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PMCOL 200 > Opiods > Flashcards

Opiods Flashcards

1
Q

what is opium?

A

dried latex from a poppy (raw product)

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2
Q

what are opiates?

A

any drug naturally derived from opium (isolated)

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3
Q

what are opioids?

A

any drug that binds to an opioid receptor (includes opiates and synthetic opioid agonists)

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4
Q

what are narcotics?

A

opioids used illegally for non-medical purposes (“to make numb” or sleep-inducing)

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5
Q

what kind of receptors are opioid receptors?

A

Gi GPCRs

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6
Q

what does activation of opioid receptors cause? (5)

A

inhibition of Ca channels, activation of K channels and inhibition of adenylyl cyclase -> decr NT release and neuronal inactivation (hyperpolarization)

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7
Q

what are the 4 types of opioid receptors?

A

mu, kappa, delta, NOP (ORL1: orphanin receptor ligand)

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8
Q

what is the same vs different btwn opioid receptors?

A

all Gi GPCRs but have very different effects when activated

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9
Q

what causes diff effects of diff opioid receptors? (2)

A

diff receptor distribution, diff ligand specificity

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10
Q

what is significant about the ORL-1 receptor? (5)

A

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

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11
Q

which aa sequences (intracell, transmemb, extracell) are similar vs diff btwn diff opioid receptors?

A

transmemb are similar, intra and extracell are different

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12
Q

what are agonist vs antagonist effects of mu activation?

A

agonist: analgesia, reward, antitussive, resp depression, constipation
antagonist: aversive, prevents reward/addiction, blocks overdose

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13
Q

what are ex of mu agonist vs antagonist?

A

agonist: morphine, codeine, heroine
antagonist: naloxone

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14
Q

what are agonist vs antagonist effects of delta activation?

A

agonist: not rewarding, no analgesia (except chronic pain/migraine), might be seizure-inducing
antagonist: no obvious effects

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15
Q

what are agonist vs antagonist effects of kappa activation?

A

agonist: aversive, hallucinogenic, anxiogenic
antagonist: potential antidepressant/anxiolytic

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16
Q

what are 4 full mu agonists?

A

morphine, methadone, fentanyl and heroin

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17
Q

what is a partial mu agonist?

A

codeine

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18
Q

what is a pro and con of codeine being a partial mu agonist?

A

decr analgesic efficacy but safer TI

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19
Q

list morphine, fentanyl, hydromorphone and codeine from most to least potent?

A

fentanyl > hydromorphone > codeine > morphine

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20
Q

t/f: potency does not affect aspects of a drug such as analgesia, euphoria, resp depression like efficacy does

A

false, potency affects aspects of a drug such as analgesia, euphoria, resp depression like efficacy does

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21
Q

what is buprenorphine?

A

partial mu agonist and delta and kappa antagonist

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22
Q

what is buprenorphine used for?

A

pain and opioid addiction therapy

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23
Q

what are biased agonists?

A

agonists that bind to receptors and initiate unique intracellular pathways

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24
Q

what are beta-arrestins?

A

family of intracellular proteins that regulate GPCR signal transduction

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25
Q

what occurs when beta-arrestins bind to activated/phosphorylated GPCRs? (3)

A

blocks further G-protein signalling, redirects signaling to other pathways, and internalizes receptors

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26
Q

t/f: beta-arrestins bind extracellularly to GPCRs

A

false, bind intracellularly

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27
Q

how do beta-arrestins lead to tolerance to chronic opioid use?

A

arrests G-protein signaling and activates other intracellular pathways that contribute to opioid effects (resp depression and constipation)

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28
Q

what is the difference btwn receptor selectivity and functional selectivity of biased agonists?

A

receptor selectivity: drug selectivity for diff receptor subtypes
functional selectivity: drug selectivity for diff pathways coupled to same receptor

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29
Q

t/f: all opioid ligands lead to beta-arrestin recruitment

A

false, diff opioid ligands can differentially activate G-protein vs beta-arrestin pathways (doesn’t have to be both)

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30
Q

for the mu opioid receptor, what does G-protein vs beta-arrestin signalling cause?

A

G-protein: analgesia

beta-arrestin: resp depression and decr GI function

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31
Q

what is the significance of diff effects for G-protein vs beta-arrestin with mu opioid receptor activation?

A

can design safer opioids that activate 1 pathway vs another (“tickle” receptor to maintain analgesia wo/ resp depression)

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32
Q

t/f: most mu agonists are well absorbed when taken orally

A

true

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33
Q

t/f: morphine does not undergo extensive 1st pass metabolism

A

false, it does

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34
Q

how does codeine avoid 1st pass metabolism?

A

is a prodrug

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35
Q

what is codeine metabolized into?

A

morphine

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36
Q

what metabolizes codeine into morphine?

A

CYP2D6 (phase 1)

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37
Q

what is linked to variation in analgesic and adverse responses to codeine?

A

fast vs slow metabolizers of codeine (genetic polymorphisms of CYP2D6)

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38
Q

what would the diff responses to codeine be btwn fast vs slow metabolizers?

A

fast: incr response (prodrug readily transformed)
slow: decr response (prodrug slowly transformed)

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39
Q

CYP2D6 poor metabolizers are prevalent in what % of white vs asian populations?

A

~6-10% in white vs ~2% in asian

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40
Q

where are opioid agonists found in highest conc in body tissues?

A

highly perfused tissues (brain, lungs, liver, kidney and spleen)

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41
Q

what affects how fast opioids reach peak plasma conc?

A

route of administration (IV > skin > oral)

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42
Q

t/f: opioid use in pregnant ppl affects the fetus

A

true, crosses placenta and causes resp depression and physical dependence in neonates

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43
Q

morphine is metabolized by phase _ glucuronidation

A

2 (adds polar groups to incr excretion)

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44
Q

what is the most important glucuronidation enzyme?

A

UGT2B7 (not CYP)

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45
Q

what is morphine metabolized into by UGT2B7? (2)

A

morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)

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46
Q

is M3G or M6G an active metabolite that can prolong effects of morphine?

A

M6G

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47
Q

M3G and M6G are polar metabolites that are excreted mainly in _____?

A

urine (also can contain unchanged drug)

48
Q

how could renal impairments affect ppl who need to take opioids?

A

can’t excrete active polar metabolites (M6G) and are at risk for adverse effects (sedation/resp depression)

49
Q

what are 3 endogenous opioid peptides?

A

beta endorphins, enkephalins, dynorphins

50
Q

how are the 3 endogenous endorphins similar?

A

widely distributed and mediate pain, reward, learning, memory and cognition

51
Q

what are the precursors for endogenous opioid peptides?

A

beta endorphins: proopiomelanocortin

enkephalins: proenkephalin
dynorphins: prodynorphin

52
Q

what converters precursors for endogenous opioid peptides to final NT?

A

proteases (posttranslational)

53
Q

t/f: cleavage by proteases can only convert precursors to one endogenous opioid peptide

A

false, each precursor can result in multiple diff active peptides

54
Q

what 4 aa sequence do all opioid peptides share?

A

Tyr-Gly-Gly-Phe

55
Q

what is added to the similar aa sequence in opioid peptides?

A

various 5-31 aa long extensions

56
Q

what are the affinities for mu, delta, and kappa receptors by beta endorphins, enkephalins, dynorphins?

A

beta endorphins: mu=delta»kappa

enkephalins: delta»mu»kappa
dynorphins: kappa»mu=delta

57
Q

dynorphins incr in what situations?

A

stressful situations

58
Q

what are the 2 endogenous enkephalins?

A

[Met] and [Leu] enkephalin

59
Q

what are the 3 endogenous dynorphins?

A

dynorphin A, B and neoendorphin

60
Q

is morphine a biased agonist?

A

no, activates both G-protein and beta arrestin pathway

61
Q

what are opioids used to treat medically?

A

acute, severe pain

62
Q

how do opioids treat pain effectively?

A

bind to mu opioid receptors in neuronal pathways signalling pain and reward

63
Q

how do opioids cause respiratory depression?

A

bind to opioid receptors in brainstem, decr signalling controlling breathing

64
Q

where are mu, delta, and kappa receptors localized for pain?

A

primary afferents (nociceptors in skin) and secondary afferents (in spinal cord)

65
Q

what does agonist binding to opioid receptors cause?

A

inhibited pain transmission to brain

66
Q

what area in the brainstem are opioid receptors localized?

A

rostroventral medulla (endogenous pain control system)

67
Q

what does opioid binding in rostroventral medulla cause?

A

incr in diffuse noxious inhibitory control (decr pain)

68
Q

what does the diffuse noxious inhibitory circuit comprise?

A

descending excitatory and descending inhibitory neurons that activate or inhibit pain synapses in spinal cord (controls nociceptive info to brain)

69
Q

what opioid receptors are on medulla ON cells? (desc exc neurons)

A

mu and delta

70
Q

what does activation of opioid receptors on medulla ON cells cause?

A

inhibition of ON cells and net dec in nociceptive/pain signals reaching brain

71
Q

what NT is involved in motivating behaviour?

A

dopamine

72
Q

where are dopamine neurons primarily located?

A

ventral tegmental area (VTA)

73
Q

which neurons are mu opioid receptors in VTA located on?

A

GABAergic interneurons

74
Q

what does opioid binding to GABAergic interneurons in VTA cause?

A

inhibition of GABA neurons which disinhibits DA neurons and incr DA release

75
Q

what 2 ways do opioids inhibit pain?

A
  1. decr nociception in nociceptor, spinal cord, and brain stem
  2. decr emotional and cognitive aspects of pain (more effective)
76
Q

what is the catch-22 of opioids?

A

opioids are good analgesics BECAUSE they are rewarding/addicting (will always be better)

77
Q

what receptor do must opioid agonists bind to?

A

mu (ex. morphine, fentanyl, codeine, oxycodone)

78
Q

agonists that bind to what receptor are being developed for chronic migraine?

A

delta (are upregulated w/ chronic pain but not good for acute)

79
Q

why was development of delta agonists initially limited?

A

severe side effects (seizures)

80
Q

how are analgesic effects isolated from severe side effects of delta agonists?

A

biased agonism (activates G-protein pathway but not beta arrestin pathway)

81
Q

what is TRV250?

A

delta opioid receptor biased agonist (developed by Trevena)

82
Q

why have kappa agonists not been developed for pain?

A

can cross BBB and have hallucinogenic/dysphoric effects (Salvia)

83
Q

what are peripherally restricted kappa agonists?

A

drugs that bind kappa receptors on skin (for pain) but do not cross BBB to cause adverse CNS effects (hallucinations/dysphoria)

84
Q

what is CR845?

A

peripherally restricted kappa agonist

85
Q

what is CR845 used for? (4)

A

potent analgesia, anti-inflammatory, anti-itch drug w/ little CNS effects (developed by Cara Therapeutics)

86
Q

what is drug tolerance?

A

decr neuronal effects to a drug, requiring incr amounts to achieve same effect

87
Q

tolerance is developed to what 4 opioid effects?

A

analgesia, euphoria, sedation, resp depression

88
Q

what dose can an opioid-tolerant person take? and what is normally lethal?

A

tolerant: 2g

normally lethal: 30mg

89
Q

how does opioid tolerance develop?

A

agonist binding causes beta arrestin activation (to shut-off signaling), desensitization/internalization of receptors and degradation by a lysosome

90
Q

when is opioid physical dependence developed and revealed?

A

develops w/ chronic opioid use and revealed w/ abrupt drug discontinuance

91
Q

how is physical dependence revealed?

A

withdrawal

92
Q

what are 7 opioid withdrawal symptoms?

A

rhinorrhea (runny nose), lacrimation (tearing eyes), chills, aches, diarrhea, yawning, anxiety (opposite to drug effects)

93
Q

t/f: dependence = addiction

A

false, dependence can lead to addiction (w/ chronic use for pain, opioid-exposed fetus)

94
Q

what is addiction?

A

brain disease driven by dysfunction in reward, motivation, and memory circuitry

95
Q

what is addiction characterized by? (5)

A

inability to abstain consistently, impaired behavioural control, drug craving, decr recognition of personal/social problems, dysfunctional emotional responses

96
Q

what do preventative measures for opioid use disorder do?

A

make drug abuse difficult (harder to grind oral tablets for snorting/injecting)

97
Q

what do physical preventative barriers for opioid use disorder do?

A

prevent chewing/crushing of oral tablets for intravenous/intranasal abuse

98
Q

what do chemical preventative barriers for opioid use disorder do?

A

resist dissolution of opioid by common solvents (water, alcohol) for injection

99
Q

how do agonist/agonist combinations prevent opioid use disorder?

A

antagonist interferes w/ euphoric agonist effects when tablet is tampered with (crushed/injected)

100
Q

what is agonist replacement therapy?

A

opioid use disorder treatment that maintains opioid agonism (weaker) with CBT to decr symptoms of withdrawal

101
Q

what do replacement opioids feature to avoid repeated high/crash cycle of opioid abuse?

A

longer half-lives (most commonly methadone or buprenorphine)

102
Q

what are 4 advantages of agonist replacement therapy for opioid use disorder?

A

decr drug cravings, incr participation in addiction treatment (CBT), improved social functioning, decr infectious disease/overdose from illicit drug use (injections)

103
Q

what is methadone?

A

long-acting full mu agonist

104
Q

what was the first approved opioid replacement therapy drug?

A

methadone

105
Q

what is a disadvantage of using methadone in agonist replacement therapy?

A

is a full agonist so can cause overdose (not for high-risk/severe cases)

106
Q

what is buprenorphine?

A

partial mu agonist, delta and kappa antagonist

107
Q

what are 2 advantages of buprenorphine for agonist replacement therapy?

A

safer agonist profile and kappa antagonism can improve mood

108
Q

what is suboxone?

A

buprenorphine and naloxone (only activated if crushed)

109
Q

what are harm reduction treatments for opioid use disorder?

A

strategies that decr morbidity and mortality from drug use but don’t treat addiction

110
Q

what are 2 examples of harm reduction treatments for opioid use disorder?

A

supervised consumption sites and injectable opioid therapy

111
Q

what are supervised consumption sites?

A

safe places for clients to take own drugs and reduce risk of harm/overdose. are provided clean needles and medical supervision. accessible and anonymous

112
Q

what is injectable opioid therapy?

A

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)

113
Q

what are 2 pros and 2 cons of harm reduction treatments for opioid use disorder?

A

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

114
Q

what is an acute intoxication treatment for opioid overdose?

A

naloxone (Narcan)

115
Q

what is naloxone?

A

non-selective competitive opioid receptor antagonist

116
Q

in what forms is naloxone available to public?

A

intramuscular and nasal (no prescription)

117
Q

how fast does naloxone work and how long does it last?

A

works within minutes and lasts ~30 min (may require >1 dose)

PMCOL 200 (27 decks)

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