Substance Use Disorders (SUD)

A and B

The following neurotransmitter opposes the development of euphoria by negatively modulating dopamine levels in the reward center, nucleus accumbens (select two that apply).

a) GABA

b) Glutamate

c) Dopamine

d) Serotonin

e) All of the above

B

Glutamatergic neurons from this region activate GABAergic neurons in nucleus Accumbens.

a) Cerebellum,

b) PreFrontal cortex,

c) Hypothalamus,

d) Ventral tegmental area

E

The following events occur in the reward pathways during withdrawal syndrome.

a) Dopamine levels in NAcc are lower than physiological

b) Glutamatergic activity is stronger

c) GABAergic activity is stronger

d) Dysphoria

e) All of the above

Disulfiram, Acamprosate, Naltrexone

What three drugs are used for Alcohol Use Disorder

Nicotine, bupropion, Varenicline

What three drugs are used for Nicotine Disorder

Methadone, Buprenorphine, Heroin (Europe)

What 3 drugs are used for opioid use disorder?

euphoria

alcohol stimulates the release of endogenous opioids, enkephalins in the mesolimbic pathway which activate opioid receptors on GABAergic nerves and cause hyperpolarization of nerves. THis causes __________

Disulfiram

MOA: inhibit acetaldehyde metabolism by blocking Aldehyde dehydrogenase (ALDH) and increase circulating concentrations of acetaldehyde

Aversive conditioning

Increased acetaldehyde in the blood causes adverse and unfavorable events from alcohol. These effects prevent alcohol intake by patients otherwise called...

True

(True/False) Disulfiram is incompletely absorbed from the GI tract. (30% is eliminated unchanged in the feces)

lipophilicity

Disulfiram has more than optimal ______________ - wide distribution of the drug particularly into the fat-containing tissues

lungs

Carbon disulfide gas is eliminated through the ________

two weeks

It takes up to ____________ for complete eliminated of disulfiram and its metabolites following the last dose

Disulfiram

Antacids and iron/calcium supplements interfere with absorption of this drug

True

(True/False) Disulfiram is generally well tolerated in patients with little ADRs

Disulfiram

Alcohol containing preps, cough syrups and aftershaves should be avoided in patients treated with ______________

Acamprosate

MOA: Restores balance b/w excitatory and inhibitory neuronal pathways

Antagonizing glutamatergic NMDA receptors

kidney

Acamprosate is exclusively eliminated through the ____________

True

(True/False) Acamprosate does NOT undergo metabolism

unknown reasons

Acamprosate can sometimes cause a skin rash due to...

Naltrexone

MOA: Antagonist at Mu- and Kappa opioid receptors. Reduces cravings and decreases relapse to drinking

Glucuronides

Naltrexone when metabolized by UGT becomes ____________ which ultimately leads to enterohepatice circulation which helps increase half life

C and E

The following is a molecular target of disulfiram metabolites (select two that apply).

a) GABAergic receptors

b) ADH

c) ALDH,

d) D1-dopaminergic receptor

e) Dopamine B-hydroxylase.

D

Glutamatergic influence from PFC on GABAergic neurons in NAcc is minimized in alcoholics by this drug.

a) Disulfiram

b) Naltrexone

c) Naloxone

d) Acamprosate

alpha-4-beta-2

Specific subtype of nicotinic receptors, ___________ type are expressed on dopaminergic neurons in VTA that release dopamine in NAcc

epinephrine

Activation of ganglionic nicotinic receptors in splanchnic nerves increase the release of ______________ from adrenal glands into blood stream

Nicotine Replacement Therapy (NRT)

Sustained administration of lower amounts of nicotine reduced nicotine-craving without producing euphoric effect thus helps with discontinuation of the use.

Bupropion

MOA: Modestly increases synaptic dopamine levels by inhibiting DAT. Also inhibits uptake of NET

Noncompetitive antagonist

Bupropion is a ______________ (noncompetitive/competitive) ____________ (antagonist/agonist) of nicotinic receptors

Glycine conjugation

Metabolism of Bupropion is made by multiple enzymes followed by _____________ _____________

CYP2D6

Bupropion is a strong inhibitor of which CYP?

Strong

Bupropion has a ____________ (weak/strong) pharmacodynamic interaction with MAOIs

Varenicline

Partial agonist at alpha-4-beta-2 nicotinic receptors | provides modest stimulation of receptor and increases DA release without producing euphoria

Full

Varenicline is a _______ agonist at 5HT-serotonergic and alpha-7-homomeric nicotinic receptors

weak

Varenicline is a ___________ agonist at alpha-3-beta-4 receptors

OCT2 (organic cation transporter-2)

Varenicline is eliminated unchanged by filtration, and to some extent by active tubular transport involving ________

Does not

Varenicline ____________ (does/does not) undergo metabolism

Nausea and Behavioral changes

What are the 2 primary side effects of Varenicline

alpha-4-beta-2 Nicotinic receptor

What is Bupropion's molecular target?

alpha-4-beta-2 Nicotinic receptor

What is Bupropion's molecular target?

Noncompetitive antagonist

Describe Bupropion's activity

partial agonist

Describe Varenicline's activity

Inhibitor

(inhibitor/ no effect)

Describe Bupropions effect on Dopamine re-uptake

No effect

(inhibitor/ no effect)

Describe Varenicline effect on Dopamine re-uptake

Inhibitor

(inhibitor/ no effect)

Describe Bupropions effect on NE re-uptake

No effect

(inhibitor/ no effect)

Describe Varenicline effect on NE re-uptake

increase

Bupropion has a modest ______________ (decrease/increase) on NAcc-Dopamine

increase

Varenicline has a modest ______________ (decrease/increase) on NAcc-Dopamine

No

Does Bupropion cause Euphoria?

No

Does Varenicline cause Euphoria?

Yes

Does Bupropion undergo Hepatic metabolism

No

Does Varenicline undergo Hepatic metabolism

Yes (CYP2D6)

Does Bupropion have any PK Drug interactions?

No

Does Varenicline have any PK Drug interactions?

MAOIs and TCAs

What are the PD Drug interactions of Bupropion

OCT1-inhibitors, cimetidine

What are the PD Drug Interactions of Varenicline

No

Does bupropion nausea

Yes

Does Varenicline cause nausea

Yes

Does Bupropion cause insomnia

Yes

Does Varenicline cause insomnia

GABAergic, VTA, DA, Nucleus accumbens

Activation of Mu-opioid receptors located on the ________________ nerve terminals in the decreases GABA release. ___________________

Decreased GABA-mediated inhibition, aka disinhibition, on dopaminergic neurons in VTA results in their activation, which in turn results in increased release in the ________________ _________________ and euphoria.

Dopaminergic, DA, Nucleus accumbens, dysphoria

Activation of Kappa-opioid receptors located on the dopaminergic nerve terminals decreases _______ release in the region _______________, which causes _________

Expression of dynorphin in the GABAergic nerves

Sustained stimulation of MOR results in progressively increased activation of adenyl cyclase, which in turn activates the transcription factor, cAMP response element binding protein (CREB), resulting in...

Dynorphin

_____________ is released as a co-neurotransmitter, hen GABAergic nerves are activated (additive inhibition => DA is even lower)

Dysphoria

A dopamine dip results in ______________

agonist, antagonist

Methadone MOA:

MOR ___________ (antagonist/agonist)

NMDA receptor ____________ (antagonist/agonist)

partial, antagonist

Buprenorphine MOA:

MOR partial __________ (antagonist/agonist)

KOR receptor ____________ (antagonist/agonist)

CYP2C9, 2C19, 2D6, 3A4

What 4 CYPs assist in the hepatic metabolism of Methadone?

CYP3A4

What CYP assists in the hepatic metabolism of Buprenorphine

Inactive

Are the metabolites of Methadone inactive OR active

Active (Norbuprenorphine)

Are the Metabolites of Buprenorphine inactive or active?

No

Does Methadone have a ceiling effect?

Yes

Does Buprenorphine has a ceiling effect

C

(Select all that apply)

Dopamine Spike (transient rise) in the NAcc

A. Euphoria

B. Dysphoria

C. Reward response

D. Substance withdrawal

A

(Select all that apply)

Sustained increase in dopamine levels in the NAcc

A. Euphoria

B. Dysphoria

C. Reward response

D. Substance withdrawal

B, D

(Select all that apply)

Lower than physiological levels of dopamine in the NAcc

A. Euphoria

B. Dysphoria

C. Reward response

D. Substance withdrawal

C

Prince has been using prescription opioids for pain in hips due to high-heel shoes that he wears whenever he performed. He gradually needed higher n higher doses for getting pain relief in a period of a year. One evening he found himself struggling to breathe, and he immediately took naloxone by using naloxone pen (Evzio), and proceeded for a concert.

What is likely to occur in this individual?

a) Severe respiratory depression,

b) Euphoria,

c) Withdrawal syndrome,

d) None of the above

Methadone is a full agonist at MOR however due to high protein binding the entry into the brain is relatively slow. SUstained low levels of the drug in the brain are sufficient to maintain physiological levels of dopamine in the NAcc and prevent dopamine dip and dysphoria therefor craving for opioid substance is alleviated.

potential written question:

describe the mechanism of action of methadone in the treatment of OUD

Buprenorphine is a partial agonist at MOR and dopamine release is increased in the NAcc but will never achieve adequate concentrations to cause euphoria (ceiling effect). Dopamine dip/dysphoria and craving for an opioid will be avoided. Abuse of an opioid, a full agonist at MOR, will not produce any effect/euphoria as the partial agonist acts an antagonist of a full agonist. Buprenorphine is an antagonist at KOR and blocks the action of dynorphin on the dopaminergic nerve termials in the NAcc thus prevent hyperpolarization of nerves and avoid dysphoria

potential written question:

describe the mechanism of action of buprenorphine in the treatment of OUD

c

dopamine spine (transient rise) in the NAcc causes:

a. euphoria

b. dysphoria

c. reward response

d. substance withdrawal

a

sustained increase in dopamine levels in the NAcc

a. euphoria

b. dysphoria

c. reward response

d. substance withdrawal

b and d

lower than the physiological levels of doapmine in the NAcc:

a. euphoria

b. dysphoria

c. reward response

d. substance withdrawal

c

Prince has been using prescription opioids for pain in hips due to high-heel shoes that he wears whenever he performs. He gradually needed higher n higher doses for getting pain relief in a period of a year. One evening he found himself struggling to breathe, and he immediately took naloxone by using naloxone pen (Evzio), and proceeded for a concert.

What is likely to occur in this individual?

a) Severe respiratory depression,

b) Euphoria,

c) Withdrawal syndrome,

d) None of the above.

Disulfiram and its metabolites act by blocking ALDH thus causing acetaldehyde to accumulate which in turn produces aversive effects. Disulfiram and its metabolites owing to their highly lipophilic property, stay in the fat-rich areas for a longer time and slowly release back into the circulation therefore Continue blocking ALDH. For about two weeks following the cessation of the drug intake, the drug metabolites are expected to be active.

48-yo Sortirius was admitted to ER with syncope, hypotension, tachycardia, diffuse erythema, and shivering. His wife reported that Sortirius was on Antabuse (disulfiram) until a week before, and has tasted Ouzo to celebrate his freedom from alcohol with the Greek community two hours before his admission to ER. Interpret the pharmacodynamics of this condition?

b

47-yo MJ presents to ER with severe pain in the stomach and several symptoms of hepatic dysfunction. The condition was diagnosed as Ewing's Sarcoma in the liver extending into the diaphragm. He was immediately put on hydromorphone i.v., which took four times higher dose up to five hours of i.v. drip than normally needed to bring the pain level to 5 from 10. 'Use of drugs' was not admitted by the patient however opioid metabolites are found in the urine sample.

The following would best-explain the need of higher dose of opioid for pain relief.

a) Increased metabolism,

b) Increased tolerance,

c) Increased renal elimination,

d) Reduced entry into CNS.

b

47-yo MJ presents to ER with severe pain in the stomach and several symptoms of hepatic dysfunction. The condition was diagnosed as Ewing's Sarcoma in the liver extending into the diaphragm. He was immediately put on hydromorphone i.v., which took four times higher dose up to five hours of i.v. drip than normally needed to bring the pain level to 5 from 10. 'Use of drugs' was not admitted by the patient however opioid metabolites are found in the urine sample.

What would happen if he had received nalbuphine?

a) Pain relief and euphoria,

b) Pain relief and dysphoria,

c) No pain relief and euphoria,

d) No pain relief and dysphoria.

b

50-yo woman, who smokes up to 25 cigarettes a day, is seeking therapy for nicotine use disorder. She has a history of hypertension and epilepsy. The following medication is not suitable for this individual:

a) Varenicline,

b) Bupropion,

c) Nicotine gum,

d) Nicotine patch

blood pressure

Bupropion increases NE levels in the brain, by inhibiting the reuptake (via blocking the transporter NET), which may exacerbate the centrally mediated increase in _______ and locomotor activity.

methadone can cross the placental barrier so sudden lack of supply following birth is likeely to precipitate withdrawal syndrome

Heroin addict, Angie, realized that she is 18-wk pregnant and wanted to have the baby. She was immediately put on methadone, and frequent checkup was scheduled. Methadone dose was frequently adjusted as needed during the rest of the pregnancy. Angie was very compliant and stayed away from heroin. Caesarean was planned at 30 weeks of pregnancy or earlier as dictated by the condition of the baby. Withdrawal therapy for Angie, and the newborn were preplanned. Why does the newborn need withdrawal therapy?

a and c

40-yo KK is a chronic user of alcohol. He regularly takes vitamin supplements and Milk of Magnesia to overcome routinely observed alcoholinduced side effects. KK was prescribed with disulfiram when he decided to achieve complete abstinence from alcohol. KK is required to avoid the following:

a) Cough syrup,

b) Naltrexone

c) 'Milk of Magnesia'

d. none of the above