Week 8 Opioid Analgesics and Antagonists Flashcards

1
Q

What are the 3 families of endogenous opiates? What are the 3 families of receptors?

A
  1. beta-endorphin
  2. enkephalins
  3. dynorphins
    RECEPTORS
  4. mu
  5. kappa
  6. delta
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2
Q

List the precursor molecules for:

  1. beta-endorphin
  2. enkephalins
  3. dynorphins
A
  1. POMC–>beta endorphin
  2. preprodynorphin–>dynorphins
  3. preproenkeplin–>met-enkaphalin and leu-enkephalin
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3
Q

What is the distribution of opioid system?

A
  • Very wide distribution
  • endorphins synthesized in arcuate nucleus of the hypothalamus and nucleus tracts solitaries (NTS)
  • enkephalins distributed in central and peripheral nervous systems, adrenal gland, enteric nervous sytem
  • dynoprhins in certain CNS structures
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4
Q

What are the actions of opioid receptors?

A
  • G protein coupled, lead to inhibition of adenylyl cyclase and decreased cAMP production
  • inhibit presynaptic voltage gated Ca2+ channels and inhibit efflux of K+ from post synaptic neuron
  • lead to inhibition of neurotransmitter release and postsynaptic hyper polarization and decreased neuronal excitability
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5
Q

Describe the effect of opioids on the DA release from the VTA.

A
  • activation of opioid receptors in VTA–>increase DA release by inhibiting release of GABA from local inhibitory neurons
  • opioids target mu receptors on GABAergic interneurons, inhibiting it–>disinhibition, releases its inhibition of VTA DA neurons
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6
Q

Describe the role of opioids in modulation of pain pathways in the spinal cord by higher order centers in the brain.

A
  • opioid receptors found on dendrites of dorsal horn projection neurons and presynaptic termination of nociception neurons
  • activation of nociceptors release glutamate and sub P–>STT activation and transmission of pain signals to thalamus
  • NE and 5HT from brain stem can stimulate enk neurons and inhibit release of glutamate and sub P. Blocks pain signals to thalamus.
  • NE and 5HT synapse on ENK neurons and STT projection neurons
  • mechanism for brain to over ride pain info in times of extreme stress or injury
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7
Q

What are the natural opiates?

A

Morphine and codeine (weak agonist)

-all other opioids are prepared from morphine

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8
Q

What types of activity result from mu receptor activation by opioids?

A

Analgesia, euphoria, and respiratory depression

-kappa and delta receptors do more spinal analgesia

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9
Q

What is the mechanism of action of morphine?

A

-binds to opioid receptors in CNS, GI, and urinary bladder
-normally: activated nociceptive pain fibers leads to release of glutamate at presynaptic terminal and activation of neurons of nucleus proprious in dorsal horn of spinal cord when encephalin is inactive
-presynaptic: decreases Ca2+ influx, inhibits glutamate release on presynaptic opioid receptors
-postsynaptic: increase K+ conductance, causes hyper polarization
-acts at opioid receptors in dorsal horn of spinal cord to decrease release of Sub P (modulates pain perception in cord)
-

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10
Q

What are the physiological effects of opioids in the CNS?

A
  • Analgesia-dull pain blocked more than sharp pain
  • sedation, esp with morphine
  • antitussive effect-suppresion of cough
  • dysphoria
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11
Q

What are the physiological effects of opioids on emotions?

A

morphine produces powerful sense of well being and contentment by causing dish inhibition of DA release of the VTA neurons and drug addiction

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12
Q

What are the physiological effects of opioids on respiration?

A
  • respiratory depression by reducing the sensitivity of respiratory center neurons to carbon dioxide
  • pontine and medullary respiratory centers may also be depressed
  • most common cause of death in acute morphine overdose
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13
Q

What are the physiological effects of opioids on the eye?

A
  • causes pinpoint pupils due to activation of neurons of the Edinger-Wesphal nucleus of CN III and enhanced parasympathetic stimulation of the eye
  • little tolerance to the effect
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14
Q

What are the physiological effects of opioids on emesis, renal system, bronchial effects, skin?

A
  • emesis: stimulates neurons in chemoreceptor trigger zone of area postrema of medulla, causing vomiting and nausea
  • renal system: depression, elevated ADH release, urinary retention
  • bronchial: histamine release form heparin histamine complex in mast cell resulting in bronchoconstriction, depression of reparatory drive and cough reflex
  • skin: vasodilation and flushing, itching and uricaria, due to histamine release, following displace from heparin in the mast cell
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15
Q

What are the physiological effects of opioids on the GI tract?

A
  • causes constipation by increasing tone of the intestinal circular smooth muscles, decreases peristaltic waves
  • delayed stomach emptying and decreased stomach utility
  • reduction in gastric acid secretion
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16
Q

What are the physiological effects of opioids on cardiovascular system?

A
  • therapeutic doses have little effect on heart rate or blood pressure in supine patient
  • in standing position, orthostatic hypotension or fainting can occur
  • hypotensive response partly due to release of histamine dn partly due to depression of vasomotor center.
17
Q

Describe the pharmacokinetics of opioids.

A
  1. Metabolism and excretion: most metabolized in liver. 4-6 hrs if given systematically.
  2. Absorption: im, iv, sc admin of drug most reliable because of first pass metabolism Absorption generally good.
  3. Distribution: heroin and codeine pass BBB much more easily than morphine.
18
Q

Summarize clinical uses of morphine, fentanyl (sublimaze), Zohydro ER.

A
  1. morphine: more effective b parenteral vs. oral, main use for severe acute pain, long duration of action due to active metabolite
  2. Fentanyl: very high potency, short duration. Useful in anesthesia due to fast induction and emergence. Use for severe chronic pain too (intrathecal, epidural, transdermal).
  3. Zohydro ER: for daily severe pain, oral formulation of hydrocodone, but pill form can be abused
19
Q

Summarize the toxic effects of opioids.

A
  • respiratory depression, coma, miosis
  • nausea and vomiting
  • addiction
  • constipation
  • urinary retention
  • dysphoria in some cases, marked by hyperactivity
  • postural hypotension
20
Q

Describe the pharmakinetics of opioid antagonists Naloxone, naltrexone, nalmefene.

A

Competitive antagonists of mu, k, and d receptors

  1. absorption:
    - naloxone has low oral bioavail, short duration of action (1-2 hr) parenterally.
    - Naltrexone: good oral bioavail, but undergoes first past metabolism. t1/2 10 hrs
    - nalmefene: for acute opiate overdose, longer half life 8-10 hrs than naloxone
  2. Distribution: pass BBB more easily than morphine
  3. Metabolism and excretion: metabolized in liver microsomal fraction via glucuronidation
21
Q

What are the effects of opioid antagonists?

A
  • reverse the effects of morphine in 1-3 mins. Opiate effects are normalized, including reparatory depression, euphoria, pupils
  • withdrawal symptoms immediately precipitated in opiate users
  • tolerance doesn’t develop to antagonists
22
Q

Describe the clinical usage of naloxone, nalmefene, and naltrexone.

A
  1. naloxone: choice treatment for acute opiate overdose. dosing may be repeated due to short duration of action.
  2. nalmefene: for acute opiate overdose, has long duration
  3. naltrexone: maintenance drug for addicts. blocks heroin effects up to 2 days.