Opiods 2 Flashcards
Explain the first pass metabolism of opiods
most opioids undergo extensive first-pass metabolism
many different enzymes and pathways involved depending on the opioid
some produce metabolites that are identical to pharmaceutical opioids as well as other active metabolites
example - taking prescription oxycodone - one metabolite is oxymorphone which by itself is a powerful semisynthetic opioid
others produce no ac&ve metabolites (fentanyl, methadone)
What is the pattern of use for opioids
many users are chippers - occasional use - proves people do not become instantly addicted
also have “needle freaks” who associate IV injec&on with the drug and start to enjoy the act of injection almost more than the drug itself
true addicts use minimum once daily, can be 20 or more &mes a day
can be expensive - up to $600/day or more
What are he positive tests related to poppy seeds
can you test posi&ve for opioids if you eat poppy seeds (e.g. on a bagel or muffin)?
yes - the seeds may have opioids that may be detected (morphine and codeine)
one bagel 250 ng/ml of opiates in urine - several tests use a 300 ng/ml threshold
tes&ng facili&es have increased the threshold that determines a posi&ve test to 2000 ng/ml
but some studies have shown that even these new standards will result in posi&ve tests
List the 4 distinct endogenous opioid like substances
enkephalins (delta), endorphins (mu), endomorphins (mu) and dynorphins (kappa)
each family is derived from different precursor proteins
all contain a tyrosine at their N-terminus
parts of morphine mimic the tyrosine - an amine group
separated from a phenol ring by two carbons
may func&on as neurotransmitters, neurohormones or neuromodulators
involved in pain, placebo responses, acute stress responses, social attachment
Explain mu, kappa and delta receptors – probably exist as dimers between same and different opioid receptor
- mu, kappa and delta receptors – probably exist as dimers between same and different opioid receptor
mu - euphoria, respiratory depression, analgesia, dependence – rela&vely large, open binding pocket may allow for rapid exchange of ligands
delta - some analgesic effects
kappa - dysphoria (make you fell bad), some analgesic effects
What are the generals of opioid receptors
when ac&vated, all inhibit adenylate cyclase - reduce cAMP levels
presynap&cally - inhibit neurotransmi:er release by inhibi&ng Ca2+ influx via inhibi&on of the opening of mostly N-type voltage gated calcium channels
postsynap&cally - hyperpolarize the membrane by enhancing K+ flow outwards by s&mula&ng the opening of specific potassium channels
opioids tend to decrease neuronal excitability at the cellular level
they increase dopamine release in the nucleus accumbens by inhibi&ng inhibi&on
Explain how opioids decease GABA
in absence of opioids, GABA is released from one presynap&c terminal
it binds to a GABA-A receptor on a different presynap&c terminal
this has an inhibitory effect on neurotransmi:er (dopamine) release
when opioids are present they bind to presynap&c receptors
this has an inhibitory effect on GABA release
therefore, there is no inhibitory pressure on dopamine release
net result is that more dopamine is released
more ac&va&on of postsynap&c dopamine receptors
Explain opioids and dopamine release
surprisingly small changes in dopamine levels in the nucleus accumbens in animals
human scanning studies in addicts failed to detect any changes in dopamine levels
morphine produces about the same change in dopamine levels as nico&ne
heroin users have claimed that qui[ng cigare:es was as difficult or even more so
is dopamine the most important part of opioid addic&on?
Nuts paper proposes that dopamine is only important for the craving of opioids, not the euphoria/reward
Explain the symptoms of opioid tolerance
develops to analgesia, vomi&ng, euphoria and respiratory depression
constipation and pupil constriction affected very li:le
addicts can take 50 times the normal analgesic dose of
morphine with li:le respiratory depression
this can lead to problems if they stop using for a period of &me, lose tolerance, and then resume with same dose
Explain the mechanism of opioid tolerance
some mu receptor internaliza&on acutely
loss of effect of ac&vated receptor on cAMP levels -
ac&vated receptor no longer inhibit adenylate cyclase
long term receptor downregula&on, but not always shown to coincide with tolerance
up-regula&on of other neurotransmi:er receptors
effects on neurogenesis and neuronal structure
What are the major damages with opioid
many studies have found no major damage to any organs in chronic heroin addicts
most damage due to poor nutri&on, adulterated drugs, infec&on from needles (hepa&&s, HIV etc), concomitant drug use, general lifestyle of users
analgesic effects mask pain of infec&ons, abscesses
Explain overdose with opioids
the opioid overdose “triad” consists of coma
depressed respira&on
pinpoint pupils
death from respiratory depression
Why does overdose occur with opioids
overdoses can happen when a new supplier is used
heroin is more pure
adulterated with fentanyl or other substances
also environment might play a role
or have undergone treatment, lost their tolerance and
use same dose
What are the percentages in studies of overdose deaths
in one study of overdose deaths
85% had a depressant
45% had benzodiazepines
36% had alcohol
What are some overdose treatments
naloxone is a fast-ac&ng opioid antagonist but only lasts 20 - 40 minutes
can reverse opioid-induced respiratory depression, coma and miosis and prevent death if given within minutes of the overdose
nalmefene is newer and longer las&ng (4 - 8 hours)
they precipitate withdrawal symptoms
no significant effects on undrugged subjects
Explain opioid antagonists
subs&tu&on of nitrogen with bulky groups tends to produce opioids with antagonist proper&es
naloxone is a “pure” antagonist
naltrexone is a longer-las&ng version, better oral absorp&on than naloxone
nalmefene is rela&vely new but more potent than naloxone and naltrexone, lasts longer, be:er oral absorp&on than naloxone and naltrexone
Explain withdrawal with opioids
can start to get symptoms four hours or less aer previous use
start to feel quite ill six to eight hours aer a dose
therefore need at least three to four injec&ons per day to
stop feeling ill
intensity and dura&on of symptoms are correlated with the
intensity and dura&on of the drug’s effects
eg heroin withdrawal is intense but short
methadone withdrawal is mild but prolonged
$30 to $100 a day minimum
What is methadone
methadone is a synthe&c opioid meant to subs&tute for the opioid that was being used
rela&vely long half-life compared to heroin
it is clean, pure, and o`en free to the addict
has some mood-eleva&ng effects but euphoric effects are minimal compared to heroin, s&ll causes cons&pa&on
taken orally to prevents needle-related health issues
also an NMDA glutamate antagonist - possible role in trea&ng
addic&on?
only treatment shown to prevent mortality, HIV risk, crime
What is buprenorphine
a semi-synthe&c par&al agonist with high affinity at mu receptors so blocks effects of heroin, but only mild effects itself
taken orally - 37 hour half-life requires only 1- 3 doses per week
does not cause respiratory depression
causes cons&pa&on in some people
reported to be easier to withdraw from than methadone
Explain tolerance with opioids
chronic opioid use suppresses firing rate of adrenergic neurons in locus ceruleus (LC) - less noradrenaline release
LC projects extensively to limbic system and autonomic centres
tolerance develops in the presence of chronic opiate exposure, firing rate and noradrenaline release normalize
when opiates are removed, LC becomes hyperac&ve, get massive noradrenaline release and withdrawal symptoms
What is clonodine
a non-opioid alpha-2-adrenoreceptor agonist
binds to presynap&c alpha-2 adrenergic autoreceptors to prevent noradrenaline release in and from locus coeruleus (LC)
does not address psychological issues or reduce craving, can lead to low blood pressure
but does address many of the physical symptoms of withdrawal
What is iboganine
a non-opioid hallucinogenic alkaloid from a rain forest shrub na&ve to West Africa
there is a large and growing ibogaine treatment subculture for treatment of every kind of addic&on
the drug provides “introspec&on”
apparently reduces severity of withdrawal and prevents craving in humans
What are the effects if ibogonine
affects glutamate, serotonin, dopamine, opioids, calcium channels
antagonist at nico&nic receptors
s&mulates release of a glial-derived neurotrophic factor in
the ventral tegmental area
mild hallucina&ons may be part of the process (5HT(serotonin) 2A agonist)
Explain opioid antagonize therapies
one way to treat is to administer antagonists that will block all of the euphoric effects of abused opioids
some programs allow pa&ent to keep using and engaging heroin use
eventually the behaviour is ex&nguished because it no longer results in a high due to antagonist also being present
designed to reduce craving - mixed results
