Opioids Flashcards
Opioids
opium: rare, untransformed material from poppies
opiates: any drug derived from opium
opioids: drugs that bind to opioid receptors
Morphine
opiate and opioid
full agonist at Mu receptor
Heroin
semi-synthetic opiate and opioid
full agonist at Mu receptor
Fentanyl
opioid
full agonist at Mu receptor
Pharmacodynamics
opioid receptors = Gi GPCRs
neuronal inactivation
receptors
structurally similar but different effects
receptor distribution (different neurons)
ligand specificity (drugs are selective for different receptors)
brain, brainstem, spinal cord, peripheral neurons, intestine
Mu
densely expressed in subcortical regions - emotion and behaviour
agonist: analgesia, reward, antitussive, respiratory depression, constipation
antagonist: aversive, prevent reward, block overdose
Delta
densely expressed in cortex - decisions, processing information, executive function
agonist: not rewarding, analgesia only in chronic pain + migraine, seizure inducing (large distribution of receptors)
antagonist: no obvious effects
Kappa
densely expressed in cortex - decisions, processing information, executive function
agonist: aversive, hallucinogenic, anxiogenic
antagonist: possible antidepressant
ORL-1 (orphanin receptor ligand/nociceptin opioid peptide)
widely expressed in CNS
possibly fear processing
Buprenorphine
partial mu agonist
mixed agonist-antagonist: partial mu agonist + kappa+delta antagonist
treatment for pain and opioid addiction
beta-arrestins
intracellular proteins that regulate signal transfuction at GPCRs
receptor activation → phosphorylation of GPCR → signals beta-arrestin to bind
= blocks further G-protein signalling
biased agonism
beta-arrestin activates own intracellular signalling that leads to side effects
ligand activates G-protein pathway instead of beta-arrestin
tolerance
decreased response to drug effects = need higher dose for same effect
recruitment of beta-arresting to shut off signalling (desensitization) → receptor and agonist are pulled off the membrane
chronic use = less receptors on membrane for ligand to bind to
pharmacokinetics
absorption
well absorbed
distribution
well distributed
greatest concentration in highly perfused tissues
crosses BBB and placental barrier
metabolism
morphine → first pass metabolism (glucuronidation to M3G and M6G - phase II)
codeine: prodrug → morphine (CYP 2D6) = less first pass effect but more susceptible to pharmacogenomic diversity
excretion
polar metabolites are excreted in urine
renal impairment - risk of sedation and respiratory depression
Endogenous Opioid Peptides
widely distributed neurotransmitters
pain, reward, learning, memory, cognition
generated from protein precursor - modified at site they are used, cleaved into active form
common amino acid sequence: Tyr-Gly-Gly-Phe
Enkephalin
pro-enkephalin
highest affinity at delta, high at mu, low at kappa
Beta endorphin
pro-opioimelanocortin
highest at mu and delta, low at kappa
Dynorphin
pro-dynorphin
high at kappa, low at mu and delta
selectivity, not specificity
opioid peptides have different affinities for the three opioid receptor
opioid effect on pain
opioids inhibit transmission from periphery to spinal cord
mu and kappa receptors on primary and secondary afferents in skin and spinal cord
pain experience
receptors in brainstem (rostroventral medulla) increase diffuse noxious inhibitory control
circuit of descending excitatory and inhibitory neurons in medulla inhibit or activate pain synapses in spinal cord
= gate amount of nociceptive information that reaches brain
pain inhibition
activation of mu and delta receptors (Gi) on the ON cells in brainstem = inhibition of cells
block descending amplification from rostroventral medulla = net reduction in nociceptive signals
analgesia
reward
Mu receptors in ventrotegmental area are located on GABAergic interneurons that synapse onto dopamine neurons (project to striatum)
opioids inhibit inhibition = disinhibition = dopamine release
nociception
relay of pain signal from periphery to brain
pain
interpretation of pain signal with context (subjective)
opioids inhibit pain
- decreasing nociception
- decreasing emotional and cognitive aspects of pain
analgesics
most = mu agonists
delta agonists: development for chronic migraines but beta-arrestin pathway causes seizures - TRV250 = biased agonism
kappa agonists: target brain = dysphoria and hallucinations but target periphery = inhibit pain transmission in skin receptors (CR845)
Chronic Use
tolerance
dependence - withdrawal symptoms
Opioid Use Disorder
addiction
treatments
preventative - physical + chemical barriers, agonist/antagonist combination (buprenorphine + naloxone)
agonist replacement therapy - use + therapy
harm reduction - supervised consumption sites + injectable opioid therapy
acute intoxication treatment - Narcan: Naloxone is a non-selective competitive opioid receptor antagonist
