Lecture 15: Opioids (Part 1) Flashcards
What is opium?
dried latex obtained from the poppy
What are opiates?
any drug derived from opium
What is an opioid?
any drug that binds to an opioid receptor
includes opiates, as well as synthetic opioid agonists (fentanyl, heroin, oxycontin)
What is a narcotic?
from Greek “narco” = “to make numb”
originally referred to any drug with sleep inducing properties, but now usually used by law enforcement to refer to illegal use of opioids for non-medical purposes
What are the characteristics of opioid receptors?
inhibitory G-protein coupled receptors
activation of opioid receptors inhibits adenylate cyclase, inhibits calcium release, and activates K+ channels –> neuronal inactivation and reduced neurotransmitter release
What are the four types of opioid receptors?
opioid receptors come in four types: mu, delta, kappa, ORL-1 (orphanin receptor ligand)
all are Gi GPCRs, but produce very different effects when activated
Why do the different types of opioid receptors produce different effects when activated?
differences are due to receptor distribution (different neurons, different brain circuits)
ligand specificity: drugs are selective for different opioid receptors
What is the opioid receptor distribution in the brain?
Mu: midbrain, amygdala
Delta: cortex
Kappa: cortex
What are ORL-1 receptors?
widely expressed in the central nervous system
it was the last opioid receptor to be identified based on sequence homology (not function)
poorly studied, but does not share functional similarities with the other opioid receptors
may be involved in fear processing
What are the functions of Mu opioid receptor agonists?
analgesia
reward
antitussive (cough suppression)
respiratory depression
constipation
(i.e., morphine, codeine, heroine)
What are the functions of Mu opioid receptor antagonists?
aversive
prevent reward
block overdose
(i.e. naloxone)
What are the functions of Delta opioid receptor agonists?
not rewarding
no analgesia (except in chronic pain, migraine)
some are seizure-inducing (not commercially available, under investigation)
What are the functions of Delta opioid receptor antagonists?
no obvious effects
What are the functions of Kappa opioid receptor agonists?
aversive
hallucinogenic
anxiogenic
(i.e. Salvia)
What are the functions of Kappa opioid receptor antagonists?
potential antidepressant/anxiolytic
What are examples of full mu opioid receptor agonists?
morphine, methadone, fentanyl, and heroin
What are examples of partial mu opioid receptor agonists?
buprenorphine
mild to moderate analgesic efficacy, but safer therapeutic index
What are high versus low potency of opioid ligands?
full agonists can have different potencies (fentanyl versus morphine)
like efficacy, potency applies to all aspects of the drug (analgesia, euphoria, respiratory depression)
In what way are opioid ligands mixed agonist-antagonists?
opioid ligands can have multiple effect on more than one opioid receptor
buprenorphine is a partial agonist at the mu opioid receptor and antagonist at the delta and kappa opioid receptor
common treatment for pain and opioid addiction (opioid agonist therapy)
In what way are opioid ligands biased agonists?
beta-arrestins are a family of intracellular proteins important for regulating signal transduction at GPCRs
following receptor activation and G-protein cleavage, GPCR is phosphorylated, which signals beta-arrestin to bind
beta-arrestin binding blocks further G-protein signaling redirects signaling to alternative pathways, and targets receptors for internalization
beta arrestin arrests G protein signaling that leads to tolerance following chronic opioid use
beta arrestin also activates its own intracellular signaling pathways that contribute to some of drug effects
What is receptor selectivity?
selectivity for different receptor subtypes
What is functional selectivity?
selectivity for different signaling pathways coupled to the same receptor
Why do not all opioid ligands lead to beta-arrestin recuitment?
different opioid ligands can differently activate G-protein versus beta-arrestin signaling pathways
these signaling pathways drive different aspects of the drug
What is the absorption of opioids?
most mu agonist opioids are well absorbed when taken orally
but, morphine undergoes extensive first pass metabolism
codeine is a prodrug that is metabolized into morphine by liver enzymes, therefore, less impacted by first-pass metabolism (but more susceptible to pharmacogenomic diversity)
What is the distribution of opioids?
opioid agonists are widely distributed through body tissues, with highest concentrations in highly perfused tissues such as the brain, lungs, liver, and kidney and spleen
depends on route of administration
cross placental barrier, and exert effects on fetus that can result in both respiratory depression and physical dependence on neonates
What is the metabolization of opioids?
morphine is metabolized by phase II glucuronidation into morphine-3-glucuronide and morphine-6-glucuronide
the most important glucuronidation enzyme is UGT2B7
morphine-6-glucuronide is an active metabolite (can prolong morphine effects)
codeine metabolized into morphine by CYP2D6 (i.e. codeine is a prodrug)
genetic polymorphisms of YP2D6 (fast or slow metabolizers) linked to variatuin in analgesic and adverse responses among patients, particularly for codeine
What is the excretion of opioids?
polar metabolites, including glucuronide conjugates (M3G and M6G) of opioid analgesics, are excreted mainly in the urine
small amounts of unchanged drug may also be found in the urine
in patients with renal impairment the effects of active polar metabolites (Morphine-6-Glucuronide) should be considered before the administration of potent opioids such as morphine due to the risk of sedation and respiratory depression
