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Pmcol 305 > Opioids > Flashcards

Opioids Flashcards

1
Q

medical uses

A

pain → anti-nociceptive
blocks afferent transmission in the spinal cord/brainstem + PAG

safe and effective when used appropriately

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2
Q

PAG

A

periaqueductal gray
dorsal midbrain (tegmentum)
modulation of pain transmission - sets thresholds

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3
Q

opioid epidemic

A

skyrocketing opioid prescriptions preceded opioid-related death epidemic

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4
Q

opioids + sedatives

A

lethal mix
polypharmacy - depressant drugs
synergism of respiratory response
depression of critical brain functions (respiration) = low (or no) resp rate = no O2 flow

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5
Q

prevention of overdose

A

Naloxone
Methadone
First Responders

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6
Q

naloxone

A

opioid receptor antagonist

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7
Q

methadone

A

mu partial agonist → competes with other opioids for binding
delayed kinetics; reduces symptoms of withdrawal → used clinically to help recovery
NMDA receptor antagonist

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8
Q

sources of opioids

A

natural
semi-synthetic
synthetic

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9
Q

natural opioids

A

opium
contains morphine, codeine

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10
Q

semi-synthetic opioids

A

derived from opium
heroin
hydro-codone/-morphone, oxycodone
krokodil
buprenorphine, etorphine

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11
Q

synthetic opioids

A

methadone, meperidine
tramadol
fentanyl

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12
Q

composition of opium

A

narcotic (morphine [10%] + codeine [0.5%]) and non-narcotic alkaloids

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13
Q

kinetics of opium

A

morphine is 10x more potent than opium
CYP2D6 converts codeine to morphine in brain + liver

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14
Q

codeine

A

prodrug
requires metabolism to be active

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15
Q

pharmacogenomics of codeine

A

10% of caucasians have deficient CYP2D6 = codeine has no effect
2% of population has overactive CYP2D6 = morphine intoxication

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16
Q

heroin

A

semi-synthetic opioid = produced by modifying naturally-derived chemical
morphine + two acetyl groups = 10x more lipophilic
→ faster distribution to brain = rapid onset of euphoria

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17
Q

synthetic opioid sources

A

diphenylacetonitrile → methadone
cyclohexanone → tramadol
4-piperidone hydrochloride → fentanyl

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18
Q

discovery of opioid receptors

A

synthesis of naloxone → saw reversal of morphine effects

later, tracing of radiolabelled drugs to determine targets
Pert and Snyder

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19
Q

Pert and Snyder

A

discovery of opioid receptors in the brain by radio-labelling
→ radioligand binding
4 classes: mu, delta, kappa, ORL-1

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20
Q

presynaptic receptors

A

modulate neurotransmitter release
dopamine, norepinephrine, GABA

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21
Q

post synaptic receptors

A

alter membrane potential

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22
Q

endogenous opioids

A

18 different peptide ligands that bind to opioid receptors
endorphins are widest class → range of functions

all contain N-terminal tyrosine residue → morphine structure mimics tyrosine

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23
Q

functions of endorphins

A

pain, emotional responses, euphoria, eating, memory, stress, seizures, and alcohol dependence

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24
Q

mu opioid receptors

A

most opioids bind mu receptors

morpheus - sleep (tranquilizing effects)
expressed in VTA, NAc, PAG, hypothalamus, LC, brainstem, pupils, GI tract
involved in reward, addiction, analgesia, euphoria, anxiolysis, respiration, blood pressure, nausea, itch, vasoconstriction, constipation

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25
Q

delta opioid receptors

A

found in vas deferens tissue
expressed in neocortex, striatum, NAc, substantia nigra, olfactory bulb

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26
Q

enkephalins

A

endogenous opioids
bind delta receptors

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27
Q

kappa opioid receptors

A

ketocyclazocine → ligand specific to kappa receptor

expressed in pituitary, hypothalamus, PAG, spinal cord

bound by endorphins and dynorphins, + PCP and ketamine

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28
Q

kappa receptor → dysphoria

A

most aversive withdrawal symptoms → leads to relapse/binge
= target of potential treatments

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29
Q

ORL 1 opioid receptor

A

expressed in limbic system and spinal cord
bound by buprenorphine

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30
Q

contamination of drugs with fentanyl

A

fentanyl: similar appearance to rx pills (80mg oxycontin)
sold as heroin

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31
Q

fentanyl

A

use as surgical anaesthetic + analgesic
100x more potent than morphine
40-50x more potent than heroin
highly lipophilic

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32
Q

fentanyl derivatives

A

increased affinity for mu receptors + enhanced entry into the brain = higher potency
carfentanil
3-methylfentanyl

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33
Q

absorption

A

higher purity (rx) = safer administration → street opioids are often contaminated with adulterants (baking soda, talcum, fentanyl)

administration:
inhalation, injection, ingestion

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34
Q

distribution

A

most are not lipophilic (heroin and fentanyl are) → do not readily cross BBB
liver, lungs, spleen, GI, brain

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35
Q

metabolism

A

heroin → morphine in the brain
metabolized in the liver

pills → first pass metabolism = reduced bioavailability
alter route of administration (crush, heat, + inject) to get higher [ ]

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36
Q

excretion

A

kidneys

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37
Q

chasing the dragon

A

heat up on tin foil + inhale fumes
metal aerosolizes → metal toxicity, accumulation of metals in brain
linked to leukoencephalopathy

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38
Q

leukoencephalopathy

A

aversive effect of ‘chasing the dragon’ method of administration
destruction of white matter in CNS
brain tissue → spongiform (holes in brain)
progresses (over time) to ataxia, apathy, akathisia, to inability to move or speak

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39
Q

injecting heroin

A

mix drug with water, dissolve with acid/heat
drawn up through cotton ball (filtration)

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40
Q

risks of injection

A

track marks
damage to blood vessels - needle, drug, injection rate, infection
uneven blood flow, thrombosis, clots
vessels collapse

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41
Q

heroin pharmacokinetics

A

faster distribution to the brain (lipophilic) = higher potency
can be snorted
metabolized to morphine in the brain → metabolites:
3-MAM and 6-MAM

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42
Q

6-MAM

A

6-monoacetylmorphine
metabolite of heroin - not naturally occurring, indicative of heroin use
binds mu receptor (3-MAM does not)

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43
Q

acute effects of opioids

A

brain
(medulla)
eyes
circulatory system
lungs
skin
GI
muscles

44
Q

acute effects in brain

A

brainstem chemotrigger zones in area postrema of medulla → triggers nausea, vomiting (usually develop tolerance to effects)

euphoria
impaired judgement
reduced pain

45
Q

acute effects in medulla

A

lowers blood pressure = hypotension
bronchoconstriction
itching

46
Q

acute effects in eyes

A

mu and kappa receptors in oculomotor nucleus → constricted pupils
heroin = parasympathomimetic response

47
Q

acute effects in skin and muscles

A

lowered body temp, flushed skin
muscle relaxation

48
Q

acute effects in CV and lungs

A

vasodilation, lowered blood pressure
slowed respiration

49
Q

physiological effects of opioids

A

reproduction
constipation
decreased urination
NAS

50
Q

effect on reproduction

A

reduced levels of GnRH, LH, FSH = decreased libido, impotence, amenorrhea

51
Q

constipation

A

isometric muscle contractions reduce bowel movements, secretions

52
Q

decreased urination

A

constriction of ureter and sphincters of bladder, stimulation of anti-diuretic hormone release

53
Q

neonatal abstinence syndrome

A

withdrawal
babies are irritable, vomit, diarrhea, seizures, respiratory distress

54
Q

reinforcing mechanism of opioids in NAc

A

opioid binds to receptor on GABA interneuron = inhibition
→ less GABA release → no inhibition of dopamine neuron (= disinhibition)
→ increased dopamine release

55
Q

opioid receptor origin

A

mu, delta, and kappa → separate Opr genes
expressed in multiple brain regions, spine, GI tract, etc.

ORL receptor shows structural homology

subtypes likely due to allelic variation → impacts function

56
Q

receptor peptides

A

delta = enkephalin (met and leu)
kappa = dynorphin (A and B)
mu = endorphin (β, 1, 2)

57
Q

opioid receptor signaling

A

ligand binds → triggers GPCR cascade (Gi = inhibition)
= inhibition of AC → reduced cAMP, inhibits PKA

alpha-GTP: activation of PLCβ and MAPK pathways

58
Q

βy subunits - OR signaling

A

activate GIRK3 (K+ channel) = hyperpolarization
block Ca2+ channels = reduced intracellular Ca2+ → suppress NT release

59
Q

ORs are GPCRs

A

Gi/o = inhibitory

60
Q

chronic exposure to morphine

A

G-protein coupled receptor kinase-mediated phosphorylation of opioid receptors and binding of β arrestin → desensitization

61
Q

two pathways connected to OR GPCR

A

G-protein → analgesia
β-arrestin → respiratory depression (shut off pathway)

62
Q

biased agonism

A

differential activation of signaling pathways by OR ligand
selective operation of signaling cascades

63
Q

selective activation of OR GPCR

A
  1. not all signaling is G-protein mediated → selective G-protein independent cascades depend on scaffold formation, direct physical contacts
  2. orthosteric stabilization of receptor conformations alter scaffolding
64
Q

classic opioid signaling

A

biased G-protein effects:
morphine keeps receptor phosphorylation low
other opioids produce high receptor phosphorylation → receptor internalization, increased tolerance and dependence ex. fentanyl

65
Q

non-synonymous mutations in mu opioid receptor

A

affect signaling and function
L85I and R181C are mutants that show altered patterns of internalization in presence of morphine

66
Q

descending pain pathway

A

cortex → thalamus → PAG → RVM →dorsal horn of spine
*sometimes thalamus is bypassed

67
Q

pain afferent threshold

A

set by tonic firing of GABA interneurons in RVM to dorsal horn

68
Q

mechanism of opioid-mediated analgesia

A

activation of mu opioid receptor on GABA RVM interneurons
= reduced inhibition of RVM “off” projecting cells to spinal cord
→ elevated signaling from RVM to spinal cord = ↓ afferent pain transmission into the spine

activation of muOR on RVM ‘ON’ projecting cells to the spinal cord = decreased outputs to the dorsal horn
→ + analgesic effect

69
Q

indirect role of amygdala

A

modifies pain transmission
state of mind; when in fight-or-flight, do not feel pain

70
Q

in dorsal spine horns

A

pre-synaptic muOR activation on afferent pain neurons reduces neurotransmitter release and pain transmission

71
Q

contextual memory → associative conditioning

A

hippocampal mu receptors
astrocyte mu receptors

72
Q

hippocampal mu receptors

A

disinhibition of CA1 and dentate gyrus cells via GABA interneurons

73
Q

astrocyte mu receptors

A

activation causes Glu release onto CA1 neurons

74
Q

NAc medium spiny neurons

A

express D1-like receptors + D2-like receptors
→ functions are subdivided

75
Q

D1 receptors

A

co-express dynorphin

mu receptors are usually co-expressed on D1 receptor expressing cells

76
Q

D2 receptors

A

co-express enkephalin

77
Q

metabolic tolerance

A

changes in distribution → faster breakdown = more tolerant of effects

78
Q

cellular tolerance

A

opioid receptors are down-regulated→ need higher dose for same effects
molecular uncoupling may disrupt OR signals (internalization of receptor → desensitization)

79
Q

behavioural tolerance

A

behaving sober when intoxicated

80
Q

tolerance reduces some effects

A

tolerant to: analgesia, vomiting, euphoria, respiratory depression

no tolerance to: constipation + pupil constriction

81
Q

lower tolerance in different locations

A

tolerant rats given high doses in same or different environments
higher (nearly double) mortality in different environment

82
Q

rat park experiment

A

morphine administration is influenced by psychosocial environment
isolated rats administered much more morphine

83
Q

behavioural sensitization

A

gauge psychological addiction → escalation of behavioural responses to a stimulus (drug of abuse) after drug-free period

factors: receptor density, NT levels, cell signaling deregulation

84
Q

behavioural sensitization driven by NAc inputs

A

dopamine-ergic projections from VTA and glutamatergic from PFC to the NAc

blocking D1 (antagonist) in NAc impairs sensitization

85
Q

morphine sensitization

A

elevated D1 expression in NAc shell + elevated transcription factor (ERK1/2 MAPK) activity

86
Q

AMPA/NMDA receptor antagonists

A

block the induction of sensitization
do not block expression of sensitization → if it has already been learned, the pathways are already established and it can’t be blocked

87
Q

desensitization

A

cellular tolerance

rapid; direct consequence of drug-receptor activation
depends on Ca2+ and K+ activities

sustained desensitization reduces acute effects (analgesia) but enhances intracellular signaling

88
Q

GRK phosphorylation of muOR

A

causes B-arrestin binding and reduced euphoria/analgesia

causes addicts to use higher doses for same effect = tolerance

89
Q

hyperalgesia

A

caused by desensitization
heroin tolerance: decreased latency in pain sensing

used barbadin: B-arrestin inhibitor = stops hyperalgesia

90
Q

short term opioid exposure

A

internalization of receptor; once B-arrestin is shut off, receptor is recycled and returns to membrane surface

91
Q

long term opioid exposure

A

internalization of receptor; eventual receptor degradation = permanent removal
increased levels of AC, PKC, PKA, and NMDA → hyperalgesia

92
Q

withdrawal

A

stages:
1. 6 hrs after last dose → emotional response = craving, anxiety
2. 12-14 hrs → physical symptoms = yawning, sweating, watery eyes, runny nose
3. 14-16 hrs → opposite of acute effects = dilated pupils, goose bumps, hot/cold flashes, fever, diarrhea, aching, no appetite
4. 2-5 days → weakness, depression, insomnia, elevated BP/heart rate/breathing, restlesness, hyperglycemia

93
Q

affective signs of withdrawal

A

cognitive symptoms
dysphoria, anxiety, irritability, cravings

mesolimbic system

targets for therapy, prevention of relapses

94
Q

mesolimbic system - withdrawal affective signs

A

NAc
LC

95
Q

NAc - affective withdrawal signs

A

naloxone injection = conditioned place aversion
D2-like receptor agonist injection attentuates somatic withdrawal signs

DA in NAc is decreased

96
Q

LC - affective withdrawal signs

A

LC expresses mu and kappa opioid receptors

chronic use suppresses LC activity = ↓ NE released
tolerance → up regulation of activity to normal
= removal of opioids → overactivity = NE surge:
sweating, chills, stomach cramps, emesis, diarrhea, muscle pain, runny nose/eyes

97
Q

LPGi

A

lateral paragigantocellularis in rostroventral medulla
stimulates LC via glutamatergic inputs
modulates withdrawal symptoms

98
Q

withdrawal treatment

A

anti-adrenergics: clonidine/lofexidine
synthetic opioids: buprenorphine, methadone

99
Q

clonidine or lofexidine

A

alpha2 adrenoceptor agonist
prevents NE release via pre-synaptic alpha2 autoreceptors
targets LC projections

100
Q

buprenorphine

A

for maintenance
semi synthetic partial agonist
out competes morphine, blocks heroin

101
Q

suboxone

A

4:1 buprenorphine:naloxone sublingual
[naloxone can not cross mucosal membranes]
→ if injected, effects are blocked (naloxone = antagonist)

102
Q

methadone

A

for maintenance
long half-life
NMDA receptor antagonist

103
Q

methadone kinetics

A

stable plasma concentration = does not reach ‘high’ level but doesn’t dip below into withdrawal symptoms

104
Q

opioid overdoses

A

triad:
coma = unresponsive
depressed respiration
pinpoint pupils

105
Q

naloxone

A

prevents opioid overdose
targets mu, kappa, and delta ORs
competitive antagonist
short-acting ~20-40 min

106
Q

main brainstem network

A

Pre-Botzinger complex + retro-trapezoid nucleus/parafacial respiratory group = coupled oscillator that influences motoneurons → produce breathing

107
Q

depressed respiration

A

reduced pre-Botzinger complex output
unresponsiveness
upperairway obstruction due to reduced upper airway muscle tone (genioglossus)

Pmcol 305 (18 decks)

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