SM_236a, 240a: Pharmacology, Opioids, and Pain Concepts I and II

Question 1

Describe the opioid receptors

Answer 1

Opioid receptors

• Mu, kappa, delta
• One gene codes for each
• Subtypes come from splice variants
• All involved in brain, spinal, GI sites

Question 2

The opioid receptors are _____, _____, and _____

Answer 2

The opioid receptors are mu, happa, and delta

Question 3

Mu opioid receptor is responsible for ____, ____, ____, ____, ____, ____, and ____

Answer 3

Mu opioid receptor is responsible for analgesia, euphoria, dependence, respiratory depression, miosis, GI effects, and pruritis

(named after morphine)

Question 4

Kappa opioid receptor is responsible for ____, ____, and ____

Answer 4

Kappa opioid receptor is responsible for mild analgesia, less respiratory depression, and pyschomimetic effects (unlike euphoria)

Question 5

Delta opioid receptor function is ____

Answer 5

Delta opioid receptor function is unknown

Question 6

Opioid receptors are found in the ____, ____, and ____

Answer 6

Opioid receptors are found in the brain, spinal cord, and gut

Question 7

Describe the location of opioid receptors in the brain

Answer 7

• Amygdala - emotion
• Brainstem - ventilation
• Area postrema - vomiting
• Periaqueductal gray - inhibitory pathway

(gate control theory, periaqueductal gray inhibits pain transmission in dorsal horn via a relay in the rostral ventral medulla)

Question 8

Opioid receptors work via ____, which ____, ____, ____, and ____

Answer 8

Opioid receptors work via G receptor proteins, which inhibit cellular adenylyl cyclase, increase K⁺ currents and decrease Ca²⁺ currents, cause hyperpolarization, and decrease nociceptive transmission

Question 9

Opioids work on ____ and ____ receptors

Answer 9

Opioids work on presynaptic and postsynaptic receptors

Question 10

Opioids activate the ____, triggering ____ and releasing ____

Answer 10

Opioids activate the periaqueductal gray, triggering the descending inhibitory pathways and releasing endorphins

(descending pathway modulates pain in transmission in the ascending pathway)

Question 11

Opioids ____ the GABA neuron, which allows for ____ of the pain inhibitory neuron

Answer 11

Opioids inhibit the GABA neuron, which allows for activation of the pain inhibitory neuron

Question 12

Opiate is a _____

Answer 12

Opiate is a drug derived from opium

Question 13

Opioid is ____

Answer 13

Opioid is all drugs, both natural and synthetic, that bind to opioid receptor

Question 14

Narcotic is ____, ____, and ____

Answer 14

Narcotic is any substance that induces sleep, acts on opioid receptors, and any illicit substance

Question 15

Opioids that are agonists are _____ and include _____, _____, and _____

Answer 15

Opioids that are agonists are mu receptor agonists and include morphine, merepiridine, and hydromorphone

Question 16

Opioids that are antagonists are _____ and include _____ and _____

Answer 16

Opioids that are antagonists are mu receptor antagonists and include naloxone and naltrexone

Question 17

Opioids that are agonist/antagonists are _____ and include _____ and _____

Answer 17

Opioids that are agonist/antagonists are kappa agonists / mu antagonists and include butorphanol and nalbuphine

Question 18

Opioids that are partial agonists are _____ and _____ and include _____

Answer 18

Opioids that are partial agonists are partial mu agonists with high affinity and meaningless kappa antagonists and include buprenoprhine

Question 19

Describe opioids that are agonist/antagonists

Answer 19

Agonist/antagonist opioids

• Analgesia is kappa mediated
• Weak mu receptor antagonist
• Ceiling effect
• Less GI side effects
• Kappa: less respiratory depression / sedation / euphoria but makes person nuts
• Can trigger withdrawal so do not use in opioid tolerant patient
• Can reverse opioid side effects at low dose

Question 20

Describe opioids that are partial agonists

Answer 20

Partial agonist opioids

• Only partial mu agonist
• Ceiling effect for agonism
• Binds mu with high affinity: higher than most opioids, prevents other opioids from binding, makes naloxone reversal difficult in overdose
• Current use: opioid maintenance, not so much for chronic pain

Question 21

Partial agonist opioids are used for ____

Answer 21

Partial agonist opioids are used for opioid maintenance

Question 22

Describe neurologic effects of opioids

Answer 22

Neurologic effects of opioids

• Analgesia: supraspinal and spinal cord level, not reliably associated with loss of consciousness, better for nociceptive pain (pain caused by stimulation of nociceptive receptors) than neuropathic pain (pain caused by damaged neural structures)
• Miosis (pinpoint pupil): seen with all opioid agonists
• No tolerance to this: useful in overdose diagnosis, even in tolerant addicts

Question 23

____ is the major way that opioids kill

Answer 23

Respiratory depression is the major way that opioids kill

(hold if sedated)

Question 24

Describe respiratory effects of opioids

Answer 24

Respiratory effects of opioids

• Therapeutic effects: prevent hyperventilation from pain and anxiety, opioids can be used for their antitussive actions, can help avoid increases in bronchomotor tone in asthma
• Adverse effect: respiratory depression is most serious, activation of mu opioid receptor in caidal medullary raphe region inhibits the ventilatory response to hypercapnia

Question 25

Direct cardiac actions are _____ than for other inhalational or IV anesthetics

Answer 25

Direct cardiac actions are lower than for other inhalational or IV anesthetics

Question 26

GI effects of opioids include ____ and \_\_\_\_

Answer 26

GI effects of opioids are slowed peristalsis and nausea/vomiting * Slowed peristalsis: via enteric NS opioid receptors * Nausea/vomiting: via chemoreceptor trigger zone

Question 27

Tolerance to opioids does NOT include ____ and \_\_\_\_

Answer 27

Tolerance to opioids does NOT include miosis and constipation (tolerant to euphoria, sedation, analgesia, N/V, respiratory depression)

Question 28

Opioid withdrawal contains symptoms of \_\_\_\_

Answer 28

Opioid withdrawal contains symptoms of sympathetic overdrive * Anxiety, insomnia, diaphoresis, yawning, rhinorrhea, lacrimation * HTN, tachycardia * Hyperventilation * Mydriasis * Also diarrhea and abdominal cramps

Question 29

Opioid overdose symptoms include \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 29

Opioid overdose symptoms include respiratory depression / arrest, sedation or unresponsiveness, and miosis (ABCs - support ventilation, use naloxone as the antagonist)

Question 30

List the agonist, antagonist, agonist/antagonist, and partial agonist opioids

Answer 30

Opioids * Agonists: morphine, codeine, hydrocodone, oxycodone, merperidine, fentanyl, hydromorphone, methadone, tramadol * Antagonists: naloxone, naltrexone * Agonist/antagonist: nalbuphine * Partial agonist: buprenorphine

Question 31

Describe morphine

Answer 31

Morphine * Hydrophilic: delayed transport across BBB so delayed onset of action * Broken down into M3G and M6G - only M6G is active * Duration of action is 4-5 hours (t_1/2 = 2-3 hours) * Causes histamine release: rash, hypotension

Question 32

Describe oxycodone

Answer 32

Oxycodone * Semisynthetic opioid closely related to morphine * High bioavailability (60%) compared to morphine (33%) * Analgesia is via parent compound but does metabolize into oxymorphone (often undetectable but 14x more potent) * Immediate release and extended release formulation

Question 33

Describe codeine

Answer 33

Codeine * Prodrug (very low mu affinity) * 10% metabolized to morpine - 7-10% of white population cannot * Considered a weak opioid but can get nausea and constipation from parent drug at high doses

Question 34

Describe hydrocodone

Answer 34

Hydrocodone * Only sold as combo drug in US: Norco or vicodin (combined with acetaminophen) * Breakdown into hydromorphone * Unknown if analgesia is via parent drug or metabolite

Question 35

Describe hydromorphone

Answer 35

Hydromorphone * Analogue of morphine and similar in action (hydrophilic, duration of analgesia) * Better side effect profile than morphine: pruritis, sedation, nausea, vomiting * 5x more potent orally and 7x more potent parenterally * Metabolized in liver to H3G: lacks analgesia, could potentiate side effects

Question 36

Describe fentanyl

Answer 36

Fentanyl * Highly lipophilic with high affinity for the mu receptor: fast onset IV, crosses skin and buccal tissue * 75-125x more potent than morphine * IV for OR anesthesia and ICU analgesia: fast onset, easy to titrate, short duration so good for outpatient surgeries * Transdermal: slow onset because builds up subcutaneously, sustained release for chronic pain, more difficult to abuse, good for patients with GI issues, variable time achieving therapeutic levels with skin differences

Question 37

Describe merperidine

Answer 37

Merperidine * Lipophilic with rapid onset * Weaker mu agonist as compared to morphine * Potent inhibitor of serotonin reuptake * Metabolite is normeperidine: long half life, CNS hyperactivity and seizures, cleared by kidneys, do NOT use in renal failure patients

Question 38

Describe tramadol

Answer 38

Tramadol * Oral analgesic * Technically a prodrug: M1 metabolite is a mu agonist * Works by two mechanisms: mu receptor agonist, blocks reuptake of 5-HT and NE * Used for mild to moderate pain

Question 39

Describe naloxone

Answer 39

Naloxone * Opioid antagonist: IV only * Short half life of 1 hour * Duration of 15 min - 4 hours * Reversal is short-lived * Very poor bioavailability so combined in opioid pills to prevent IV abuse * Competitive antagonist

Question 40

Interpatient opioid receptor variability occurs with respect to \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 40

Interpatient opioid receptor variability occurs with respect to receptor type, density, and location

Question 41

Different opioids have ____ receptor affinities due to \_\_\_\_

Answer 41

Different opioids have different receptor affinities due to splice variants (subtle differences between splice variant affinities)

Question 42

Describe opioid receptor relevance

Answer 42

Opioid receptor relevance * Interpersonal receptor density varaibility * Different opioids have different receptor affinities * Different opioids have different effects in different patients * Titrate opioid to analgesic effect * Change the opioid if side effects and not much analgesia

Question 43

\_\_\_\_ and ____ are problematic in patients with renal failure

Answer 43

Morphine and merperidine are problematic in patients with renal failure * Morphine metabolites M3G and M6G cleared by kidney -\> if not cleared can cause massive side effects * Merperidine metabolite normoperidine is cleared by kidneys -\> if not cleared can cause CNS hyperactivity and seizures