Opioids

Question 1

Ascending pain pathway

Answer 1

starts from terminals of primary afferent neuron fibers
A delta: fast conducting
C: slow conducting

Question 2

descending pain pathway exerts inhibitory effect on pain transmission through _____

Answer 2

substantia gelatinosa

Question 3

the pain-inhibitory neuron is indirectly activated by _____

Answer 3

opioids (exogenous or endogenous)
which inhibit an inhibitory GABAergic interneuron results in enhanced inhibition of nociceptive processing

Question 4

what is the mechanism of the opioid receptor transducer

Answer 4

agonist binds
conformational changes in GPCR
inhibits adenylyl cyclase
stimulates K+ current
inhibits voltage gated Ca2+ channels
decreased release of neurotransmitters

Question 5

describe the relationship between pain & endogenous/exogenous opioids

Answer 5

pain is modulated by endogenous opioid peptides
exogenous opioids are effective analgesics
many drugs of abuse act on endogenous opioid system

Question 6

definition of opioids

Answer 6

molecules that interact with opioid receptors; compounds with morphine-like activity

Question 7

diff opioid compounds?

Answer 7

opioid receptor agonists, antagonists, modulators

Question 8

what are phenanthrene derivatives

Answer 8

morphine (10% in opium)
codeine (0.5% in opium)
thebaine (0.2% in opium, nonanalgesic)

Question 9

what are the natural opium, semisynthetic, and synthetic opioids?

Answer 9

natural opium alkaloids: morphine, codeine
semisynthetic: heroin (diacetylmorphine), pholcodine
synthetic: pethidine (meperidine), fentanyl, sufentanil, alfentanil , remifentanil

Question 10

opioid classes and their receptor type

Answer 10

endorphins: mu
enkephalins: delta
dynorphins: kappa

Question 11

mu, delta, and kappa receptors are all ____

Answer 11

members of the G-protein coupled family of receptors

Question 12

both ___ and ___ ligands bind to mu, delta, and kappa receptors

Answer 12

endogenous & exogenous

Question 13

major opioid receptors are coupled to G proteins which causes what effects

Answer 13

affects ion channel gating
modulates intracellular Ca2+ disposition
alters protein phosphorylation

Question 14

what are the two well-established direct G protein-coupled actions on neurons

Answer 14

closure of voltage-gated Ca2+ channels
opening of K+ channels

Question 15

morphine’s prescription forms

and which form is the least potent

Answer 15

injectable, oral solution/tablets/capsules, suppositories

less potent orally due to extensive first-pass metabolism: 20-40% bioavailability

Question 16

pharmacokinetic pearls of morphine

Answer 16

distribution is wide, concentration in liver spleen kidney is greater than plasma
morphine freely crosses placenta
30% is plasma protein bound

Question 17

toxic/lethal doses of morphine

Answer 17

acute morphine poisoning: >50 mg morphine
lethal dose: 250 mg (causing coma, shallow breathing, BP drop, pinpoint pupil, death due to resp failure)

Question 18

how to treat morphine overdose

Answer 18

positive pressure respiration, IV fluids, gastric lavage w/ potassium permanganate
NALOXONE

Question 19

fentanyl key characteristics

Answer 19

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

Question 20

methadone key characteristics

Answer 20

synthetic delta opioid agonist
less abuse potential
use as substitute therapy for opioid dependence

Question 21

naloxone key characteristics

Answer 21

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

Question 22

3 key drugs for medication assisted treatment (MAT) for opioid addiction

Answer 22

methadone
buprenorphine
naltrexone

Question 23

between methadone, buprenorphine, naltrexone: agonists or antagonists??

Answer 23

methadone: full agonist (fully replaces opioid effect)
buprenorphine: partial agonist (partially replaces opioid effect)
naltrexone: antagonist (blocks opioid effect)

Question 24

tolerance & dependence with opioids

Answer 24

-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

Question 25

what is the message sequence

Answer 25

Tyr-Gly-Gly-Phe

Question 26

what is a structure activity relationship

Answer 26

the relationship between chemical structure and pharmacologic activity for a series of compounds

Question 27

structure activity relationships of the 4,5beta epoxymorphinan chemical class

Answer 27

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)

Question 28

_______ controls functional activity

Answer 28

piperidine nitrogen substitution

if it is CH3 it is an agonist (Morphine)
etc etc etc

Question 29

what is the role of the opioid message region

Answer 29

confers recognition at opioid receptors
similar to common message sequence for endogenous opioids: Tyr-Gly-Gly-Phe

Question 30

polar vs nonpolar interactions

Answer 30

polar: phenolic OH, piperidine nitrogen
nonpolar: cyclopropyl

Question 31

significance of the cyclopropyl group

Answer 31

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

Question 32

fentanyl metabolism

Answer 32

Fentanyl is converted to norfentanyl via CYP3A4 N-dealkylation (phase 1 reaction, first pass metabolism)

Question 33

meaning of norfentanyl

Answer 33

has no significant biological activity at mu opioid receptor

note the prefix nor means loss of a functional group

Question 34

codeine metabolism

Answer 34

via phase I to norcodeine (inactive), normorphine (less active than morphine), morphine (active)

phase II by methylation, N-acetylation, conjugation

Question 35

metabolism of methadone

Answer 35

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