Opioids Flashcards
Ascending pain pathway
starts from terminals of primary afferent neuron fibers
A delta: fast conducting
C: slow conducting
descending pain pathway exerts inhibitory effect on pain transmission through _____
substantia gelatinosa
the pain-inhibitory neuron is indirectly activated by _____
opioids (exogenous or endogenous)
which inhibit an inhibitory GABAergic interneuron results in enhanced inhibition of nociceptive processing
what is the mechanism of the opioid receptor transducer
agonist binds
conformational changes in GPCR
inhibits adenylyl cyclase
stimulates K+ current
inhibits voltage gated Ca2+ channels
decreased release of neurotransmitters
describe the relationship between pain & endogenous/exogenous opioids
pain is modulated by endogenous opioid peptides
exogenous opioids are effective analgesics
many drugs of abuse act on endogenous opioid system
definition of opioids
molecules that interact with opioid receptors; compounds with morphine-like activity
diff opioid compounds?
opioid receptor agonists, antagonists, modulators
what are phenanthrene derivatives
morphine (10% in opium)
codeine (0.5% in opium)
thebaine (0.2% in opium, nonanalgesic)
what are the natural opium, semisynthetic, and synthetic opioids?
natural opium alkaloids: morphine, codeine
semisynthetic: heroin (diacetylmorphine), pholcodine
synthetic: pethidine (meperidine), fentanyl, sufentanil, alfentanil , remifentanil
opioid classes and their receptor type
endorphins: mu
enkephalins: delta
dynorphins: kappa
mu, delta, and kappa receptors are all ____
members of the G-protein coupled family of receptors
both ___ and ___ ligands bind to mu, delta, and kappa receptors
endogenous & exogenous
major opioid receptors are coupled to G proteins which causes what effects
affects ion channel gating
modulates intracellular Ca2+ disposition
alters protein phosphorylation
what are the two well-established direct G protein-coupled actions on neurons
closure of voltage-gated Ca2+ channels
opening of K+ channels
morphine’s prescription forms
and which form is the least potent
injectable, oral solution/tablets/capsules, suppositories
less potent orally due to extensive first-pass metabolism: 20-40% bioavailability
pharmacokinetic pearls of morphine
distribution is wide, concentration in liver spleen kidney is greater than plasma
morphine freely crosses placenta
30% is plasma protein bound
toxic/lethal doses of morphine
acute morphine poisoning: >50 mg morphine
lethal dose: 250 mg (causing coma, shallow breathing, BP drop, pinpoint pupil, death due to resp failure)
how to treat morphine overdose
positive pressure respiration, IV fluids, gastric lavage w/ potassium permanganate
NALOXONE
fentanyl key characteristics
potent, synthetic (80-100x more potent than morphine)
few CV effects, little propensity to release histamine
enters brain rapidly due to high lipid solubility so quick effect but short duration
methadone key characteristics
synthetic delta opioid agonist
less abuse potential
use as substitute therapy for opioid dependence
naloxone key characteristics
mu, kappa, and delta ANTAGONIST
antagonizes all morphine actions
can reverse opioid overdose; can give a 2nd dose if it doesn’t work; takes like 2-5 minutes to work
stays in the system for one hour so somebody could go back into overdose when it wears off (shorter half life than heroin)
do not use any type of depressant following the overdose event
3 key drugs for medication assisted treatment (MAT) for opioid addiction
methadone
buprenorphine
naltrexone
between methadone, buprenorphine, naltrexone: agonists or antagonists??
methadone: full agonist (fully replaces opioid effect)
buprenorphine: partial agonist (partially replaces opioid effect)
naltrexone: antagonist (blocks opioid effect)
tolerance & dependence with opioids
-with frequently repeated doses: gradual loss in effectiveness and a larger dose must be administered
-maintenance of normal sensitivity of receptors requires reactivation by endocytosis & recycling
-morphine fails to induce endocytosis of the opioid receptor tolerance & dependence
-in contrast methadone does induce receptor endocytosis
what is the message sequence
Tyr-Gly-Gly-Phe
what is a structure activity relationship
the relationship between chemical structure and pharmacologic activity for a series of compounds
structure activity relationships of the 4,5beta epoxymorphinan chemical class
Asp147: conserved amino acid residue in opioid family
ionic interaction with protonated piperidine nitrogen
most important interaction
then OH increases activity (oxycodone, naloxone)
methylation reduces activity (codeine)
_______ controls functional activity
piperidine nitrogen substitution
if it is CH3 it is an agonist (Morphine)
etc etc etc
what is the role of the opioid message region
confers recognition at opioid receptors
similar to common message sequence for endogenous opioids: Tyr-Gly-Gly-Phe
polar vs nonpolar interactions
polar: phenolic OH, piperidine nitrogen
nonpolar: cyclopropyl
significance of the cyclopropyl group
occupies a hydrophobic pocket that is responsible for its antagonist activity: true for buprenorphine, naloxone. the other opioid agonists don’t contain the cyclopropyl group and can’t occupy the pocket
fentanyl metabolism
Fentanyl is converted to norfentanyl via CYP3A4 N-dealkylation (phase 1 reaction, first pass metabolism)
meaning of norfentanyl
has no significant biological activity at mu opioid receptor
note the prefix nor means loss of a functional group
codeine metabolism
via phase I to norcodeine (inactive), normorphine (less active than morphine), morphine (active)
phase II by methylation, N-acetylation, conjugation
metabolism of methadone
Methadone: reduction to methadol (active). CYP dealkylation to normethadol (active). CYP dealkylation to dinormethadol (active).
Methadone: CYP dealkylation to normethadone (active). CYP dealkylation to dinormethadone (active). reduction to dinormethadol (active).
I think maybe the point is that either way it ends up as dinormethadol? Idk i didn’t understand the guy
