8/30 Opiates - Welsh

Question 1

opium

Answer 1

mixture of alkaloids from opium poppy (papaver somniferum)

Question 2

alkaloids

Answer 2

class of naturally occurring organic N-containing bases

ex. morphine, cocaine, caffeine, nicotine, vincristine, atropine, quinine

Question 3

opiate

Answer 3

naturally occuring opium-derived alkaloid (morphine or codeine)

Question 4

opioid

Answer 4

ANY natural, synthetic, or semi-synthetic compound with morphine-like props

Question 5

classification of opioids

Answer 5

1. interaction with GPCR (mu, kappa, or delta)

• most opioid analgesics are relatively selective mu opioid agonists
• some kappa agonists (pentazocine, nambuphine, butorphanol), but not highly selective
• selective delta agonists are mainly peptides (none currently used clinically)

2. intrinsic activity

• pure agonists:
  
  • full agonists (morphine, fentanyl)
  • partial agonists (buprenorphine)
• pure antagonists:
  
  • naloxone, naltrexone (used for detox, overdose, maint therapy for addicts)
• mixed agonist-antagonists__:
  
  • pentazocine, nalbuphine, butorphanol
  • kappa agonists that produce analgesia but also act as mu antagonists (interfere with morphine, heroin, etc)

Question 6

endogenous opioid peptides

Answer 6

endorphins, enkephalins, dynorphins

• located primarily in brain → fx as neurotransmitters or neuromodulators
• modulate pain transmission in spinal cord
• alter acetylcholine release in GI myenteric plexus
• beta endorphins are the cleavage product of pro-opiomelanocortin (POMC; precursor hormone for ACTH)

Question 7

action of opioids in analgesia

1. cellular mech of action

Answer 7

morphine has a mostly inhibitory effect on neuron

at presyn terminal

1. inhibits formation of cAMP (catalyzed by adenylyl cyclase)

2. inhibits uptake of Ca

• binding of morphine to mu receptor suppresses Ca influx → inhibits release of nts that convey pain perception (ex. glutamate, Substance P)

at postsyn terminal

1. opens K channel

• leads to hyperpolarization of cell → dampened neuron firing, reduced neuron excitability and pain

Question 8

general clinical properties of opioid analgesics

Answer 8

both acute and chronic effects

• all mu opioid agonists produce these effects
• EXCEPTION: histamine release varies from one mu opioid to another
• EXCEPTION: meperidine (Demerol) productes mydriasis (pupil dilation)

clinical selection is usually based on PK considerations (speed of onset o action, duration, halflife, CNS permeability)

Question 9

major clinical uses of opioids

6 with examples

Answer 9

1. analgesia for ACUTE moderate to severe pain (morphine, heroin)

• myocardial infarction (most imp use of morphine)
• severe injuries (exception: head injury)
• post-op
• renal colid, kidney stones
• severe bone/jt pain
• cancer patients (fentanyl IM or IV if pt becomes morphine-tolerant)

2. analgesia for moderate lon-term, chronic pain (oxycodone, hydrocodone)

3. anesthesia (fentanyl) : regional anesthesia such as spinal/epidural

4. cough suppressant (codeine, dextromethorphan)

5. relief from diarrhea (diphenoxylate, loperamide preferred due to lower BBB penetration)

6. acute PE (morphine) : vasodilatory effects to reduce dyspnea, resp distress, pain, anxiety

• use is controversial

Question 10

3. CNS effects of opioids
   a. analgesia and mood

Answer 10

mechanisms:

1. act centrally (brainstem, dorsal horn) to inhibit transmission and processing of pain signals
   * emotional response to pain is altered by opioid actions on limbic cortex
2. act peripherally on sensory neurons
   * sometimes useful for pain caused by tissue infl and nerve ending damage (ex. herpes zoster aka shingles)

Question 11

clinical chars of opioids

• type of anagesia
• why addition?
• what types of pain respond?
• dosage?

Answer 11

• produce selective analgesia without hypnosis, sedation, impaired sensation
• potential for addiction bc can cause mood elevation/euphoria
• greater effect in chronic, burning pain than in sharp, temporary pain (ex. incision) → neuropathic pain (infl nerve pain) can be very resistant
• dosage can vary greatly from patient to patient

Question 12

euphoria

Answer 12

opioids elicit euphoria by suppressing release of GABA → stimulating release of dopamine in a neighboring neuron

Question 13

CNS effects of opioids

b. sedation

Answer 13

• drowsiness, feelings of heaviness, difficulty concentrating
• sleep may occur with relief of pain (but opioids are not hypnotics)
• most likely to occur in elderly/debilitated pts, those taking other CNS depressants (ex. alcohol, anesthetics, benzodiazepines)

Question 14

CNS effects of opioids

CNS toxicity

Answer 14

contraindicated in cases of head injury!!!

• may exacerbate damage caused to respiratory center in brain
• opioid induced miosis, nausea, and general CNS clouding can confuse neuro eval

Question 15

CNS effects of opioids

respiratory depression

• clinical chars

Answer 15

mechanisms:

• direct effects on resp centers in medulla
  
  • decreased sensitivity to incr blood levels of CO2 in resp center of brainstem
• increased arterial CO2 retention → cerebral vasodil → increased ICP

clinical characteristics:

• abnormal drive to breathe (despite normal resp rate)
• dose-related effects
  
  • v large doses can cause irreg breathing or apnea
• SLEEP depresses response to CO2 further → can potentiate opioid effect

resp depression is the major toxicity of opioids and nearly always cause of death from OD

• resp depression is directly correlated with analgesic effect
• difficult to reverse resp depression without losing some analgesic effects

Question 16

CNS effects of opioids

cough suppression (antitussive)

Answer 16

• depression of cough center in medulla (and possibly periphery)
• diff molecular mechanism from analgesia or resp depression
  
  • cough suppressed by d-isomers of opioids (ex. dextromethorphan), which have no analgesic activity
  • codeine or dextromethorphan is the preferred agent (vs. morphine)

Question 17

CNS effects of opioids

pupillary constriction

Answer 17

aka miosis

• caused by stimulation of Edinger-Westphal nucleus (PSNS) of CN III
• VISIBLE SIGN of opioid OD
• reversed by naloxone, atropine, or ganglionic blockers (ex. mecamylamine)

Question 18

CNS effects of opioids

nausea and vomiting

Answer 18

direct stimulation of chemoreceptor trigger zone (CTZ) in area posrema (floor of 4th ventricle) → activates vomiting center!

• markedly potentiated by stimulation of vestibular apparatus → ambulatory patients are much more likely to vomit than those who are lying still!

Question 19

CNS effects

muscle rigidity (skeletal tonus)

Answer 19

large IV doses can cause generalize stiffness of sk muscle

• believed to be due to mu-mediated incr in striatal dopamine synth AND inhibition of striatal GABA release
• happens most commonly with fentanyl and congeners
• may play a role in some OD fatalities

Question 20

CV effects of opioids

Answer 20

• bradycardia due to stim of central vagal nerve
• vasodilation and orthostatic hypotension due to decreased central sympathetic tone

Question 21

opioid effect on histamine release

Answer 21

morphine, fentanyl, meperidine cause non-immunological release of histamine → vasodilation, hypotension

occasionally causes redness of skin, urticaria (hives/rash), pruritis (itchy skin) near injection site

NOT an allergy (true allergic responses are v rare)

Question 22

opioid smooth muscle effects

Answer 22

1. intestine and stomach

• constipation : sm muscle spasm, diminished peristalsis, delayed gastric emptying
  
  • chronic opioid use req admin of laxatives
• application: diphenoxylate and loperamide are poorly CNS-absorbed → used in tx of diarrhea!

2. biliary system

• contraction of sm muscle along biliary tree
• spasm of sphincter of Oddi
  
  • both can precipitate biliary coli (gallstones)
• ​effect anatonized by naloxone and partially reversed by glucagon, nitroglycerin, atropine

3. urinary tract

• anti-diuretic effect → urinary retention
• prob both central and peripheral mechs involved!

Question 23

opioid effects on pregnancy and neonate

Answer 23

sometimes used (sparingly) to relieve labor pain (fentanyl, butorphanol, meperidine)

• all cross the placenta → if given during labor, can cause resp depression in baby

chronic use may cause physical dependence in utero and life-threatening neonatal withdrawal after delivery

Question 24

opioid tolerance

Answer 24

repeated dosing → reduction in effect of opioid

• end up needing higher dose to produce same effect

mechanism MAY involve adaptive response of adenylyl cyclase and/or G protein coupling (i.e. it is NOT a pharmacokinetic effect)

develops rapidly to depressant effects: analgesia, resp depression, euphoria

develops much less to stimulatory effects: miosis, constipation

ex. heroin addicts/methadone maintenance pts may have little euphoria from high doses BUT still experience constipation and miosis
ex2. terminal cancer patients are tolerant to resp depression BUT require laxatives for constipation

Question 25

physical dependence (vs. psychological dependence) withdrawal syndrome

Answer 25

produces withdrawal sx when drug stopped * small dose of opioid can stop sx giving antagonist (naloxone) to a physically dependent person → rapid onset of more severe withdrawal syndrome _symptoms_: sweating, rhinorrhea, vomiting, diarrhea, piloerection, mydriasis, shaking chills, drug seeking behavior

Question 26

physical dependence vs psychological dependence

Answer 26

_physical_: natural need for higher doses for analgesia _psych_: addiction, craving for the "high"

Question 27

methadone for opioid addiction

Answer 27

long-lasting opioid (24-35hr halflife vs 2-3hr morphine) **used for detoxification to wean addicited individual off of morphine, heroin, etc.** protracted but mild withdrawal sx * methadone must be tapered off slowly to avoid rise of acute withdrawal, craving, abuse **_benefits_** * intensity of withdrawal sx decreased (as well as drug seeking/illegal activity) * develop a tolerance to opioid euphoria (so injection of heroin is non-reinforcing) * mathadone given **orally** * obtaining methadone means regular contact with caregivers/counselors

Question 28

opioid overdose

Answer 28

resp depression is the hallmark sign of opioid intox **CLASSIC TRIAD:** 1. **miosis** 2. **apnea** 3. **stupor (coma)** * pulmonary edema (late clinical manifestation) * occasional seizures * meperidine, pentazocine/naloxone

Question 29

PK of morphine

Answer 29

fairly rapid absorption, wide distribution, rapid hepatic clearance from plasma * 70% first pass metabolism * polar metabolites cleared by kidney morphine is **hydrophilic** so **CNS penetration and exit are slow** → **slow onset and long duration** **heroin** is a more lipophilic prodrug of morphine w very fast CNA penetration

Question 30

PK of fentanyl

Answer 30

80-100x more powerful than morphine rapid absorption, wide distribution, moderately rapid hepatic clearance, short halflife (\<1 hr) * 60% first pass metabolism extremely lipophilic → rapidly crosses bbb and other membrane barriers _multiple delivery routes_: patch, intrathecal, intranasal spray, buccal mucosa

Question 31

opioid agonist dosage

Answer 31

analgesic requirements are enormously variable! therapeutic window is narrow and varies widely for each patient low starting doses for: * elderly * hypovelemic * debilitated * hypothyroid * on CNS depressants

Question 32

commonly prescribed opioids

Answer 32

**hydrocodone/acetaminophen (Vicodin)** **oxycodone/acetaminophen (Percocet)** orally active opioid formulation for moderate-severe pain dosage monitored by need to limit acetaminophen to \< 8g/day (or lower if liver impaired)

Question 33

two major opioid antagonists

Answer 33

naloxone (Narcan) naltrexone (Vivitrol)

Question 34

naloxone

Answer 34

Narcan * pure, competitive antagonist at mu, kappa, and delta receptors * highest affinity for mu * **rapid acting:** rapidly reverses opioid OD when injected IV/IM but has short duration * immediate releif from acute resp depression, but can also induce severe withdrawal sx * due to short half life, might need multiple/constant dosing * **not orally active** * added to many abuse-prone opioids (oxycodone, buprenorphine) to make them "abuse-resistant"

Question 35

naltrexone

Answer 35

Vivitrol * long-acting opioid antagonist used for maintenance therapy and relapse prevention once detox'd * orally active * NOT recomended for emergency OD tx * NOT recommended for detox thx

Question 36

opioid partial agonists and mixed agonist-antagonist

Answer 36

developed as part of effort to find analgesics with: * lower abuse potential * lower respiratory depression **all have analgesic props as well as ability to antagonize morphine effects** _2 basic strategies:_ 1. partial agonists at mu receptor 2. mixed agonist-antagonists

Question 37

partial agonists at mu receptor

Answer 37

ex. buprenorphine * oral buprenorphine-naloxone combo is used for maintenance therapy in opioid and alcohol dependence * added naloxone makes it "abuse-resistant"

Question 38

mixed agonist-antagonists (nalorphine, pentazocine, nalbuphine, butorphanol)

Answer 38

(nalorphine, pentazocine, nalbuphine, butorphanol) * act as **kappa agonists** to produce analgesia, and also act as **mu antagonists** * WARNING: as mu antagonists, they can induce acute withdrawal in heroin/morphine addicts!

Question 39

clinical chars of mixed agonist-antagonists

Answer 39

* effective analgesics (moderate-severe pain) * relatively ltd toxicity (reduced resp depression or sm muscle effects) * decreased abuse potential, but also decreased patient acceptance (side effects) * can cause dysphoria, seizures, and precipitate withdrawals in addicts/OD patients