synthetic opioid Flashcards
Opioid receptors subtypes and their location
Mu - in periphery, spine and brain
delta - mainly peripheral
kappa - mainly spinal
Molecular signalling of opioid receptors
Gai-coupled
activation of the receptors by an agonist leads to dissociation of Gai-GTP to inhibit adenylyl cylcase- reducing [cAMP].
Also increases K+ channel activation and decreases influx of calcium through Ca2+ channels. both lead to reduced excitability of the cell
Often act as heteroreceptor feedback inhibition - e.g., opioid receptors present on cholinergic neurones - lead to decreased neurone excitability and thus reduced ACh release. seen in GIT, where decreases ACh-mediated smooth muscle contraction (parasympathetic).
Endogenously, acts as a feedback loop, where it is released following high-frequency stimulation of ileal smooth muscle
B-arrestin recruitment mediates tolerance.
Examples of semi-synthetic and synthetic opioids
semi-synthetic: hydrocodone, hydromorphone, and oxycodone. these are formed from morphine, codeine or thebaine.
synthetic: fentanyl, pethidine, methadone, pentazocine, carfentanil (used in moscow theatre hostage crisis), etonitazene (been found in adulterated heroin samples)
Heroin is sometimes considered semi-synthetic, but also as a morphine analogue
Opioids subjective effects, tolerance and withdrawal
Causes analgesia, euphoria (mu-mediated), pupillary constriction, cough suppression, nausea, and respiratory depression (due to decreased sensitivity of respiratory centre - medulla- to pCO2 levels).
Tolerance occurs rapidly, with certain effects being more effected by tolerance then others, e.g., constipation does not see tolerance but nausea, sedation, and analgesia do.
Withdrawal sees sweating, aches, weakness, diarrhoea, spasms, shaking, chills, depression, and strong cravings.
What is the opioid crisis
a massive increase in the use of opioids in the USA. several-fold higher use for almost all age groups.
from over-prescription of opioids to the 20-30% of americans that suffer from chronic pain.
259m opioid prescriptions given out in 2012, with 2.1m americans suffering from opioid abuse disorder. consequently 44 deaths a day are attributed to opioid use.
Particularly prevalent in white populations. highest use is in working class white individuals, particularly rural.
Causes of opioid crisis
4/5 heroin users reported that their opioid use started with prescription pain killers. they transitioned to heroin for costs and due to no longer having access to prescription pills
Initiated by the aggressive promotion, prescribing and under regulation of pharmaceutical opioids from the 1990s-2011. consequent increases in street opioid uses occurred, with fentanyl flooding the streets by 2013.
Purdue pharma produced oxycontin and described it as non-addicted. they targeted prescribers that were known to prescribe opioids more, and had larger numbers of chronic pain patients. they also targeted primary care physicians (almost 50% of those prescribing opioids) who were not trained to deal with chronic pain management or addiction
Example of biased opioid agonist
oliceridine which has been seen in vitro to bias G-protein signalling instead of B-arrestin. Likely just a partial agonist however.
in theory would see reduced tolerance which is mediated by B-arrestin recruitment
