Lecture 16 - Opioids I

Question 1

What is opium?

Answer 1

dried latex obtained from the poppy

Question 2

What are opiates

Answer 2

only drug derived from opium

Question 3

What is an opioid?

Answer 3

any drug that binds to an opioid receptor: included opiates, as well as synthetic opioid agonists (fentanyl, heroin, oxycontin)

Question 4

What are narcotics?

Answer 4

any drug with sleep inducing properties, but now usually by law enforcement to refer to illegal use of opioids for non-medical purposes

Question 5

What is morphine?

Answer 5

• natural opiate b/c it is found in poppy extracts, also an opioid

Question 6

What is heroin?

Answer 6

semisynthetic opiate b/c it is not found in poppy extracts, but is synthesized from morphine, also a opioid

Question 7

What is fentanyl?

Answer 7

• opioid, not an opiate as it is not found on poppy extracts

Question 8

What type of receptors are opioid receptors?

Answer 8

opioid receptors are inhibitory G-protein coupled receptors

Question 9

What does activation of opioid receptors cause?

Answer 9

activation inhibits adenylate cyclase, inhibits calcium release + activates K+ channels => neuronal inactivation + reduced neurotransmitter release

Question 10

What are the 4 types of opioid receptors?

Answer 10

• mu, delta, kappa, ORL-1 (orphanin receptor ligand)
• all are Gi GPCRs, but produce different effects when activated

Question 11

Why do opioid receptors produce different functions when activated

Answer 11

• due to receptor distribution
• ligand specificity: drugs are selective for different opioid receptors

Question 12

How is ORL-1 distributed?

Answer 12

• widely expressed in the CNS
• last opioid receptor to be identified based on sequence homology
• poorly studied, but does not share functional similarities with the other opioid receptors
• may be involved in fear processing

Question 13

What is mu receptor function (agonist)

Answer 13

• analgesia
• reward
• antitussive (cough suppression)
• respiratory depression
• constipation
• morphine, codeine, heroine

Question 14

What is mu receptor function (antagonist)

Answer 14

• aversive
• prevent rewards
• block overdose
• naloxone

Question 15

What is delta receptor function (agonist)

Answer 15

• not rewarding
• no analgesia (except in chronic pain, migraine)
• some are seizure - inducing (not commercially available, under investigation)

Question 16

What is kappa receptor function (agonist)

Answer 16

• aversive
• hallucinogenic
• anxiogenic
• salvia

Question 17

What is kappa receptor function (antagonist)

Answer 17

• potential antidepressant/anxiolytic

Question 18

What is the difference between full versus partial opioid agonists?

Answer 18

• full mu opioid agonists include morphine, methadone, fentanyl + heroin
• buprenorphine is a partial agonist at the mu opioid receptor, mild - moderate analgesic efficacy, but safer therapeutic index

Question 19

What is the difference between high versus low potency in opioids?

Answer 19

• full agonists can have different potencies (fentanyl versus morphine)
• potency also applies to all aspects of the drug (analgesia, euphoria, respiratory depression)

Question 20

What are mixed agonist-antagonist opioids?

Answer 20

• opioid ligands can have multiple effects on more than one opioid receptor
• buprenorphine is a partial agonist at the mu opioid receptor + antagonist at the delta/kappa receptors
• common treatment for pain + opioid addiction

Question 21

What are beta arrestins?

Answer 21

• intracellular proteins important for regulating signal transduction at GPCRs
• following receptor activation + G-protein cleavage, GPCR is phosphorylated, which signals beta-arrestin to bind

Question 22

What is the absorption of opioids?

Answer 22

• well absorbed when taken orally
• undergoes extensive first-pass metabolism
• codeine is a prodrug that is metabolized into morphine by liver enzymes therefore less impacted by first-pass effect than morphine (but more susceptible to pharmacogenomic diversity)

Question 23

What is the distribution of opioids ?

Answer 23

• widely distributed through body tissues, with highest conc in highly perfused tissues such as the brain, lungs, liver, kidney + spleen
• depends on route of administration
• cross placental barrier + exert effects on fetus that can result in both respiratory depression + physical dependence in neonates

Question 24

What is the metabolism of opioids?

Answer 24

• morphine is metabolized by phase II glucuronidation into morphine-3-glucuronide and morphine-6-glucuronide
• most important enzyme is UGT2B7
• morphine-6-glucuronide is an active metabolite (prolong morphine effects)
• codeine metabolized into morphine by CYP2D6(codeine is a prodrug)

Question 25

What is the excretion of opioids?

Answer 25

- polar metabolites, including glucuronide conjugates (M3G + M6G) of opioid analgesics, are excreted mainly in the urine - in patient with renal impairment the effects of active polar metabolites should be considered before the administration of potent opioids such as morphine due to the risk of sedation and respiratory depression

Question 26

What are the three types of endogenous opioid peptides?

Answer 26

- beta endorphins - enkephalins - dynorphines

Question 27

What are endogenous opioid peptides

Answer 27

- endogenous opioid peptides are generated from a protein precursor - each precursors is subject to post-translational modifications that results in synthesis of multiple active peptides