Opioids (Midterm II)

Question 1

opium

Answer 1

-dried latex (sap) obtained from the opium poppy; the unrefined plant substance

Question 2

opiate

Answer 2

any drug derived from opium (the sap is purified and the naturally occurring chemicals isolated (morphine, codeine) are opiates)

Question 3

opioid

Answer 3

-any drug that binds to an opioid receptor, including opiates like morphine, but also synthetics like fentanyl and carfentanil, and semisynthetics like morphine and oxycontin

Question 4

narcotic

Answer 4

• from greek narco (to make numb)
• originally referred to any drug with sleep inducing properties, but not usually used by law enforcement in reference to illegal use of opioids for non-medical properties

Question 5

opioid receptors

Answer 5

4 types (mu, delta, kappa, ORL-1 (orphanin receptor ligand) that are all structurally very similar; all 7TM GPCRs coupled to Gi (activation inhibits Ca channels, activates K channels, and inhibits AC, leading to overall neuronal inactivation and reduced NT release)
-all produce different effects due to differential receptor distribution throughout the body and differing ligand specificity (they are least homologous in intra/extracellular termini where ligands would bind)

Question 6

ORL-1

Answer 6

• one of the four opioid receptors
• widely expressed in the CNS
• the last opioid receptor to be identified, and found based on sequence homology as opposed to function (people noticed it looked similar to other opioids, but wasn’t found during init. investigation as it doesn’t seem to be involved in analgesia)
• poorly studied, but doesn’t share functional similarity with other opioid receptors
• may be involved in fear processing, and possibly feeding behaviour as well

Question 7

mu opioid receptor effects

Answer 7

associated with most of the characteristic opioid effects
agonist (morphine, codeine, heroine):
-analgesia
-euphoria/reward (which drive abuse)
antitussive (cough suppression, hence OTC codeine syrups)
-respiratory depression (lots of mu receptors in the brainstem)
-constipation (potent inhibition of GI motility; some opioid agonists are common OTC diarrhea treatments)
antagonist (ex nalaxone):
-aversive
-prevent reward
-block overdose (can reverse the respiratory depression associated with mu agonists)

Question 8

delta opioid receptor effects

Answer 8

agonist:
-not rewarding (no real high or euphoria)
-no real signs of analgesia (although perhaps useful for chronic pain and migraine)
-some under investigation (not commercially available) are seizure inducing, which has really limited their development
antagonist:
-no obvious effects

Question 9

kappa opioid receptor effects

Answer 9

agonist (ex salvia):
-aversive
-hallucinogenic
-anxiogenic
antagonist:
-being explored as a potential antidepressant/anxiolytic

Question 10

full vs partial opioid agonists

Answer 10

full (exert the maximal response of the receptor): morpine, methadone, fentanyl, heroin, hydromorphone
partial: codeine (has mild to moderate analgesic efficacy, but safer TI, as you’ll never reach the maximal effect even at crazy high doses)

Question 11

high vs low potency opioid agonists

Answer 11

• full agonists can still have different potencies (fentanyl > hydromorphone > morphine)
• like efficacy, potency applies to all aspects of the drug (analgesia, euphoria, respiratory depression), and refers to the amount of a drug needed to elicit a given response

Question 12

mixed agonist-antagonists

Answer 12

buprenorphine

-partial agonist at the mu opioid receptor, but an antagonist at the delta and kappa receptors

Question 13

beta-arresting signaling

Answer 13

• when the GPCR is activated and the g-protein cleaved, receptor phosphorylation signals b-arrestin binding, which blocks further g-protein signaling, redirects signaling to alternative pathways and targets receptors for internalization
• the resceptor internalization leads to tolerance following chronic use of some drugs (like opioids, in which barr signaling also contributes to respiratory depression and constipation)

Question 14

opioid absorption

Answer 14

-most mu agonists are well absorbed when taken orally (such as codeine) but morphine undergoes extensive first pass metabolism

Question 15

opioid distribution

Answer 15

• agonists are widely distributed throughout the body tissues, with highest concentrations in highly perfused tissues (brain, lungs, liver, kidney, spleen)
• time to reach peak plasma conc with vary with the route of admin (IV within ~6 min, subQ ~30, and PO (oral) anywhere from 30-60)
• they can also cross the placental barrier and exert effects on fetus, resulting in respiratory depression and physical dependence in neonates

Question 16

morphine metbolism

Answer 16

• metabolized by phase II glucoronidation to morphine-3-glucuronide (90% M3G) and morphine-6-glucuronide (10% M6G)
• the most important of those phase II enzymes is UGT2B7, which is NOT a CYP (but is a liver enzyme)
• M6G is an active metabolite that prolongs morphine effects

Question 17

codeine metabolism

Answer 17

• codeine is actually a prodrug, and is metabolism by CYP2D6 in the liver to morphine
• genetic polymorphism is linked to variation in analgesic and adverse responses among patients, esp for codeine (~6-10% of whites are CYP2D6 deficient, and ~2% of asians)

Question 18

opioid excretion

Answer 18

• by and large, most opioid metabolites are excreted through the urine, especially the polar ones (these include glucoronide conjugates M3G and M6G)
• small amounts of unchanged drug may be found in the urine
• in patients with renal impairment, they may have difficulty excreted polar metabolites, so considerations need to be taken before administering potent opioids (ex the polar and active morphine metabolite, M6G, would be hard to clear and increase the risk of sedation/respiratory depression)

Question 19

endogenous opioid peptides

Answer 19

• three types (beta endorphins, enkephalins, and dynorphins) that act widely throughout the brain o mediate pain, reward, learning, and memory, cognition
• each generated from protein precursors (proenkephalin, proopiomelanocortin and prodynorpin, respectively) that are subject to post-translational mod to generate different subtypes of active peptides
• they all share a common AA sequence of Try-Gly-Gly-Phe to which various extensions are added during post-trans mods

Question 20

enkephalins

Answer 20

precursor: prenkephalin
endogenous peptide: [Met] and [Leu] enkephalins
affinity for opioid receptors: delta&raquo_space;>mu»>kappa

Question 21

endorphins

Answer 21

precursor: pro-opioimelanocortin
endogenous peptide: beta-endorphine
affinity for opioid receptors: mu=delta»>kappa

Question 22

dynorphins

Answer 22

precursor: pro-dynorphin
endogenous peptides: dynorphins A/B, neoendorphin
affinity for opioid receptors: kappa»> mu=delta

Question 23

crash course on sensory neurons

Answer 23

-sensory neurons in the periphery (skin, organs) are primary afferents; those that detect pain are called nociceptors
there are two classes of primaries; A and C fibres
-in the dorsal horn of the spinal cord, primary afferents synapse onto secondary afferents, which carry sensation up the spinal cord to the brain; it’s on these nerves in the skin and spinal cord where mu, delta, and kappa receptors are localized, and agonist binding will inhibit pain transmission from skin to brain
-receptors on the rostroventral medulla (brainstem) increase diffuse noxious inhibitory control

Question 24

A fibres

Answer 24

• myelinated for fast conduction
• end in specialized structures called corpuscles, which are tuned to detect specific, non-painful stimuli (touch, temperature, vibration, proprioception)

Question 25

C fibres

Answer 25

- polymodal nociceptors that respond to an given type of painful stimuli (thermal, mechanical, chemical and electrical) - unmyelinated (slow conducting) - end as free nerve endings in the superficial layers of the skin (the epidermis, non-vascularized dead tissue)

Question 26

diffuse noxious inhibitory control

Answer 26

- circuit comprised of descending excitatory and inhibitory neurons in the medulla that inhibit or activate pain synapses in the spinal cord, allowing the brain to gate the amount of nociceptive info that is passed up - ON cells in the medulla will send signals down the spinal cord that amplify the pain response - activation of mu and delta receptors on these ON cells will inhibit the endogenous amplification pathway, producing a net reduction in nociceptive signals reaching the brain

Question 27

opioids and reward

Answer 27

- DA is involved in reward and motivated behaviour - dopaminergic neurons are primarily located in the VTA - mu opioid receptors in the VTA are located on inhibitory GABAergic interneurons that regulate DA releasing neurons - opioid binding inhibits the GABAergic activity, indirectly stimulating DA release by inhibiting thr braking system (this is called disinhibition)

Question 28

opioid analgesics

Answer 28

- most opioids used for pain are mu agonists (morpine, fentanyl, codeine, oxycodone), whose differences are due to efficacy (full vs partial agonism) and potency - delta agonists such as TRV250 are in development for chronic migraine, as biased agonism toward te g-protein pathway seems to suggest isolatable benefits without certain severe side effects (ex b-arresting related seizure liability encountered wen delta agonists were first being investigated) - while kappa agonists like salvia that penetrate the brain cause dysphoria and hallucination, peripherally restricted kappa agonists that bind to receptors in the skins seem to inhibit pain transmission while avoiding adverse CNS effects (ex CR845, a potent analgesic with anti-inflammatory and anti-itch properties and few CNS side effects currently under development)

Question 29

opioids and gut motility

Answer 29

-activation of mu opioid receptors on motor efferents in the intestine inhibits gut peristalsis and secretion (mu agonists are associated with constipation, delta/kappa aren't all that abundant in the GI and play no role)

Question 30

loperamide

Answer 30

-a mu opioid agonist and common OTC treatment for diarrhea that, like morphine, is distributed widely throughout most bodily tissues, brain included -it's a substrate for permeability-glycoprotein (p-gp) which is located on endothelial cells at the blood brain barrier and actively pumps the drug out of the brain (as opposed to morphine, which is not a P-gp substrate, and is therefore able to elicit euphoria and reward) NOTE: P-gp is inhibited by tricyclic antidepressants such as amitiptyline that will increase brain conc of loperamide if taken simultaneously, which can lead to respiratory depression and abuse

Question 31

opioid tolerance

Answer 31

- tolerance develops only to analgesic, euphoric, sedative and respiratory effects of the drug (ppl rarely adapt to effects like constipation) - a tolerant indv can take enormous doses (2g, when the lethal dose for the drug naive is ~30 mg) - physiologically, after agonist binding and g-protein signaling, b-arr is recruited to shut-off signaling (desensitization); the receptor and agonist are pulled off the membrane and degraded or recycled (as less and less membranes are left on the receptors, the agonist effect is reduced) - upregulation of metabolizing enzymes and opponent process (compensatory changes) can also contribute (and lead to w/drawal symptoms such as hyperalgesia, diarrhea and anxiety when the drug is removed)

Question 32

opioid dependence and withdrawal

Answer 32

- physical dependence develops following chronic use and is revealed as withdrawal when the drug is abruptly discontinued - acute opioid withdrawal includes rhinorrhea (runny nose), lacrimation (tearing eyes), chills, muscle aces, diarrhea, yawning, anxiety - withdrawal is highly aversive and some symptoms can persist for months, which can drive the transition from dependence to addiction

Question 33

addiction

Answer 33

-a brain disease driven by dysfunction in reward, motivation and memory circuitry characterized by: -inability to abstain consistently -impairment of behavioural control (rewiring of PFC) -drug craving -diminished recognition of significant problems with one's behaviours and interpersonal relationships -dysfunctional emotional response

Question 34

preventative treatments for opioid use disorder

Answer 34

-most aim to make snorting or injecting ground oral tablets difficult physical barriers: prevent chewing/crushing or oral tablets for IV/intranasal use (ex the new formulation of oxycontin won't powder) chemical barriers: can be added to resist extraction of the opioid by common solvents like water/alcohol agonist/antagonist combos: the antagonist is only released wen an oral tablet is tampered with (it would be degraded by firs t pass metabolism), and prevents abuse-associated euphoria aversion: addition of substances to produce dysphoria when tampered with extended delivery system: ex. depots injected IM/subQ provide extended drug release over days/weeks and can't be tampered with of diverted to black markets prodrug: won't do anything if injected or snorted bc it's inactive unless taken orally for 1st pass metabolism

Question 35

agonist replacement therapy

Answer 35

- comprehensive treatment approach including CBT alongside maintenance on an opioid agonist, which blunts the symptoms of withdrawal - replacement agonists such as methadone and buprenorphine have longer half-lives too, avoiding the repeated high/crash cycle - they reduce craving, allow for better participation in behavioural therapy since withdrawal symptoms aren't a distraction, improve social functioning and reduce infectious disease/death associated with illicit drug use (esp IV)

Question 36

methadone

Answer 36

- a long acting (t1/2 = 24-42 hrs) full agonist at the mu opioid receptor; the first approved replacement therapy for opioid use disorder - it being a full agonist though, overdose and abuse are still possible

Question 37

buprenorphine

Answer 37

- a partial mu receptor agonist, as well as a kappy/delta antagonist - the partial mu agonist means less likelihood of overdose and therefore a better safety profile - the antagonist activity at kappa may also improve mood - sold as suboxone, which is buprenorpine + naloxone (added to counter the effects of buprenorphine if the indv tries to take it IV)

Question 38

acute opioid intoxication treatment

Answer 38

- naloxone (narcan) is a non-selective competitive opioid receptor antagonist that can be given IM or intranasally within minutes to block respiratory depression from acute overdose - relatively safe for indv who haven't actually consumed opioids (mildly dysphoric perhaps) - only lasts about 30 min, so multiple doses may be necessary