathomimetic effects: palpitations, tachycardia, vasodilation, hypotension, and conjunctival injection

- psychoactive effects: euphoria, paranoia, withdrawal, irritability

What drug-drug interactions are important to note with THC?

CYP1A2 inducer

Can decrease effects of clozapine, duloxetine, naproxen, cyclobenzaprine, olanzapine (may need higher doses of these medications)

What drug-drug interactions are important to note with CBD?

*CYP3A4 inhibitor* - increase concentration of macrolides, CCB, BZDs, cyclosporine, sildenafil (&other PDE5s), antihistamines, haloperidol, antiretrovirals, atorvastatin, simvastatin

*CYP2D6 inhibitor* - increase concentrations of SSRIs, TCAs, antipsychotics, BB, opioids, (codeine & oxycodone)

What are the psychological/mental effects associated with recreational cannabis use?

- altered senses

- changes in mood (these are contextual - will be happier around happy people, more anxious around anxious people)

- impaired body movement (Patients should NOT drive!)

- difficulty thinking (especially with decision making, impaired time perception)

- impaired memory (of things that happened while on the drug)

- hallucinations/delusions (especially with high doses)

What are the potential long-term effects of recreational cannabis use?

- IQ/developmental (juvenile use)

- no major long-term effects seen in adults

What are the physical effects of recreational cannabis use?

- breathing difficulties (with smoking)

- increased heart rate (with smoking) - make sure to counsel patients with tachycardia, even if not smoking

- child development in pregnancy (concerns but no evidence)

- intense nausea & vomiting (cannabinoid hyperemesis syndrome) - more likely with larger use

What is cannabis use disorder (CUD)?

- loss of control over use, repeated failures to quit, and continuous usage despite negative consequences

- chronic neuroadaptation over time

- reduction in synapses of the hippocampal neurons

How long are amphetamines detectable on a urine drug test?

48 hours

What drugs may cause a false positive for amphetamines on a urine drug screen?

- amantadine

- *buproprion*

- chlorpromazine

- desipramine

- fluoxetine

- L-methamphetamine

- labetalol

- methylphenidate

- phentermine

- phenylephrine

- promethazine

- pseudoephedrine

- ranitidine

- thioridazine

- *trazodone*

How long are benzodiazepines detectable on a urine drug test?

- short-acting = 3 days

- long-acting = 30 days

What drugs may cause a false positive for benzodiazepines on a urine drug screen?

- oxaprozin

- *sertraline*

How long is cocaine detectable on a urine drug test?

- 2-3 days with occasional use

- up to 8 days with heavy use

What drugs may cause a false positive for cocaine on a urine drug screen?

"cocaine is always cocaine"

The only times it can show up is for topical anesthetics containing cocaine. There are no legal prescription medications that can cause a false positive for cocaine on a urine drug screen.

How long are opiates detectable on a urine drug screen?

2 to 4 days

What drugs may cause a false positive for opiates on a urine drug screen?

- dextromethorphan (Delsym)

- diphenhydramine

- fluoroquinolones

- *poppy seeds* (chill out with that everything bagel seasoning)

- quinine

- rifampin

-verapamil

How long is phencyclidine detectable on a urine drug screen?

8 days

What drugs may cause a false positive for phencyclidine on a urine drug screen?

- dextromethorphan

- diphenhydramine

- ibuprofen

- imipramine

- ketamine

- meperidine

- thiodiazine

- tramadol

- venlafaxine

How long is marijuana detectable on a urine drug screen?

- 3 days with single use

- 5-7 days with use around 4/times per week

- 10-15 days with daily use

- >30 days with long-term heavy use

What drugs may cause a false positive for marijuana on a urine drug screen?

- dronabinol

- NSAIDs (especially naproxen, ibuprofen, and sulindac)

- proton pump inhibitors

What are the metabolites for morphine that may show up on a urine drug screen?

- normorphine

- hydromorphone

- norphine-3-G-glucuronide

- morphine-6-G-glucuronide

What are the metabolites for hydromorphone (dilaudid) that may show up on a urine drug screen?

- hydromorphone-3-glucuronide

(no other metabolites that may be similar to other pharmaceutical opioids)

What are the metabolites for hydrocodone that may show up on a urine drug screen?

- norhydrocodone

- hydromorphone

What are the metabolites for codeine that may show up on a urine drug screen?

- norcodeine

- hydrocodone

- morphine

What are the metabolites for oxycodone that may show up on a urine drug screen?

- oxymorphone

- noroxycodone

What are the metabolites for oxymorphone that may show up on a urine drug screen?

- oxymorphone-3-glucuronide

- 6-hydroxy-oxymorphone

What are the metabolites for fentanyl that may show up on a urine drug screen?

- norfentanyl

What are the metabolites for tramadol that may show up on a urine drug screen?

- nortramadol

- O-desmethyltramadol

What are the metabolites for methadone that may show up on a urine drug screen?

- EDDP

- EMDP

What are the metabolites for heroin that may show up on a urine drug screen?

- normorphine

- morphine

- 6-monoacetylmorphine

What are the metabolites for lorazepam that may show up in a urine drug screen?

none

What are the metabolites for alprazolam that may show up in a urine drug screen?

alpha-hydroxyalprazolam

What are the metabolites for clonazepam that may show up in a urine drug screen?

7-aminoclonazepam

What are the metabolites for chlordiazepoxide that may show up in a urine drug screen?

- nordiazepam

- oxazepam

What are the metabolites for diazepam that may show up in a urine drug screen?

- nordiazepam

- temazepam

- oxazepam

Which is the only stimulant that does NOT metabolize to amphetamine?

Methylphenidate (Ritalin)

This will metabolize to ritalinic acid. If amphetamine shows up on the patients drug screen, they are getting stimulants elsewhere

You receive a phone call from a physician asking for help interpreting a urine drug screen for a patient. The patient tested positive for cocaine on a recent UDS and reports no recent substance use.

They are wondering if any of the patient's current medications could have resulted in this positive screen.

Current medications include: naproxen 500 mg BID, sertraline 100 mg daily, and bupropion XL 300 mg daily

How would you respond?

• There is no other drugs that will interact with the urine drug screen and show a false positive for cocaine ("cocaine is cocaine") à would probably want to recommend a confirmatory test in this case

• Naproxen - NSAIDs can interfere with marijuana

• Buproprion - can interfere with amphetamine screen

• Sertraline - can interfere with benzodiazepine screen

A 48-year-old female patient with chronic back pain has been taking hydrocodone/APAP 10/325 mg-4 tablets daily. Her last reported dose was this morning.

methamphetamine - detected

hydrocodone - detected

hydromorphone - detected

norhydrocodone - detected

How would you interpret the urine drug test?

• The hydrocodone, norhydrocodone, and hydromorphone results are expected (hydrocodone is metabolized to norhydrocodone and then hydromorphone)

• Methamphetamines are not expected to be present in this patient's urine.

• Will need to have a conversation with the patient to determine what has happened. (it is up to the prescriber what to do with the information, but likely will not stop the norco right away)

A 45-year-old female has been on methadone 10 mg three times daily and alprazolam 0.5 mg twice daily for the previous 5 years. Her last reported doses were this morning.

alpha-OH-alprazolam - not detected

alprazolam - detected

methadone - detected

EDDP - not detected

How would you interpret the urine drug test?

• No alprazolam metabolite present - worried about "shaving" and not actually taking the drug but adding parent compound to urine

• EDDP is a metabolite of methadone (again, metabolite not present but parent drug is)

• May be worried about patient failing to truly take medication and may be selling or giving away (likely stop prescribing the medication, because nothing is going to happen if they weren't taking it in the first place)

A 59-year-old male has been on hydrocodone/APAP 5/325 mg- 3 tablets daily for the previous 7 years. His last fill of hydrocodone/APAP was 3 weeks ago (#90 tablets).

cocaine - detected

hydrocodone - detected

hydromorphone - detected

norhydrocodone - detected

You get a phone call from the physician asking what could have caused the results of this UDS. How would you respond?

• The opiate results are all expected results from a Norco prescription (all are metabolites)

• Cocaine is cocaine (Norco will not cause any showing up in the urine, and it indicates relatively recent use)

• Talk to the patient - what is their story? Give them another chance?

A 23-year-old male reports to his doctor today for a follow-up on ADHD. He was prescribed lisdexamfetamine (Vyvanse) 40 mg daily several months ago, but stopped taking the medication when the prescription ran out. He is interested in restarting Vyvanse, but is requesting a higher dose than what he was on before.

A urine drug test collected on the day of his appointment returned with the following information...

Amphetamine - negative

methylphenidate - negative

mitragynine - positive

How would you interpret these results?

• Negatives for amphetamine are expected because his Rx has run out so he does not have any around to take

• Illicit drug results (mitragynine)- Kratum's "chemical cousin" ->what is going on here? (this is an herbal supplement, not necessarily illegal, can be used in low doses for a stimulant-like effect, may have been using this as a supplemental while he has been trying to get more adhd medication)

• Doesn't rule out stimulant use going forward, worried about potential abuse of Kratum (talk to patient!)

A 66-year-old female has been taking pregabalin 100 mg three times daily for diabetic neuropathy for the last year with good effects.

A urine drug test was collected as part of her ongoing treatment plan with the following results...

gabapentin - negative

pregabalin - positive

morphine - positive

• Lyrica presence - expected

• Morphine presence - not expected (talk to patient, did she have a procedure recently? Did she use a friend's medication?)

turns out patient was using an excessive amount of everything bagel seasoning every day, and the poppy seed concentrations were enough to have morphine show up in the urine

What is stigma?

- a mark of disgrace associated with a particular circumstance, quality, or person

- in medicine (stigmata): a visible sign or characteristic of a disease

- a self-conscious emotion, informs one of an internal state of inadequacy, unworthiness, dishonor, regret, or disconnection

If people who misuse substances end up feeling stigmatized, they may not seek out any treatment.

What is tolerance?

- decrease in pharmacological response

- increase dose to achieve similar effects

- CDC: reduced response to a drug with repeated use