Opiods 2

Question 0

Explain the first pass metabolism of opiods

Answer 0

 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)

Question 1

What is the pattern of use for opioids

Answer 1

 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

Question 2

What are he positive tests related to poppy seeds

Answer 2

 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

Question 3

List the 4 distinct endogenous opioid like substances

Answer 3

 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

Question 4

Explain mu, kappa and delta receptors – probably exist as dimers between same and different opioid receptor

Answer 4

• 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

Question 5

What are the generals of opioid receptors

Answer 5

 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

Question 6

Explain how opioids decease GABA

Answer 6

 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

Question 7

Explain opioids and dopamine release

Answer 7

 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

Question 8

Explain the symptoms of opioid tolerance

Answer 8

 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

Question 9

Explain the mechanism of opioid tolerance

Answer 9

 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

Question 10

What are the major damages with opioid

Answer 10

 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

Question 11

Explain overdose with opioids

Answer 11

 the opioid overdose “triad” consists of  coma
 depressed respira&on
 pinpoint pupils
 death from respiratory depression

Question 12

Why does overdose occur with opioids

Answer 12

 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

Question 13

What are the percentages in studies of overdose deaths

Answer 13

 in one study of overdose deaths
 85% had a depressant
 45% had benzodiazepines
 36% had alcohol

Question 14

What are some overdose treatments

Answer 14

 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

Question 15

Explain opioid antagonists

Answer 15

 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

Question 16

Explain withdrawal with opioids

Answer 16

 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

Question 17

What is methadone

Answer 17

 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

Question 18

What is buprenorphine

Answer 18

 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

Question 19

Explain tolerance with opioids

Answer 19

 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

Question 20

What is clonodine

Answer 20

 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

Question 21

What is iboganine

Answer 21

 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

Question 22

What are the effects if ibogonine

Answer 22

 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)

Question 23

Explain opioid antagonize therapies

Answer 23

 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

Question 24

What is ultra rapid detoxification

Answer 24

 pa&ent is premedicated with clonidine
 pa&ent is anesthe&zed or heavily sedated usually with
propofol
 exposed to high repe&&ve doses of nalmefene, naloxone or naltrexone for 24 - 48 hours
 physiological withdrawal happens without having to experience it because of seda&on
 pa&ent is kept on opioid antagonists
 claims of less relapse over 12 months with this technique
 but - risk of pulmonary and or renal failure, cardiovascular problems, death
 medical community feels that there are too many risks, high cost ($15,000)