10- Opioids

Question 1

codeine

Answer 1

Opioid agonist (morphine derivative)

• prodrug in which 10% of administered dose converted to morphine via demethylation by CYP2D6 to cause analgesia
• people who are rapid metabolizers via CYP2D6 can have inc. active drug levels (can have dangerous effects)
• less 1st pass metabolism when taken orally
• commonly mixed with acetaminophen (Tylenol #3)

Question 2

fentanyl (Duragesic)

Answer 2

Opioid mu receptor agonist

• 50-100x more potent then morphine (100mcg fentanyl = 10mg morphine)
• onset 3-5 min, with variable T1/2 depending on length of administration
• 100% hepatic extraction (inactive metabolites)
• –clearance directly correlated to liver blood flow
• –decreased with P450 inhibitors (cimetidine, erythromycin)

Question 3

heroin

Answer 3

Opioid agonist (morphine derivative)

• acetylated morphine
• 2-4x more potent then morphine with faster onset

Question 4

hydrocodone (Vicodin)

Answer 4

Opioid agonist (morphine derivative)

• metabolized to hydromorphone by CYP2D
• commonly mixed with acetaminophen

Question 5

hydromorphone (Dilaudid)

Answer 5

Opioid agonist (morphine derivative)

• about 5x more potent then morphine and more lipid soluble so faster onset
• onset in 5min; peak 10-20min
• can be given IV or PO
• 1-2mg IV Dilaudid = 10-20mg IV morphine
• glucuronide metabolism forms hydromorphone-6G (less efficacy then morphine-6G) and hydromorphone-3G (inactive metabolite)

Question 6

meperidine (Demerol)

Answer 6

Opioid agonist

• 1/10th the potency of morphine but more lipid soluble so has faster onset
• less bradycardia and resp. dep. than with equianalgesic dose of morphine
• dysphoric and psychotomimetic effects- kappa receptor
• metabolized in the liver which produces an active metabolite normeperidine that has T1/2 of 14-21 hrs (can cause seizures and death)
• useful for post-op shivering
• inhibits serotonin reuptake and can cause Serotonin Syndrome in ppl taking MAOIs or SSRIs

Question 7

morphine

Answer 7

• classic mu opioid receptor (mu 1 and 2) and influences motivational-effective aspect of pain
• only 23% non-ionized and able to cross BBB and also has low lipid solubility (1.4) so slow onset of action
• T1/2 of 2-3 hours and DOA of 4-6 hrs
• decreases ventilatory responses to inc. CO2 AND dec. O2
• metabolized (70%) in liver via glucuronidation
• liver disease has minimal effect on metabolism
• –reduced blood flow will slow metabolism
• metabolites excreted by the kidney
• –M-3-glucuronide 75-85% inactive metabolite
• –M-6-glucuronide 5-10% active metabolite (10x more potent then parent morphine)
• excretion of active metabolite can be impaired in renal disease leading to dangerous build-up

Question 8

Alfentanil

Answer 8

μ receptor agonist

• roughly 10x more potent than MSO4 and 1/10th to 1/4th the potency of fenatnyl (1000mcg Alfent=100mcg Fent=10mg MSO4).
• Rapid onset of action (1-2”)
• Approximately 90% in the unionized form at physiological pH
• lower lipid solubility than fentanyl, so less accumulation in tissues.
• metabolized in liver, no active metabolites.
• Give in small increments to decrease onset of respiratory depression.

Question 9

Remifentanil

Answer 9

μ receptor agonist
-“equipotent to Fentanyl”
-Very rapid onset (1”) and offset
-Offset not determined by length of infusion.
+metabolized by nonspecific esterases
-Not great for continued, ongoing pain post-op.
-Dose long acting narcotic and allow MEC to be reached before stopping Remi gtt to prevent hyperalgesia.

Question 10

buprenorphine (Buprenex)

Answer 10

μ receptor Agonist-antagonist

• partial μ receptor agonist and K receptor agonist
• high affinity for μ (hard to reverse)
• good for opioid addiction at higher doses.

Question 11

nalbuphine (Nubain)

Answer 11

μ receptor Agonist-antagonist

• K receptor agonist, partial μ receptor agonist, and μ receptor antagonist.
• good for acute moderate to severe pain (not for chronic pain).
• lower S/E profile.
• butorphanol is similar, but nubain is 10x more potent than butorphanol.

Question 12

pentazocine (Talwin)

Answer 12

Opioid receptor Agonist-antagonist

• 2 isomers, but only + has affinity for K receptors.
• has ceiling effect.

Question 13

tramadol

Answer 13

μ receptor partial agonist

• also inhibits MAO reuptake.
• metabolized by CYP2D6 to active metabolite
• combined with acetaminophen (Ultracet)
• for mild to moderate acute and chronic pain.

Question 14

tapentadol

Answer 14

μ receptor partial agonist

• also inhibits MAO reuptake.
• less pharmacological variability than tramadol.
• greater μ receptor efficacy
• metabolized by CYP2C9, 2C19, and 2D6.
• for mild to moderate acute and chronic pain.

Question 15

opioids

Answer 15

mu, kappa, delta receptor agonist
analgesic effects and other unwanted side effects
inhibit NT- block Ca2+ influx and increase K+ efflux

Question 16

nocieptors

Answer 16

specialized nerve endings

gate control theory- input from afferent and nociceptors are gated in the spinal cord (T cell and substantia gelatinosa)

Question 17

opioid intoxication

Answer 17

overdose
sedation, stupor, coma, death
-unresponsive, respiratory depression, pupil constriction

Question 18

serotonin syndrome

Answer 18

Delirium
Fever
Convulsion
Meperidine inhibits the re-uptake of serotonin

Question 19

dynorphins

Answer 19

endogenous opioid for the KAPPA receptor

Question 20

endomorphins

Answer 20

endogenous opioid for the MU receptors

Question 21

endorphins

Answer 21

endogenous opioid for the MU and DELTA receptor

Question 22

enkephalins

Answer 22

endogenous opioid for the DELTA receptor

Question 23

delta receptor

Answer 23

Location: BRAIN
Action: analgesia, antidepressant effects, CONVULSANT EFFECTS, physical dependence

Question 24

kappa receptor

Answer 24

Location: brain, spinal cord, peripheral sensory neurons
Actions: analgesia, anticonvulsant effects, dissociative & delirium, diuresis, dysphoria, miosis, sedation, REDUCED SHIVERING

Question 25

mu receptor

Answer 25

Location: brain, spinal cord, peripheral sensory neuron, intestinal tract Actions: sedation, analgesia, physical dependence, respiratory depression, miosis, euphoria, reduced GI motility, vasodilation

Question 26

motivational-affective

Answer 26

unpleasantness and bother to the patient (nauseating, sickening) - opioids are most effective against this dimension of pain

Question 27

sensory-discriminative

Answer 27

sensation, location, quality of pain

Question 28

CYP2D6

Answer 28

metabolizes codeine to morphine metabolizes oxycodone to oxymorphone metabolizes tramadol and tapentadol

Question 29

CYP3A

Answer 29

metabolize tramadol

Question 30

morphine glucuronides

Answer 30

M3-glucuronides-- 75-85% inactive metabolite, no analgesia, maybe hyper analgesic M6-glucuronides-- 5-10% ACTIVE metabolite, 10x more potent that parent morphine (excreted by organic ion transporters in the kidney)

Question 31

addiction

Answer 31

- primary, chronic, neurobiological disease with genetic, psychosocial and environmental factors influencing its development and manisfestations - characterized by: impaired control over drug use/psychological dependence, compulsive use, continued use despite physiologic, psychosocial and/or econonmic harm, craving - uncommon with appropriate medical treatment of acute pain

Question 32

physical dependence

Answer 32

- withdrawl symptoms that are precipitated when an opioid agonist is stopped or an antagonist is given - develops concurrently with tolerance - common with prolonged use

Question 33

psychological dependence

Answer 33

- impaired control over drug use - taking it for the reinforcement - related to the mesolimbic dopamine system

Question 34

tolerance

Answer 34

decreased response to a drug with repeated use | develops to most opioids, but not to ocular/GI effects

Question 35

withdrawl

Answer 35

s/sx: restlessness, insomina, perspiration, abdominal cramps, nausea, vomiting, diarrhea, tachycardia, tachypnea, HTN, hypotension, hot/cold flashes -gradual reduction of the opioid dose may reduce or eliminate s/sx

Question 36

side effects of opioids

Answer 36

``` bradycardia constipation dysphoria euphoria itching miosis othrostatic hypotension respiratory depression sedation stupor/coma vasodilation vomiting ```

Question 37

Sufentanil

Answer 37

highly selective for μ receptors (synthetic derivative). -Roughly 500-1000x more potent than eqivalent dosing of MSO4. +5-10mcg Sufent=5-10mg MSO4. -more lipid soluble than fentanyl, remifentail, and alfentanil. +slower onset and offset than remifentanil and alfentanil. +plan to discontinue infusion about an hour or so before conclusion of case to allow for offset. -we do not have sufentanil on formulary at UIHC

Question 38

oxycodone

Answer 38

- less first pass metabolism. CYP2D6 active metabolite oxymorphone - sustained release when taken whole, bolus dose when crushed

Question 39

methadone

Answer 39

- ultra long acting, half-life 15-60 hours | - useful for chronic pain management, addicted patients maintenance

Question 40

naloxone

Answer 40

- competitive antagonist at mu, kappa, and delta receptors - IV or IM effective in 1-2 minutes - half-life 60 min (3hrs in infants), may need to redose for opioid reversal - metabolized via glucuronidation

Question 41

naltrexone

Answer 41

- oral opioid antagonist, much slower than naloxone, not for acute reversal

Question 42

oxymorphone

Answer 42

- mu receptor and partial delta receptor agonist. 6-8 times more potent than morphine - oral medication, NOT metabolized by CYP2D6