Opiate Addiction and Neuropharm of Opiates Flashcards
What affect do opiates have on the CNS? (name 7)
Analgesia, euphoria, sedation, respiratory depression, release of prolactin, nausea, anti-tussive effect.
Effect of opiates on the cardiovascular system?
Peripheral vasodilatation.
Effect of opiates on eyes?
Pupil constriction.
Effect of opiates on lungs?
Respiratory depression
Effect of opiates on GI?
Decrease in propulsive contractions in small intestine. Spasms. Note that loperamide (Imodium) for diarrhea is an opioid receptor agonist.
What’s the new epidemic in opioid abuse / dependence?
Non-medical use of pain relievers. (now about twice as common as heroin use)
What is cross-tolerance?
Somebody who uses heroin regularly will need a higher dose of methadone…
What “pathway” in the brain produces the high from opioids (or winning a race)?
The mesolimbic pathway. And it’s all about dopamine.
What separates buprenorphine from other opiates?
It’s a partial agonists. It stimulates the opioid receptors, but has a “ceiling effect” - activity plateaus at a lower level of activation.
What are the 3 opioid receptor families, and what do effect does agonism produce?
Mu - analgesia/euphoria
Kappa - dysphoria, hallucinations, analgesia
Delta - analgesia? unclear.
4 medical signs of opiate abuse?
Infection (esp things like endocarditis, abcesses), nasal/pulmonary scarring, scars from injection, drug requests
4 pharmacological treatment modalities for opioid dependence?
Detox - use agonist and taper
Substitution - methadone/buprenorphine
Antagonist - naltrexone
Relapse prevention - naltrexone +/- buprenorphine
3 most common signs of opiate withdrawal?
Anxiety
Dilated pupils
Craving
(other signs include diaphoresis, yawning, increased BP and RR, piloerection, rhinitis, abdominal cramps, diarrhea)
What’s the major advantage of using buprenorphine instead of methadone for substitution?
Buprenorphine can be given by a trained PCP. You don’t have to send patients to a methadone clinic.
Advantages of methadone?
Cheap
Oral -> gets rid of injection risk (vs. using heroin)
Smooths out experience
How well does methadone treatment work?
Not that well. Lots of people drop out then relapse. It’s good at preventing HIV injection while people are in treatment, though…
MoA of naltrexone?
Specific antagonist of mu opioid receptors.
Is there any proven advantage to rapid detox?
Nope.
How does the subjective experience of local anesthesia vs. an opioid analgesic contrast?
Local: It’s numb.
Opioid: It hurts, but who cares?
Where are mu opioid receptors, anatomically?
Spinal cord (dorsal root ganglia) Supra-spinal: periaqueductal grey, thalamus, sensory cortex
Where are delta opioid receptors, anatomically?
Mainly spinal cord: dorsal horn, spinothalamic tract.
Which neurons / what brain regions produce the euphoria from opioids?
Ventral tegmental area (VTA) dopaminergic neurons project to nuc. accumbens and medial prefrontal cortex.
Where in the brain does opioid-induced nausea come from? What kind of receptors?
the area postrema (in the medulla) - kappa receptors
How do opioids cause respiratory depression?
Mu receptors in brainstem -> dampens relexes in response to high P(CO2).
Are anti-tussive effects caused by opioids acting in the brainstem?
yep
What isomers of opiates do all the analgesia?
L-isomers
What isomers of opiates predominantly have an anti-tussive effect? (Prototypical drug that does this?)
D-isomers. Dextromethorphan (i.e. Robitussin)
levomethorphan does have analgesic effects, but was never clinically developed, says Wikipedia
Where do opiates act to cause constipation? What kind of receptors?
Local gut autonomic ganglia. Mu receptors.
What do you do if you see an unconscious person in the ER with pinpoint pupils?
Give IV naloxone, as they might have an opioid OD. (and naloxone won’t hurt them if they don’t)
Why does IV morphine help fluid buildup in the lungs of a person with congestive heart failure?
Peripheral vasodilatation -> fluid drawn away from lungs.
Where do opioids act to cause peripheral vasodilatation?
the vagal nucleus (or as we called it, the dorsal motor nucleus of CN X)
What are the 3 endogenous opioid receptor ligands, and to what receptor do they bind?
Endorphin -> Mu
Enkephanlin -> delta
Dynorphin -> kappa
What are the downstream cellular effects of Mu agonism? (more simply, to what G protein is the receptor coupled?)
Coupled to Gi. Thus adenylated cyclase inhibition -> low cAMP -> decreased CREB -> altered gene expression.
Also neuronal hyperpolarization via increased K+ permeability.
What is injected antagonize Mu in opiate OD?
Naloxone
What is taken orally to help combat alcohol and opioid addiction?
Naltrexone.
Mnemonic?: “trex” -> trek = journey, and breaking an addiction is a long journey
2 enzymes responsible for opioid tolerance?
Src kinases
G-protein kinases
What’s the mechanism for src kinase-mediated opioid tolerance?
Phosphorylation causes Mu receptor not bind Gi as well, thus increasing cAMP levels.
What’s the mechanism of G-protein kinase-mediate opioid tolerance?
Phosphorylation of Mu receptor leads to internalization, and thus less mu receptor on cell surface.
Clinical implication of opioid tolerance? Is there a ceiling to tolerance?
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.
4-5 symptoms of opioid withdrawal? (and symptom of opioid intoxication to which it is opposite)
Anxiety (instead of euphoria) Agitation (instead of sedation) Diarrhea (instead of constipation) Pupil Dilation (instead of constriction) Craving
Can opioid withdrawal kill you?
Nah. But it sucks.
Which withdrawal symptom most drives relapse?
Craving
What 2 drugs compose suboxone? Why is the 2nd drug given?
Buprenorphine - for safer substitution therapy
Naloxone - so you can’t inject the buprenorphine.
What genetic variation most predicts euphoria in response to EtOH? Which specific allele? Downstream effect?
The “G” allele of the Mu opioid receptor.
Ultimately affects dopamine levels (in the ventral striatum).
For what genotype does naltrexone work best for treating alcohol use disorder?
People with the G allele, who tend to get a “high” more from alcohol.
