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PHAR 300 > L13: Opioid Analgesics > Flashcards

L13: Opioid Analgesics Flashcards

1
Q

What is the major use of opioids?

A

To handle pain (but not just that…)

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2
Q

What are the 2 major locations involved in sensations of pain? What drug acts on each location?

A
  1. Peripheral nervous system: NSAIDs

2. Central nervous system: Opioids

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3
Q

What is the pain transmission pathway and what is the pain suppression pathway of the central nervous system?

A
  1. Pain transmission pathway: First you have the relay in the spinal cord, (goes up spinothalamic tract), then reach the thalamus, then cortex where you are conscious of the pain.
  2. Pain suppression pathway: pain inhibitory tract in the dorsolateral funiculus (descending).
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4
Q

How do we get pain suppression in the CNS?

A
  1. Endogenous opioid peptides

2. Ingested opioids that interact with receptors for the endogenous peptides

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5
Q

Where are opioid synthesizing neurons and opioid receptors found?

A

Throughout the brain and spinal cord.

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6
Q

What are the endogenous opioids?

A

Beta-endorphins, enkephalins, dynorphins

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7
Q

What are the opioid receptors?

A

µ (Mu) , Delta, Kappa

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8
Q

What is the main site for opioid analgesics?

A

Brain and spinal cord.

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9
Q

Where does pain start and how can it be treated?

A

Pain starts in the periphery with trauma and it can be treated by anti inflammatory drugs and local anaesthetics.

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10
Q

How can local anaesthetics work in the spinal cord?

A

By injection into the spine

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11
Q

What is an opiate? What is an Opioid?

A

Opiate: Alkaloids found in the opium poppy. Derived from the plant.
Opioids: Compounds with opiate-like actions, including but not confined to, opiates (ex: synthetic, endogenous opioids)

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12
Q

Where does opium come from?

A

Drug comes from the unripe seed capsules of opium poppy plant. When you scratch the seed capsule, a milky substance leaks out.

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13
Q

What are the main groups of opioids? Give examples of each.

A
  1. Naturally occurring:
    (a) Morphine
    (b) Codeine
  2. Endogenous opioids
    (a) Endorphins
    (b) Enkephalins
    (c) Dynorphins
  3. Synthetic opioids
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14
Q

What is the main effect of Morphine?

A

Drowsiness and dream enhancement.

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15
Q

What is another name for Codeine? How is it administered?

A

Methylmorphine

Easy to administer orally

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16
Q

What is heroin a derivative of? Compare them.

A

Heroin (Diacetylmorphine) is a derivative of Morphine. It is 10x more potent than morphine. Crosses BBB more quickly than morphine, once it crosses it is converted to morphine, gives a better high.

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17
Q

What endogenous opioid has a similar structure to morphine? What does this imply?

A

Enkephalins have a similar structure to Morphine which means it can interact with the same receptors.

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18
Q

Where are the opioid receptors distributed? Which of the receptors is the most prevalent?

A

µ (Mu) , Delta, and Kappa are distributed all over CNS (brain, spinal cord). Mu is the most prevalent.

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19
Q

What is a synthetic opioid?

A

A drug with Morphine like action that has a similar structure to Morphine. Alterations to the basic structure gives a number of variations.

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20
Q

What is a challenge of making synthetic opioids?

A

Most synthetic opioids are addictive so scientists try to modify the structure to find non-addictive derivatives.

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21
Q

What synthetic opioids can be used to treat opioid addicts? How are they administered?

A

Helps former addicts by blocking drug effects (can’t get high):
1. Naltrexone: opioid antagonist, oral absorption (sublingual)

Can save someone having an opioid overdose:
2. Naloxone: opioid antagonist, injection

To help people quit opioids because it lowers withdrawal symptoms:

  1. Methadone: partial agonist, oral absorbtion (sublingual)
  2. Buprenorphine: partial agonist
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22
Q

What kind of opioid is Pentazocine? What is its effect on opioid receptors?

A

It is a synthetic opioid and it functions as an agonist-antagonist. This means that it can activate a receptor a little bit on its own but it also blocks the access of other more powerful drugs to the receptor.
Gives less pain relief and there is a low abuse potential.

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23
Q

What are the 2 kinds of opioid analgesia?

A
  1. Decrease pain signal

2. Increasing inhibition

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24
Q

How do opioids decrease the pain signal?

A

Afferent transmission is reduced at 2 sites: presynaptic and post-synaptic (there are opioid receptors on both).

  1. Opioids bind to opioid receptors (Mu, delta, kappa) which are GPCRs. The calcium channels are inhibited presynaptically and the potassium channels are activated post-synaptically via the beta and gamma subunits of the GPCR.
    Calcium channel blocked causes:
  2. Decrease of calcium influx into presynaptic terminal
  3. Decrease of transmitter release to synapse

Potassium channel activation causes:

  1. Opening of potassium channel
  2. More potassium leaves the neuron
  3. Post-synaptic membrane is hyper-polarized = less likely to fire action potentials (IPSP)

Summary: decreasing neurotransmitter release and decrease in the response to the neurotransmitters that are released.

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25
Q

How do opioids increase the inhibition of pain signals?

A

Increasing the descending inhibition by decreasing GABA release onto descending noradrenergic and seratonergic neurons that prevent the transmission of the painful stimulus to the brain.
The opioids decrease GABA release by blocking the calcium channels.

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26
Q

Explain the descending inhibition pathway.

A
  1. Primary afferent, from the peripheral nervous system, synapses on the spinothalamic tract and releases glutamate (stimmulates)
  2. The descending pain inhibitory tract also synapses on the spinothalamic tract and releases serotonin and norepinephrine/noradrenaline (inhibitiory)
  3. The descending pain inhibitory tract also synapses onto the Enkephalin neuron (endogenous opioid) and stimulates it via releasing serotonin.
  4. Enkephalin neuron synapses onto the spinothalamic tract and inhibits it by releasing Enkephalin.
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27
Q

Why do opioids affect physical and emotional pain?

A

Pain is sent to the cortex which makes it a sensation and an emotion. Opioids directly decreases the pain signal being sent to the cortex and increases the inhibition of the pain signal.

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28
Q

Where is the Mu receptor most prevalent?

A

The limbic system (region controlling emotions), spinal cord, and brainstem.

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29
Q

Which opioid receptors are better at blocking calcium channels?

A

Mu, delta, and kappa (all)

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30
Q

Which opioid receptors are better at activating potassium channels?

A

Mu

31
Q

Explain the receptor recycling process.

A
  1. Agonist binds receptor
  2. G protein activation and signalling
  3. Receptor phosphorylation
  4. Beta arrestin binding to phosphorylated receptor
  5. Receptor endocytosis
  6. Receptor degradation in lysosome or receptor recycling
32
Q

Describe the tolerance from chronic morphine and chronic pain.

A

Chronic morphine and chronic pain can alter the number of opioid receptors on the plasma membrane by increasing insertion of receptors at the cell membrane. Chronic use leads to tolerance, so even though chronic morphine and pain cause receptor insertion, there is an increased turnover and degradation of receptors such that overall their numbers decrease.

33
Q

What’s a major problem of opiates acting on the brain stem?

A

Opiates can change the brainstem which controls the automatic body functions and can depress breathing. So far, they have not been able to separate these side effects from the pain relief.

34
Q

What receptor do all classical opioid drugs of abuse have a preference for? give examples.

A

µ receptors.

Ex: morphine, heroin, methadone, fentanyl, etc.

35
Q

What are the physiological effects of exogenous opioids?

A
  1. Analgesia: which is the relief of pain in absence of impairment in other sensory modalities like touch, consciousness, hearing, and vision because of the selective distribution of the opioid receptors on pain pathways. There is therefore specific action in the CNS not the periphery.
  2. Gastro intestinal effects : Mu and Kappa receptors inhibit motility and cause constipation. Treats diarrhea.
  3. Cough suppression.
  4. Euphoria: which is pleasure caused by the activation of the Mu receptor and produces a sense of well-being and reduces anxiety.
  5. Respiratory depression: caused by the Mu receptor in respiratory neurons in the medullary and solitary tract.
  6. Meiosis.
  7. Motor effects: with side effects such as seizures.
36
Q

What are the opioid receptors involved in analgesia? Gastro-intestinal effects and sedation? Respiratory depression?

A

Analgesia: µ, delta, kappa
Gastro-intestinal effects and sedation: µ, kappa
Respiratory depression: µ
µ is crucial for all of these effects.
You cannot separate analgesia from respiratory depression.

37
Q

What does it mean to say “opioid tolerance is differential”

A

The different opioid receptors respond differently to chronic use.

38
Q

What are the different administration methods for morphine?

A
  1. Oral: high first pass metabolism in liver before it reaches brain and spinal cord
  2. Rectal
  3. Injection: intramuscular, subcutaneous, or intravenous, NOT SKIN
  4. Inhalation: rapid but uncommon
39
Q

What is the most common route to administer morphine? most common medical route?

A

route: injection

medical route: IM

40
Q

When is IV used to administer morphine and why?

A

IV is used in case of emergencies because you get a really high peak of morphine in blood right away (goes above the therapeutic effect).

41
Q

What is the difference between IV and IM administration of morphine? Talk about their different absorptions.

A

Intramuscular injection means that the morphine absorption takes place from the muscle into the vasculature whereas intravenous injections injects morphine straight into the blood. Therefore, morphine levels in the blood from intramuscular administration increases considerably slower and reaches a lower peak level but, the concentration decline is also much lower. Furthermore, intramuscular injections give a longer time span of pain relief with fewer side effects and stay in the therapeutic window so it is a safer way to administer morphine. IV injections give analgesic effects for a much shorter time and with increasing side effects initially (because it is outside of the therapeutic range) which is more dangerous.

42
Q

Does morphine cross the BBB?

A

yes, only 20%.

43
Q

Describe the metabolism of morphine. What’s the half life?

A
  • Metabolized predominantly in the liver
  • Short half life of 2-4 hours
  • Different metabolites for oral and parenteral
  • Some metabolites of morphine are highly active
44
Q

What are the different metabolites of morphine if it is administered parenterally? What are their half lives? How are they excreted?

A
  1. Morphine-3-Glucuronide:
    - 60%
    - Inactive metaobolite because position 3 is occupied by glucorinide instead of being free to bind to its receptor and cause pain relief.
    - T1/2 = 4h
  2. Morphine-6-Glucuronide
    - 40%
    - Active metabolite because position 3 is free (glucuronide is on position6)
    - Increased drug binding and activation of receptor (more potent than morphine)
    - T1/2 = 3h

Both are excreted in the urine once conjugated (water soluble)

45
Q

How long does it take someone with renal failure to clear Morphine-6-Glucuronide?

A

Greater than 50 hours, which can be dangerous.

46
Q

Describe the metabolites of morphine if it is administered orally.

A

Metabolites are Normorphine and 2 others.
Normorphine has negative psychoactive effects and can be neurotoxic. This is usually not a problem for therapeutic doses because there is not enough of this metabolite to have a negative effect. But, can be a problem if dose is too high.

47
Q

How can morphine be used to treat diarrhea? why?

A
  • Morphine binds to peripheral Mu opioid receptors in the GI tract which impairs motility of the GI tract.
  • Mu receptors are all over the place, including the intestines.
48
Q

What are the 2 layers of neurons in the intestine?

A
  1. Myenteric plexus

2. Submucosal plexus

49
Q

Describe opioid induced constipation. (OIC)

A

Opioids bind to opioid receptors in the myenteric plexus (intestine) causes:

  • Increase circular muscle contraction compared to longitudinal muscle contraction: makes foods stay in intestines longer which allows for more fluid absorption, increased sequestration, and decreased peristalsis
  • Increased rectal sphincter tone
  • Decreased colonic mucosa secretion
  • Decreased sensitivity to rectal distension

Summary:

By increasing the tone and decreasing the motility of the intestines you get very severe cramps and increased water absorption which causes significant constipation and anti-diarrhea. This means that the poop will stay inside the intestines and will become very hard and dry since so many fluids are being absorbed. Constipation that is caused by chronic use of opioids can be painful.

50
Q

Why does morphine induce nausea and vomiting as a side effect?

A
  • Morphine stimulates the chemoreceptor trigger zone in the brain which is designed to protect you.
51
Q

Why are patients kept horizontal after a surgery where they were given morphine?

A
  • Motion increases the side effects of morphine (vomiting and nausea) (input from inner ear)
  • keeping them still helps decrease nausea
52
Q

Why can morphine cause respiratory arrest?

A

Because morphine depresses respiratory center sensitivity to CO2.

53
Q

What are the side effects of morphine?

A
  • constipation
  • nausea and vomiting
  • Miosis of pupils
  • Decreased urine production
54
Q

Why does morphine cause miosis of pupils?

A
  • Morphine depresses the tonic inhibition of pupil constriction, this means that the pupils will constrict.
55
Q

Can you develop tolerance to constipation? miosis of pupils? decreased urine? nausea and vomiting? due to opioids.

A

Constipation: no tolerance
Miosis of pupils: no tolerance
Decreased urine: high degree of tolerance
Nausea and vomiting: high degree of tolerance

56
Q

Why does morphine cause a decrease in urine?

A

Because morphine increases the anti-diuretic hormone (ADH) which causes:

  • Spasms and pain of uterine wall
  • Decrease in urinary output because ADH increases water re-absorption from tubules in kidney
57
Q

What is codeine usually administered along with and why?

A

Alone, codeine has a moderately effective analgesia compared to placebo, but when it’s combined with aspirin or ibuprofen (NSAIDs) it has a much higher analgesic, affect (more pain relief and lasts longer).

58
Q

How is codeine mainly metabolized? What is the main metabolite of codeine?

A

Codeine is mainly metabolized by CYP2D6 to make Morphine. Morphine is an active metabolite which gives the analgesic affect felt by codeine.

59
Q

What happens to codeine if you have low activity in CYP2D6?

A

Will not be able to metabolize as much codeine into morphine so other metabolites will be made instead.

60
Q

How does codeine interact with the brain?

A

Codeine gets into the blood-brain barrier and then gets converted to morphine.

61
Q

What are the consequences on codeine administration because of CYP2D6 being a highly polymorphic enzyme?

A

The CYP2D6 gene is highly polymorphic which means it has a lot of deletions, critical SNPs, and duplications. Therefore, 5 to 10% of people are poor metabolizers of codeine with regards to CYP2D6 which means that they’re not responsive to codeine. 5 to 10% of people have very high levels of CYP2D6 which means they respond right away to codeine. There’s no way of knowing or predicting who has non-working variations of CYP2D6 you only find out after administering codeine.

62
Q

What is a consequence of CYP2D6 variation on breast cancer?

A

CYP2D6 is involved in creating the major metabolite of the anti breast cancer drug Tamoxifen. The metabolite is the major attribute for the drug so a small fraction of people deficient in CYP2D6 are not able to respond to Tamoxifen as it is the active metabolite that inhibits tumour growth. People are now tested ahead of time forCYP2D6 viability before their treatment

63
Q

Name opioids other than morphine that are agonists.

A
  1. Meperidine: to treat pain, full agonist, taken orally
  2. Fentanyl: very powerful opioid
  3. Hydromorphone (Dilaudid): µ agonist, absorbed orally, used for chronic severe pain (ex: terminal cancer)
64
Q

Compare Meperidine to Morphine.

A
  • Meperidine is better absorbed orally than morphine.
  • Has a longer T1/2
  • Different side effects
  • Less potent than morphine but equally effective (right shift on dose response curve but reaches same degree of pain relief).
65
Q

What is Meperidine metabolized into?

A
  • Metabolite: Normeperidine which is an active metabolite that causes CNS excitation. This balances out some of the depression, so there is less depression.
66
Q

What are the advantages of Fentanyl?

A

Fentanyl is highly lipid soluble so it can be given in skin patches which allow for slow absorption and a longer duration of action. It can also be given in the form of lollipops, which is useful for children. Fentanyl gets into the bloodstream fast so it’s fast acting.

67
Q

Why is oral transmucosal technology efficient?

A
  1. Large surface area
  2. Uniform temperature
  3. High permeability
  4. Well-vascularized
  5. Facilitates rapid absorption
  6. No first-pass effect
68
Q

What is Loperamide, what is it used for?

A

The trade name for loperamide is imodium. Loperamide is in the opioid family but it has minimal penetration of the blood-brain barrier and it’s only used to treat diarrhea because it cannot get into the CNS thus it does not cause analgesia. It goes into the intestine and acts on opioid receptors there as it gets absorbed so it’s good for IBS or other bowel problems.

69
Q

What happens when you take heroin after taking methadone?

A

You don’t get a high from heroin because Methadone is occupying the receptors and is a weak agonist.

70
Q

What happens when babies are exposed to opioids in utero?

A

They can suffer from opioid withdrawal.

71
Q

Why aren’t Kappa compounds self-administered?

A

They are psychotomimetic (similar to psychotic state) and aversive in humans therefore, they don’t feel good to take.

72
Q

What is the classic administration of Heroin and what are the effects?

A
  • Smoked
  • It is a narcotic
  • Acute effect: euphoria (rush, followed by a high), then tranquility and sleepiness. Opiate receptors in reward pathway.
  • chronic addict has permanent Miosis
73
Q

Put morphine, heroin, fentanyl and carfentanil (large animal tranquilizer) in order of least to most potent.

A

morphine < heroin < fentanyl < carfentanil.

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