Opiate Addiction and Neuropharm of Opiates

Question 1

What affect do opiates have on the CNS? (name 7)

Answer 1

Analgesia, euphoria, sedation, respiratory depression, release of prolactin, nausea, anti-tussive effect.

Question 2

Effect of opiates on the cardiovascular system?

Answer 2

Peripheral vasodilatation.

Question 3

Effect of opiates on eyes?

Answer 3

Pupil constriction.

Question 4

Effect of opiates on lungs?

Answer 4

Respiratory depression

Question 5

Effect of opiates on GI?

Answer 5

Decrease in propulsive contractions in small intestine. Spasms. Note that loperamide (Imodium) for diarrhea is an opioid receptor agonist.

Question 6

What’s the new epidemic in opioid abuse / dependence?

Answer 6

Non-medical use of pain relievers. (now about twice as common as heroin use)

Question 7

What is cross-tolerance?

Answer 7

Somebody who uses heroin regularly will need a higher dose of methadone…

Question 8

What “pathway” in the brain produces the high from opioids (or winning a race)?

Answer 8

The mesolimbic pathway. And it’s all about dopamine.

Question 9

What separates buprenorphine from other opiates?

Answer 9

It’s a partial agonists. It stimulates the opioid receptors, but has a “ceiling effect” - activity plateaus at a lower level of activation.

Question 10

What are the 3 opioid receptor families, and what do effect does agonism produce?

Answer 10

Mu - analgesia/euphoria
Kappa - dysphoria, hallucinations, analgesia
Delta - analgesia? unclear.

Question 11

4 medical signs of opiate abuse?

Answer 11

Infection (esp things like endocarditis, abcesses), nasal/pulmonary scarring, scars from injection, drug requests

Question 12

4 pharmacological treatment modalities for opioid dependence?

Answer 12

Detox - use agonist and taper
Substitution - methadone/buprenorphine
Antagonist - naltrexone
Relapse prevention - naltrexone +/- buprenorphine

Question 13

3 most common signs of opiate withdrawal?

Answer 13

Anxiety
Dilated pupils
Craving
(other signs include diaphoresis, yawning, increased BP and RR, piloerection, rhinitis, abdominal cramps, diarrhea)

Question 14

What’s the major advantage of using buprenorphine instead of methadone for substitution?

Answer 14

Buprenorphine can be given by a trained PCP. You don’t have to send patients to a methadone clinic.

Question 15

Advantages of methadone?

Answer 15

Cheap
Oral -> gets rid of injection risk (vs. using heroin)
Smooths out experience

Question 16

How well does methadone treatment work?

Answer 16

Not that well. Lots of people drop out then relapse. It’s good at preventing HIV injection while people are in treatment, though…

Question 17

MoA of naltrexone?

Answer 17

Specific antagonist of mu opioid receptors.

Question 18

Is there any proven advantage to rapid detox?

Answer 18

Nope.

Question 19

How does the subjective experience of local anesthesia vs. an opioid analgesic contrast?

Answer 19

Local: It’s numb.
Opioid: It hurts, but who cares?

Question 20

Where are mu opioid receptors, anatomically?

Answer 20

Spinal cord (dorsal root ganglia)
Supra-spinal: periaqueductal grey, thalamus, sensory cortex

Question 21

Where are delta opioid receptors, anatomically?

Answer 21

Mainly spinal cord: dorsal horn, spinothalamic tract.

Question 22

Which neurons / what brain regions produce the euphoria from opioids?

Answer 22

Ventral tegmental area (VTA) dopaminergic neurons project to nuc. accumbens and medial prefrontal cortex.

Question 23

Where in the brain does opioid-induced nausea come from? What kind of receptors?

Answer 23

the area postrema (in the medulla) - kappa receptors

Question 24

How do opioids cause respiratory depression?

Answer 24

Mu receptors in brainstem -> dampens relexes in response to high P(CO2).

Question 25

Are anti-tussive effects caused by opioids acting in the brainstem?

Answer 25

yep

Question 26

What isomers of opiates do all the analgesia?

Answer 26

L-isomers

Question 27

What isomers of opiates predominantly have an anti-tussive effect? (Prototypical drug that does this?)

Answer 27

D-isomers. Dextromethorphan (i.e. Robitussin)

levomethorphan does have analgesic effects, but was never clinically developed, says Wikipedia

Question 28

Where do opiates act to cause constipation? What kind of receptors?

Answer 28

Local gut autonomic ganglia. Mu receptors.

Question 29

What do you do if you see an unconscious person in the ER with pinpoint pupils?

Answer 29

Give IV naloxone, as they might have an opioid OD. (and naloxone won’t hurt them if they don’t)

Question 30

Why does IV morphine help fluid buildup in the lungs of a person with congestive heart failure?

Answer 30

Peripheral vasodilatation -> fluid drawn away from lungs.

Question 31

Where do opioids act to cause peripheral vasodilatation?

Answer 31

the vagal nucleus (or as we called it, the dorsal motor nucleus of CN X)

Question 32

What are the 3 endogenous opioid receptor ligands, and to what receptor do they bind?

Answer 32

Endorphin -> Mu
Enkephanlin -> delta
Dynorphin -> kappa

Question 33

What are the downstream cellular effects of Mu agonism? (more simply, to what G protein is the receptor coupled?)

Answer 33

Coupled to Gi. Thus adenylated cyclase inhibition -> low cAMP -> decreased CREB -> altered gene expression.
Also neuronal hyperpolarization via increased K+ permeability.

Question 34

What is injected antagonize Mu in opiate OD?

Answer 34

Naloxone

Question 35

What is taken orally to help combat alcohol and opioid addiction?

Answer 35

Naltrexone.

Mnemonic?: “trex” -> trek = journey, and breaking an addiction is a long journey

Question 36

2 enzymes responsible for opioid tolerance?

Answer 36

Src kinases

G-protein kinases

Question 37

What’s the mechanism for src kinase-mediated opioid tolerance?

Answer 37

Phosphorylation causes Mu receptor not bind Gi as well, thus increasing cAMP levels.

Question 38

What’s the mechanism of G-protein kinase-mediate opioid tolerance?

Answer 38

Phosphorylation of Mu receptor leads to internalization, and thus less mu receptor on cell surface.

Question 39

Clinical implication of opioid tolerance? Is there a ceiling to tolerance?

Answer 39

If somebody is on a opioid painkiller for multiple days, they may need their dose increased to control the pain.
Yes, there is a ceiling effect.

Question 40

4-5 symptoms of opioid withdrawal? (and symptom of opioid intoxication to which it is opposite)

Answer 40

Anxiety (instead of euphoria)
Agitation (instead of sedation)
Diarrhea (instead of constipation)
Pupil Dilation (instead of constriction)
Craving

Question 41

Can opioid withdrawal kill you?

Answer 41

Nah. But it sucks.

Question 42

Which withdrawal symptom most drives relapse?

Answer 42

Craving

Question 43

What 2 drugs compose suboxone? Why is the 2nd drug given?

Answer 43

Buprenorphine - for safer substitution therapy

Naloxone - so you can’t inject the buprenorphine.

Question 44

What genetic variation most predicts euphoria in response to EtOH? Which specific allele? Downstream effect?

Answer 44

The “G” allele of the Mu opioid receptor.

Ultimately affects dopamine levels (in the ventral striatum).

Question 45

For what genotype does naltrexone work best for treating alcohol use disorder?

Answer 45

People with the G allele, who tend to get a “high” more from alcohol.