Opioids Flashcards
what is an opiate?
natural alkaloid derived from the papaver samniferum plant
examples of opiates
morphine
codeine
papaverine
thebaine
what are opioids?
these are synthetic molecules that mimic natural opiate activity
what is the function of the tertiary nitrogen of morphine? what is the effect of a quaternary nitrogen?
important for the analgesic effect
helps anchor morphine to opioid receptor
a quaternary nitrogen decreases the analgesic effect greatly
how can morphine become an antagonist?
extension of the side chain to 3+ carbons
changing side chains to methyl groups (this also decreases the analgesic effect)
how does the structure of morphine compare to codeine and heroin?
- The hydroxyl group at position 3 (required for binding) Codeine undergoes metabolism to become activated and reveal its hydroxyl
- The hydroxyl group at position 6 – when in oxidised form, the lipophilicity of the drug increases 10-fold
heroin is a diacetyl morphine
codeine is a methyl codeine
how does the lipid solubility of heroin compare to morphine?
much higher
what type of drug is codeine?
a prodrug
how do the structures of methadone and fentanyl compare to morphine?
o Methadone – tertiary nitrogen.
o Fentanyl – 2x tertiary nitrogen’s
therefore great analgesic effects
what are the important structures required for opiate activity?
aromatic ring base
tertiary nitrogen
spacer
quaternary carbon centre
how are opioids generally administered?
oral
IV
how well are opioids absorbed in the stomach?
not well due to pKa> pH so predominantly in ionised state
absorption is better further down the GIT
what is the pKa of opioids?
weak bases pKa>8
what is the order in potency of the opioids from least potent to most potent?
codeine< morphine< heroine< methadone< fentanyl
what is the order of lipid solubility of the opioids from least soluble to most soluble?
morphine< codeine< heroine< methadone< fentanyl
not the same as for potency
what is the relationship between lipid solubility and potency?
the more lipid soluble, the greater the potency
what are is an example of an active metabolite created from morphine? what effects does it have and what effect does it fortunately not have?
Morphine-6-glucuronide (M6G)
creates euphoria
does not lead to cardio-respiratory failure
what receptor does morphine have an affinity to?
Mu
what are the active metabolites of fentanyl and methadone?
sike!
they don’t have active metabolites
which drugs produce morphine as an active metabolite?
heroin and codeine
what mediates metabolism of fentanyl and at what rate?
fast metabolism by CYP3A4
what mediates methadone metabolism and at what rate?
slow metabolism by six CYP enzymes
why does codeine have a low potency?
only 5-10% of codeine is metabolised to produce morphine
there is the involvement of slow (activating) and fast (inactivating) acting enzymes
what are the enzymes involved in codeine metabolism and what are their products? what is the rate of each enzyme?
CYP2D6- slow therefore activating- produces the low proportion of morphine
CYP3A4- fast therefore inactivating- produces the inactive normorphine metabolite.
ie. slow metabolism of codeine produced the active metabolite morphine
i. e. fast metabolism of codeine produced the inactive metabolite normorphine