Opiods Flashcards
what is opium?
dried latex from a poppy (raw product)
what are opiates?
any drug naturally derived from opium (isolated)
what are opioids?
any drug that binds to an opioid receptor (includes opiates and synthetic opioid agonists)
what are narcotics?
opioids used illegally for non-medical purposes (“to make numb” or sleep-inducing)
what kind of receptors are opioid receptors?
Gi GPCRs
what does activation of opioid receptors cause? (5)
inhibition of Ca channels, activation of K channels and inhibition of adenylyl cyclase -> decr NT release and neuronal inactivation (hyperpolarization)
what are the 4 types of opioid receptors?
mu, kappa, delta, NOP (ORL1: orphanin receptor ligand)
what is the same vs different btwn opioid receptors?
all Gi GPCRs but have very different effects when activated
what causes diff effects of diff opioid receptors? (2)
diff receptor distribution, diff ligand specificity
what is significant about the ORL-1 receptor? (5)
widely expressed in CNS, last opioid R to be discovered by sequence homology, does not share functional similarities w other opioid Rs, poorly studied, may be involved in fear processing
which aa sequences (intracell, transmemb, extracell) are similar vs diff btwn diff opioid receptors?
transmemb are similar, intra and extracell are different
what are agonist vs antagonist effects of mu activation?
agonist: analgesia, reward, antitussive, resp depression, constipation
antagonist: aversive, prevents reward/addiction, blocks overdose
what are ex of mu agonist vs antagonist?
agonist: morphine, codeine, heroine
antagonist: naloxone
what are agonist vs antagonist effects of delta activation?
agonist: not rewarding, no analgesia (except chronic pain/migraine), might be seizure-inducing
antagonist: no obvious effects
what are agonist vs antagonist effects of kappa activation?
agonist: aversive, hallucinogenic, anxiogenic
antagonist: potential antidepressant/anxiolytic
what are 4 full mu agonists?
morphine, methadone, fentanyl and heroin
what is a partial mu agonist?
codeine
what is a pro and con of codeine being a partial mu agonist?
decr analgesic efficacy but safer TI
list morphine, fentanyl, hydromorphone and codeine from most to least potent?
fentanyl > hydromorphone > codeine > morphine
t/f: potency does not affect aspects of a drug such as analgesia, euphoria, resp depression like efficacy does
false, potency affects aspects of a drug such as analgesia, euphoria, resp depression like efficacy does
what is buprenorphine?
partial mu agonist and delta and kappa antagonist
what is buprenorphine used for?
pain and opioid addiction therapy
what are biased agonists?
agonists that bind to receptors and initiate unique intracellular pathways
what are beta-arrestins?
family of intracellular proteins that regulate GPCR signal transduction
what occurs when beta-arrestins bind to activated/phosphorylated GPCRs? (3)
blocks further G-protein signalling, redirects signaling to other pathways, and internalizes receptors
t/f: beta-arrestins bind extracellularly to GPCRs
false, bind intracellularly
how do beta-arrestins lead to tolerance to chronic opioid use?
arrests G-protein signaling and activates other intracellular pathways that contribute to opioid effects (resp depression and constipation)
what is the difference btwn receptor selectivity and functional selectivity of biased agonists?
receptor selectivity: drug selectivity for diff receptor subtypes
functional selectivity: drug selectivity for diff pathways coupled to same receptor
t/f: all opioid ligands lead to beta-arrestin recruitment
false, diff opioid ligands can differentially activate G-protein vs beta-arrestin pathways (doesn’t have to be both)
for the mu opioid receptor, what does G-protein vs beta-arrestin signalling cause?
G-protein: analgesia
beta-arrestin: resp depression and decr GI function
what is the significance of diff effects for G-protein vs beta-arrestin with mu opioid receptor activation?
can design safer opioids that activate 1 pathway vs another (“tickle” receptor to maintain analgesia wo/ resp depression)
t/f: most mu agonists are well absorbed when taken orally
true
t/f: morphine does not undergo extensive 1st pass metabolism
false, it does
how does codeine avoid 1st pass metabolism?
is a prodrug
what is codeine metabolized into?
morphine
what metabolizes codeine into morphine?
CYP2D6 (phase 1)
what is linked to variation in analgesic and adverse responses to codeine?
fast vs slow metabolizers of codeine (genetic polymorphisms of CYP2D6)
what would the diff responses to codeine be btwn fast vs slow metabolizers?
fast: incr response (prodrug readily transformed)
slow: decr response (prodrug slowly transformed)
CYP2D6 poor metabolizers are prevalent in what % of white vs asian populations?
~6-10% in white vs ~2% in asian
where are opioid agonists found in highest conc in body tissues?
highly perfused tissues (brain, lungs, liver, kidney and spleen)
what affects how fast opioids reach peak plasma conc?
route of administration (IV > skin > oral)
t/f: opioid use in pregnant ppl affects the fetus
true, crosses placenta and causes resp depression and physical dependence in neonates
morphine is metabolized by phase _ glucuronidation
2 (adds polar groups to incr excretion)
what is the most important glucuronidation enzyme?
UGT2B7 (not CYP)
what is morphine metabolized into by UGT2B7? (2)
morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)
is M3G or M6G an active metabolite that can prolong effects of morphine?
M6G
M3G and M6G are polar metabolites that are excreted mainly in _____?
urine (also can contain unchanged drug)
how could renal impairments affect ppl who need to take opioids?
can’t excrete active polar metabolites (M6G) and are at risk for adverse effects (sedation/resp depression)
what are 3 endogenous opioid peptides?
beta endorphins, enkephalins, dynorphins
how are the 3 endogenous endorphins similar?
widely distributed and mediate pain, reward, learning, memory and cognition
what are the precursors for endogenous opioid peptides?
beta endorphins: proopiomelanocortin
enkephalins: proenkephalin
dynorphins: prodynorphin
what converters precursors for endogenous opioid peptides to final NT?
proteases (posttranslational)
t/f: cleavage by proteases can only convert precursors to one endogenous opioid peptide
false, each precursor can result in multiple diff active peptides
what 4 aa sequence do all opioid peptides share?
Tyr-Gly-Gly-Phe
what is added to the similar aa sequence in opioid peptides?
various 5-31 aa long extensions
what are the affinities for mu, delta, and kappa receptors by beta endorphins, enkephalins, dynorphins?
beta endorphins: mu=delta»kappa
enkephalins: delta»mu»kappa
dynorphins: kappa»mu=delta
dynorphins incr in what situations?
stressful situations
what are the 2 endogenous enkephalins?
[Met] and [Leu] enkephalin
what are the 3 endogenous dynorphins?
dynorphin A, B and neoendorphin
is morphine a biased agonist?
no, activates both G-protein and beta arrestin pathway
what are opioids used to treat medically?
acute, severe pain
how do opioids treat pain effectively?
bind to mu opioid receptors in neuronal pathways signalling pain and reward
how do opioids cause respiratory depression?
bind to opioid receptors in brainstem, decr signalling controlling breathing
where are mu, delta, and kappa receptors localized for pain?
primary afferents (nociceptors in skin) and secondary afferents (in spinal cord)
what does agonist binding to opioid receptors cause?
inhibited pain transmission to brain
what area in the brainstem are opioid receptors localized?
rostroventral medulla (endogenous pain control system)
what does opioid binding in rostroventral medulla cause?
incr in diffuse noxious inhibitory control (decr pain)
what does the diffuse noxious inhibitory circuit comprise?
descending excitatory and descending inhibitory neurons that activate or inhibit pain synapses in spinal cord (controls nociceptive info to brain)
what opioid receptors are on medulla ON cells? (desc exc neurons)
mu and delta
what does activation of opioid receptors on medulla ON cells cause?
inhibition of ON cells and net dec in nociceptive/pain signals reaching brain
what NT is involved in motivating behaviour?
dopamine
where are dopamine neurons primarily located?
ventral tegmental area (VTA)
which neurons are mu opioid receptors in VTA located on?
GABAergic interneurons
what does opioid binding to GABAergic interneurons in VTA cause?
inhibition of GABA neurons which disinhibits DA neurons and incr DA release
what 2 ways do opioids inhibit pain?
- decr nociception in nociceptor, spinal cord, and brain stem
- decr emotional and cognitive aspects of pain (more effective)
what is the catch-22 of opioids?
opioids are good analgesics BECAUSE they are rewarding/addicting (will always be better)
what receptor do must opioid agonists bind to?
mu (ex. morphine, fentanyl, codeine, oxycodone)
agonists that bind to what receptor are being developed for chronic migraine?
delta (are upregulated w/ chronic pain but not good for acute)
why was development of delta agonists initially limited?
severe side effects (seizures)
how are analgesic effects isolated from severe side effects of delta agonists?
biased agonism (activates G-protein pathway but not beta arrestin pathway)
what is TRV250?
delta opioid receptor biased agonist (developed by Trevena)
why have kappa agonists not been developed for pain?
can cross BBB and have hallucinogenic/dysphoric effects (Salvia)
what are peripherally restricted kappa agonists?
drugs that bind kappa receptors on skin (for pain) but do not cross BBB to cause adverse CNS effects (hallucinations/dysphoria)
what is CR845?
peripherally restricted kappa agonist
what is CR845 used for? (4)
potent analgesia, anti-inflammatory, anti-itch drug w/ little CNS effects (developed by Cara Therapeutics)
what is drug tolerance?
decr neuronal effects to a drug, requiring incr amounts to achieve same effect
tolerance is developed to what 4 opioid effects?
analgesia, euphoria, sedation, resp depression
what dose can an opioid-tolerant person take? and what is normally lethal?
tolerant: 2g
normally lethal: 30mg
how does opioid tolerance develop?
agonist binding causes beta arrestin activation (to shut-off signaling), desensitization/internalization of receptors and degradation by a lysosome
when is opioid physical dependence developed and revealed?
develops w/ chronic opioid use and revealed w/ abrupt drug discontinuance
how is physical dependence revealed?
withdrawal
what are 7 opioid withdrawal symptoms?
rhinorrhea (runny nose), lacrimation (tearing eyes), chills, aches, diarrhea, yawning, anxiety (opposite to drug effects)
t/f: dependence = addiction
false, dependence can lead to addiction (w/ chronic use for pain, opioid-exposed fetus)
what is addiction?
brain disease driven by dysfunction in reward, motivation, and memory circuitry
what is addiction characterized by? (5)
inability to abstain consistently, impaired behavioural control, drug craving, decr recognition of personal/social problems, dysfunctional emotional responses
what do preventative measures for opioid use disorder do?
make drug abuse difficult (harder to grind oral tablets for snorting/injecting)
what do physical preventative barriers for opioid use disorder do?
prevent chewing/crushing of oral tablets for intravenous/intranasal abuse
what do chemical preventative barriers for opioid use disorder do?
resist dissolution of opioid by common solvents (water, alcohol) for injection
how do agonist/agonist combinations prevent opioid use disorder?
antagonist interferes w/ euphoric agonist effects when tablet is tampered with (crushed/injected)
what is agonist replacement therapy?
opioid use disorder treatment that maintains opioid agonism (weaker) with CBT to decr symptoms of withdrawal
what do replacement opioids feature to avoid repeated high/crash cycle of opioid abuse?
longer half-lives (most commonly methadone or buprenorphine)
what are 4 advantages of agonist replacement therapy for opioid use disorder?
decr drug cravings, incr participation in addiction treatment (CBT), improved social functioning, decr infectious disease/overdose from illicit drug use (injections)
what is methadone?
long-acting full mu agonist
what was the first approved opioid replacement therapy drug?
methadone
what is a disadvantage of using methadone in agonist replacement therapy?
is a full agonist so can cause overdose (not for high-risk/severe cases)
what is buprenorphine?
partial mu agonist, delta and kappa antagonist
what are 2 advantages of buprenorphine for agonist replacement therapy?
safer agonist profile and kappa antagonism can improve mood
what is suboxone?
buprenorphine and naloxone (only activated if crushed)
what are harm reduction treatments for opioid use disorder?
strategies that decr morbidity and mortality from drug use but don’t treat addiction
what are 2 examples of harm reduction treatments for opioid use disorder?
supervised consumption sites and injectable opioid therapy
what are supervised consumption sites?
safe places for clients to take own drugs and reduce risk of harm/overdose. are provided clean needles and medical supervision. accessible and anonymous
what is injectable opioid therapy?
clients are prescribed specific doses of injectable opioid (hydromorphone) to self-administer at iOAT clinic. requires referral and failure of all other possible treatments. are closely monitored for adverse rxns (different from agonist replacement therapy)
what are 2 pros and 2 cons of harm reduction treatments for opioid use disorder?
pros: decr morbidity/mortality, provide info for treatments
cons: moral argument in giving drugs to addicts, NIMBY (not in my backyard) related to location of SCS/iOAT clinics
what is an acute intoxication treatment for opioid overdose?
naloxone (Narcan)
what is naloxone?
non-selective competitive opioid receptor antagonist
in what forms is naloxone available to public?
intramuscular and nasal (no prescription)
how fast does naloxone work and how long does it last?
works within minutes and lasts ~30 min (may require >1 dose)
