2 opiods Flashcards
what is opium
dried latex obtained from the poppy
what is opiates
any drug derived from opium
what are opioids
any drug that binds to an opiod receptor
are all opiates opioids
yes, even synthetic ones
what are narcotics
origionally for any drug with sleep inducing properties, but now used by law enfocement to talk about illegal use of opiods for non medical purposed
what kind of opiate is morphine
natural opiate
what kind of opiate is heroin
semisynthetic opiate (synthesized from morphine)
what kind of opiate is fentanyl
not an opiate, its just an opioid
how many times to GPCRs span the membrane
7 times
where are the N and C terminuses for GPCRs
N outside
C inside
which terminus binds the ligand
N
it outside
which terminus binds the effectors and like G protein stuff
C terminus
inside
what kind of G pathway are opiod receptors
Gi
what does activation of opioid receptors cause (3 direct + 1 overall)
inhibit calcium channels
activate K+ channels
inhibit adenylyl cylase
neuronal inactivation and reduced transmitter release
what are the four types of opioid receptors
mu
delta
kappa
ORL-1
what type of G proteins are the 4 types of opioid receptors
all Gi
what causes the 4 types to be different
due to receptor distribution differences (diff neurons, diff brain circuits)
what part of the opioid receptors differ the most
near the N and C terminus
whats a ligand
a molecule which binds a protein (receptor) to produce a biological effect
agonists or antagoinsts
what does mu agonism cause
analgesia, reward, antitissive, resp depression, constipation
example of mu agonist
morphine fentanyl heroin
what does mu antagonism cause
prevent reward, block overdose, aversive
example of mu antagonist
naloxone
what does delta agonism cause
not reward, no analgesia (yes migraine and chronic pain), some cause seizures
what does delta antagonism cause
no obvious effects
what does kappa agonism cause
aversive, hallucinogenic, anxiogenic
example of kappa agonist
salvia
what does kappa antagonism cause
potential antidepressant, anxiolytic
example of kappa antagonist
buphrenorphine
what does ORL-1 agonism cause
block opioid analgesia (no current theuraputic use)
what does ORL-1 antagonism cause
no obvious effects
what are 4 full mu opioid receptor agonists
morphine
methadone
fentanyl
heroin
what is 1 partial mu opioid receptor agonist
CODEINE
so its safer therapeutic index
why is codeine safer than morphine
methadone
fentanyl
heroin
it is a partial agonist instead of a full agonist
mild to moderate analgesic efficacy, safer therapeutic index
what differs between full agonists
they have different potencies (fentanyl more potent than morphine, but full agonists)
does efficacy or potency effect analgesia, euphoria, respiratory depression
both!
which receptors does buprenorphine affect
partial agonist at mu opioid receptor and antagonist at delta and kappa
what does buprenorphine do
treatment for pain and opioid addiction (opioid agonist therapy)
what are arrestins
family of proteins important for regulating signal transduction at GPCRs
what signal causes β-arrestin to bind
after receptor activation and G-protein cleavage, GPCR is phosphorylated and causes β-arrestin to bind
whats does β-arrestin cause
blocks further G-protein signalling, redirects signalling to alternative pathways, and targets receptors for internalization
do all opioid ligands lead to β-arrestin recruitment
not all
different opioid ligands can differently activate G-protein versus β-arrestin signaling pathways
some are balances, some are biased towards G protein or β-arrestins
these signalling pathways drive different aspects of the drug
what does the G-protein signalling pathway drive in mu opiod receptor
drives analgesia
what does the β-arrestins signalling pathway drive in mu opiod receptor
drives respiratory depression and GI function
what are two ways that the G protein biased agonist do their thing
the pathway drives analgesia AND since β-arrestins stop analgesia, inhibiting β-arrestins causes an extra increased analgesia
how are mu agonist opioids absorbed when taken orally
most are well absorbed
which opioid undergoes extensive first-pass metabolism
morphine
which opioid bypasses extensive first-pass metabolism
codeine
how does opioids affect neonates
they cross the placental, effect fetus that can cause respiratory depression and physical dependence
how are opioids agonists distributed through the body
widely distrubuted through the tissues, especially in highly perfused tissues (brain, lungs, kidney, spleen, liver)
what is morphine metabolized by and into
by CYP2D6 and into M3G & M6G (morphine-3-glucuronide and morphine-6-glucuronide) (way more powerful)
what is codeine metabolized by and into
CYP2D6
morphine
what does genetic polymorphisms of CYP2D6 cause
fast or slow metabolizes
linked to variation in analgesic and adverse responses, especially in codeine
can heroin pass the BBB and why
no because there is an acetyl group
what does plasma esterases
it rapidly converts heroin into morphine, which easily corsses BBB
how are polar metabolites excreted
in the urine
what are the glucoronide conjugates
M3G and M6G
how are M3G and M6G excreted
in the urine
why do you have to worry with patients with renal impairment
active polar metabolites (M6G) cause even more sedation and resp. depression because they are not able to pee it out
what are the three types of endogenous opioid peptides
endorphines
enkephalins
dynorphins
which receptors do endogenous opioid peptides bind to
all opioid receptors
but with different affinities
which receptor do endorphins bind best at
mu
which receptor do enkephalins bind best at
delta
which receptor do dynorphins bind best at
kappa!!
what are the roles of the endogenous opioids
mediate variety pf behavioural effects like pain, reward, learning, memory and cognition
how do endogenous opioids become themselves
they come from polepeptide precursors and are cleaved by distinct proteases (trypsin like)
what is the claustrum
tiny brain region that connects to many regions of the cortex (visual, auditory, somatosensory, limbic)
integrates sensory information, maybe causes consciousness
what is special with nerves in claustrum
3 neurons that extensively span the brain, 1 that wraps around the entire circumference of the brain like a crown of thorns
what does stimulation of the claustrum cause
blocks volitile behaviour, unresponsiveness, amnesia, lost consciousness, no impact on motor skills
what kind of receptors is the highest density in the claustrum
kappa opioid receptors
why does kappa agonism cause hallucinogenic effects
because most kappa in claustrum which is connected to consciousness
is codeine an opiate
yes
what are the main functions of the opioid receptors in the brain
pain perception, reward, emotion, addiction
what does opioid activity in the brainstem cause
it can cause respiratory depression
what does opioid activity in the spinal cord cause
transmission of pain signals is dampened, especially the dorsal horn (receive sensory input)
what does opioid activity in the peripheral neurons cause
curb pain sensation because of sensory neurons being bound to opioids
what does opioid activity in the intestine cause
blocks peristalsis, causes constipation
which receptors are used for pain
mu opioid agonists
which receptors are used for migraine
side effects
delta opioid
seizure
what would be some clinical benefits of kappa agonists
analgesic, anti-inflammatory, anti-itch, no CNS effects
which horn receives sensory input
dorsal horn
how is pain detected in the skin
C fiber primary afferent neurons
where do C fiber primary synapse onto
secondary afferents in the dorsal horn in the spinal cord
what is the role of secondary afferents
carry nociceptive information up to the brain
are mu opioid receptors are localized on primary or secondary afferents?
both
what does activation of mu opioid receptors does to pain
inhibits pain transmission from skin to brain
what is the role of opioid receptors on the brainstem (PAG and medulla)
increase descending noxious inhibitory control
inhibit pain signal at the level of the spinal cord
what is the rule of dopamine
motivational behaviour
where are the neurons primarily located
ventral tegmental area (VTA)
where are mu opioid receptors in the VTA located on
inhibitory GABAergic interneurons
what is disinhibition
opioid inhibit inhibition, which leads to dopamine release
how does opioid cause dopamine release
disinhibition
what are the two ways that mu opioid receptors inhibit pain
decrease nociception at C fiber
decrease emotional and cognitive aspects of pain
what makes the best analgesic
drugs that target the sensory, cognitice and emotional circuits
what is the catch-22 of making a good pain relief
the best ones are also rewarding (and addicting!)
the analgesic and euphoric system overlap, hard to remove one without the other
what is loperamide
mu agonist used for diarrhea
inhibits peristalsis and secretion
what are the targets of loperamide (where located-specific)
mu opioid on cholinergic neurons of the gastrointestinal tract
why isnt loperamide addicting
p-glycoprotein pumps it out from the brain
what happens if you block p-glycoproteins
increase brain concentration of loperaminde
what kind of drugs are dangerous to combine with loperamide
tricyclic antidepressants
how does desensitization happen after using opioids
beta arrestin is recruited to shut off signalling, receptor removed from membrane
what are the circuitry adaptations to opioids
increased pain, diarrhea, anxiety
what are the metabolic adaptations to opioids
upregulation of enzymes that metabolize the drugs
is dependence the same as addiction
no
addiction is more extreme, its more about the behaviour
what is addiction
a brain disease driven by dysfunction in reward, motivation and memory circuitry. inability to abstain, cant control behaviour
are all drug dependent users addiction
no
are all addicted drug users dependent
yes
how do drug companies try to prevent drug abuse
make them non crushable
make prodrug that must be metabolized in GI (cant be bypassed by intravenous use)
what is agonist replacement therapy
maintenance on an opioid agonist (buprenorphine, methadone) and CBT
what is buprenorphine
partial mu opioid agonist and kappa antagonist
what is methadone
long lasting full agonist at the mu receptor (24-42 hrs)
what is naloxon
non-selective competitive opioid receptor antagonist
how do opioids increase dopamine release
disinhibition of GABAergic inhibitory tone on dopaminergic neuronal cell bodies in the VTA
