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Therapeutics > exam 5 lecture 3 > Flashcards

exam 5 lecture 3 Flashcards

1
Q

What are the two classifications of pain

A

Acute and chronic

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2
Q

Difference between acute, subacte and chroncic pain

A

Chronic- lasts >3 months
acute<1 month
Subacute- 1-3 months

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3
Q

Explain the dfferent types of pain

A

Noriceptive- result of inflammatory condition like OA or RA. skin/deep tissue

Neuropathic- Can occur from a central mechanism (as a result of stroke, MS, spinal cord injury) or from peripheral pain (viral infection, diabetic neuropathy)

Visceral- Pain/pressure around internal organ (pancreatitis, IBS)

Mixed- lower back pain, cancer, fibromyalgia

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4
Q

What is the function of pain

A

Warning system (avoid injury) aid in repair (hypersensitivity)

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5
Q

Describe the different characterizations of pain

A

Temporal features- Onset, duration, course, pattern

Intensity- Average, least, worst, current pain

Location- Focal, multifocal, generalized, referred, superficial, deep

quality-
inflammatory- throbing, pulsating
neuropathic- stabbing, shooting, burning, tingling
visceral- squeezing

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6
Q

Explain pain circuiting in the periphery

A

Start with a peripheral stimulus of some sort (damage, inflammation) and then signal is conducted into the spinal cord where the signal is processed.

It is then sent to the brain for processing and is sent back down to spinal cord (descending modulation) to help control the action of the afferent neuron that is bringing information into the spinal cord

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7
Q

What are peripheral receptors and channels involved in pain signalling

A

1)Temperature sensitive
-transient receptor potential cation channels (TRP)
-TRPV- Heat
-TRPM- Cold

2)Acid sensitive
-Acid sensing ion channel (ASIC)
-activated H+
-conduct Na+

3)chemical irritant sensitive
-histamine
-bradykinin

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8
Q

Are there reflexes that can bypass CNS and go to muscle?

A

Yes, Reflex upon painful stimuli

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9
Q

Which ions are responsible for sending afferent signal from peripheral to spinal cord

A

Na and K+ ions

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10
Q

Which Na is responsible for conduction of pain signals

A

NA 1.8

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11
Q

What can targeting NA 1.8 do as pain killers

A

It is an important drug target to block pain by non-opioid mechanism

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12
Q

What is the major neurotransmitter plays an important role in pain conduction in spinal cord

A

Glutamate

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13
Q

lobj
What are the dfferent pain fibers present in the body

A

AB fibers
Aδ fibers
C fibers

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14
Q

what is the AB fiber important for? Structural features?

A

conducting non-noxious (not pain related). Producing touch + pressure.
Thick Myelin coating and very fast. No pain.

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15
Q

What are Aδ fibers important for? structura features?

A

Important for pain and cold.

Myelinated (not as thick as AB fibers), fast but slower than AB.

1st pain, sharp prickly

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16
Q

What are C fibers important for?

A

Prolonged pain.
Temeprature, touch, pressure, itch

unmyelinated, slow, second pain (dull, achy)

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17
Q

What neurotransmitter plays an important role in heightening pain

A

Substance P

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18
Q

What does repeated firing do to firing threshold

A

Repeated stimuli REDUCES firing threshold

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19
Q

What is substance P? What is it used for?

A

Substance P is a peptide released during injury/insult.
It stimulates 1. Vasodilation
2. Degranulation of mast cells
3. Release of histamine
4. Inflammations and prostaglandins

Increase in expression of pain receptors known as peripheral sensitization

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20
Q

In neuropathic pain sensitization, what does nerve injury lead to

A

Peripheral nerve degeneration (neuroma)

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21
Q

in peripheral nerve sensitization, what occurs after peripheral nerve degeneration

A

3 things-
1. spontaneous afferent activity
2. Spinal sensitization
AB afferent fibers

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22
Q

Describe spontaneous afferent activity caused by peripheral nerve sensitization. (EXAM)

A

afferent neuron carrying information begins tofire due to expression of NA channel subtypes, contributing to increased cellular excitability and generation of ectopic action potential.

Leads to spontaneous dysthesia, ahooting, burning pain

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23
Q

Describe spinal sensitization caused by peripheral nerve sensitization

A

due to neuropeptides being released (CGRP, substance P and glutamate) in spinal cord, leads to AMPA and NMDA expression and sensitivity.

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24
Q

What does AMPA and NMDA expression and sensitivity of spinal sensitization lead to

A

leads to spontaneous dysthesia (shooting, burning pain) and allodynia (light touch hurt)

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25
Q

What does AB afferent fibers lead to in nerve injurt/nerve sensitization

A

leads to allodynia (light touch hurt) as a result of increased AMPA and NMDA expression and sensitivity

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26
Q

What is the pain circulatory system in the brain

A

Peripheral injury sends info to the spinal cord

Spinal cord sends info to brain for processing

There are high expressions of opioid receptors in brainstem along descending pathway (inhibit transmission into brain)

Mu Opioid receptor plays an important role in modulation of pain signals in CNS

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27
Q

What does activation of Mu opioid in brain do?

A

alter mood
Produce sedation
Reduce emotional rxn

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28
Q

What does Mu opioid receptor in brainstem do?

A

increases activity of descending fibers

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29
Q

What does Mu opioid receptor in brain do?

A

-alter mood
-produce seation
-reduce emotional rxn

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30
Q

What does Mu opioid receptor in spinal cord do?

A

Inhibit vesicle release
hyperpolarize post synaptic membrane

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31
Q

What does Mu opioid receptor in periphery do?

A

-reduce activation of primary afferent neurons
-modulate immune activity

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32
Q

What are the two types of alkaloids contained in opioids

A

-Phenanthrenes
-Benzylisoquinalones

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33
Q

What are the types of phenanthrenes? Types of benzylisoquinolones?

A

Phenanthrenes- Morphines
codeine
Thebaine

Benzylisoquinolone- Noscapine
Papaverine

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34
Q

What are the opioids that occur naturally called?

A

Opiates

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35
Q

Explain the SAR pf phenanthrenes

A

3 position substitution ester or esther products decrease potency (codeine)
6 position increases activity (hydromorphone or hydrocodone)
14 position OH has increased potency (oxycodone)

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36
Q

What are the names of some peptides active endogenously

A

Pro-opiomelanocortin (POMC)
Preproenkephalin
preprodynorphin
Nociceptin/orphanin

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37
Q

What is pro-opiomelanocortin (POMC) cleaved to? What does it then act on?

A

Cleaved to B endorphin and acts on Mu opioid receptor

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38
Q

What is preproenkephain cleaved to? What does it then act on?

A

Preproenkephalin is cleaved to
1)leu-enkephalin- which ats on delta opioid receptor
2)Met-enkephalin- which acts on Mu and delta receptors

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39
Q

What is preprodynorphan cleaved to? What does it act on?

A

cleaved to Dynorphan which acts on Kappa opioid receptors

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40
Q

What are the main opioid receptors

A

Mu Opioid receptors
Kappa Opioid receptors
Delta opioid receptors

They are all GPCR Gi coupled

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41
Q

What are the endogenous compounds that act on the Opioid receptors

A

Mu-endorphin
Kappa- dynorphin
Delta- enkephalin
nociceptin- nociceptin

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42
Q

How do opioids work at a molecular level to reduce firing of pain signals

A

Action of opioids open K channels to hyperpolarize membrane and close calcium channel. This makes it harder for neurons to fire.

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43
Q

opioid receptor of sigma molecule

A

does not exisyt

44
Q

Presynaptic and post synaptic action of opioid receptors

A

Presynaptic- inhibits Ca channel, decrease in neurotransmitter release

Postsynaptic- activate GIRK channel. efflux of K+, leading to hyperpolarization

45
Q

Where do B-endorphins come from?

A

B endorphins are the endogenous opioids that work on Mu opioid receptors.

Come from pro-opiomelanocortin

46
Q

What is the therapeutic use of Mu opioid receptor

A

Analgesia
Sedation
Antitussive

47
Q

What type of analgesis is My opioid receptors involved in?

A

Not as effective for chronic pain, useful for acute pain. Can be used for cancer pain, palliative pain and PCA.

48
Q

Opioid induced side effects are mostly

A

ON TARGET effects

49
Q

What does it mean that Mu opioid side effects are mostly on target

A

This means that they are a result of action of mu opioid receptor activation

50
Q

What are the side effects associated with opioids

A

Respiratory depression (action in brainstem and medulla)

Constipation and GI tract

Pruritis (Itch)- not allergic response

Addiction- nucleus accumbens

Urine retention

N/V

Miosis- caused by oculomotor nerve

51
Q

can we use some opioids as antidiarrhea meds

A

Yes, Some opiods do not cross BBB

52
Q

Kappa opioid natural ligand? Effect on body? therapeutic use?

A

preprodynorphin, dynorphin is natural ligand.

Activation is dysphoric (negative effect)

Potential use for treatment of addiction, reduce dopamine release.

Opposite effect of Mu opioid receptor

53
Q

Delta opioid receptor natural ligand? adverse effects in body?

A

Enkephalin is natural ligand

Role in hypoxia, ischemia, stroke.

Hypernation also includes release of enkephalin opioid.

54
Q

Use of Delta Opioid receptors

A

reduce anxiety and depression
Treat alcoholism
Relieve hyperalgesia, chronic pain

NO FDA approved delta opioid (seizure is side effect)

55
Q

What are opioid sites of action ion the brain. Uses of these areas

A

Nucleus accumbens and ventral tegmental area (VTA)

both important for reward. Linked to addiction.

All substances of abuse have connection in this circuit.

56
Q

How do opioids affect VTA and nuc acc and GABA

A

Opioid peptides and neurons have connections to Nuc Acc and into GABAergic interneuron (main inhibitory neuron in brain)

GABA is inhibited by opioid receptors increasing dopamine and reward

57
Q

Can depressants cause opioid release

A

Yes

58
Q

How addiction happens in opioids

A

Opioid binds to Mu receptor
GI signalling inhibits GABA release
Less GABA to activate GABA a
Less inhibition of dopamine neuron activity
increase dopamine release
leads to addiction

59
Q

Administration routes of opioids

A

IV
IM
oral
Topical
epidermal

60
Q

PK of the different routes of administration of opioids

A

Oral dose- slow rise. We want it to go past analgesia threshold, but below CNS side effect
SC/IM- fast rise/fast fall
IV- Rapid rise in concentration, much greated risk of side effects

61
Q

PK of morphine? Fentanyl?

A

Morphine has slow rise
Fentanyl has rapid peak

62
Q

Explain the metabolism and bioavailability of morphine

A

Readily absorbed, significant 1st pass metabolism
Bioavailability 25%

63
Q

Enzymes for morphine absorption

A

Hepatic- 2D6 and 3A4

64
Q

Excretion of morphine

A

glomerular filtration (kidney)

65
Q

What are some opioids that are prodrugs

A

Heroin, Codeine, tramadol

66
Q

Which opioids do not produce active metabolites

A

Fentanyl and methadone

67
Q

How does lipophilicity influence onset/duration of opioids? Give examples

A

Morphine- low lipophilicity, slower passage, prolonged duration of action

Fentanyl- high lipophilicity, rapid onset, short durationC

68
Q

Codeine is metabolized to

A

Morphine and hydrocodone

69
Q

Heroin is metabolized to

A

Morphine

70
Q

What is the enzyme that transforms codeine to morphine

A

2D6

71
Q

Which enzyme is responsible for making the Nor- metabolites (norhydrocodone, noroxymorphone)

A

CYP3A4

72
Q

Mnemonic to remember 3A4 and nor

A

Four=Nor=less active

73
Q

Which enzymes play an important role in drug-drug interaction in opioids

A

2D6 and 3A4

74
Q

What are the types of metabolizers of oipioids

A

PM-poor metabolizer
IM- intermediate metabolizer
EM- extensive metabolizer
UM- ultra rapid metabolizer

75
Q

Which phenotype causes more side effects

A

ultra rapid metabolizer

76
Q

Which phenotype has no therapeutic effect from codeine

A

PM

77
Q

How potent is fentanyl? What is it used for?

A

100x more than morphine
50x more than heroine
used for palliative care and breakthrough pain

78
Q

What are some opioid agonists that are used in hospital procedures

A

fentanyl (sufentanil, remifentanil)- Anesthesia/sedation.
break down is by plasma esterase due to esther linkage

hydromorphone, oxymorphone- no opioid active metabolite

morphine

hydrocodone/oxycodone

79
Q

What are some non-phenanthrene opioids

A

Tramadol
Maperidine
Methadone

80
Q

What kind of drug is tramadol? What is it used for?

A

Tramadol is a drug with SNRI like properties that is used as a painkiller

81
Q

What is Meperidine used for? Toxic metabolite name? What does this toxic metabolite lead to?

A

Used to treat rigors.

Has a toxic metabolite called normeperidine.

Metaboliet is devoid of analgesic activity and has neurotoxic effects.

Not recommended without good justification.

82
Q

What is an opioid that is an NMDA antagonist

A

Methadone

83
Q

WHat is methadone used for? Side effects?

A

Methadone- primarily used for opioid dependence. Causes prolonged QTc.

84
Q

Why would we want to block NMDA receptors?

A

NMDA is important for the conduction of pain signals. Blocking this leads to blocking pain signals.

85
Q

What are some opioids used as antitussives

A

Codeine
Dextromethorphan- limited opioid activity

86
Q

What are some anti-diarrheal opioids? How do they act?

A

Diphenoxylase
Loperamide
Eluxadone

Slow GI tract and lower diarrheal

87
Q

What are some opioids that act in MOR (Mu) and KOR (kappa) that are used for moderate pain

A
  1. Pentazocine and butorphanol
  2. Nalbuphine
    3, Buprenorphine
88
Q

How do Pentazocine and butorphanol act? Side effects?

A

K agonist and partial agonist/antagonist at Mu

side effects- Less dysphoria
Hallucinations
increased HR and BP

89
Q

How does Nalbuphine work?

A

Full agonist at K, antagonist at Mu

90
Q

How does buprenorphine work? What is it used for?

A

Partial Mu agonist, weak K agonist and gamma antagonist.
Primarliy used in opioid replacement therapy

91
Q

Preventative and acute management of constipation

A

Senna
PEG
Sodium docusate

92
Q

Biggest risk of death in opioid withdrawn patients

A

Respiratory depression

93
Q

What is opioid induced hyperalgesia?

A

Occurs when there is a prolonged exposure to opiates and a secondary pain pathway begins to form.

94
Q

What is opioid induced hyper algesia linked to neurotransmitter wise

A

Glutamate

95
Q

will giving more opioid give an analgesic effect in opioid induced hyperalgesia

A

Giving more opioid will not give analgesic effects because of the glutamate pathway

96
Q

Symptoms with limited/no tolerance

A

Constipation
Itching
Miosis

97
Q

Treatments for opioid dependence

A
  1. methadone- full agonist
  2. Buprenorphine- partial agonist
  3. Naltrexone/Narcan- antagonist
98
Q

How does Methadone treat opioid dependence

A

Provides relief from withdrawal.

Slow acting (reduced risk of high) 2-4 hrs

Slow PK- accumulates with repeated doses

NMDA antagonist

99
Q

How does Buprenorphine treat opioid dependence

A

Blocks full agonist effect of heroin as an antagonist
provides some activation as agonist to prevent withdrawal

subutex- Some abuse potential

100
Q

How does Naltrexone treat opioid dependence?

A

Antagonist taken once month IM inj

Decent oral bioavailability.

101
Q

Are Naloxone and Naltrexone interchangeable?

A

Naloxone- antidote for OD, limited oral bioavailability, rapid onset, short t1/2

Naltrexone- Decent oral bioavailability, medium half life

Not interchangeable

102
Q

How often to give naloxone to a patient that has overdosed and is going through respiratory depression

A

Repeat every 2-5 minutes if not conscious (short half life and rapid onset)

103
Q

Effect of opioid abuse on neonates?

A

Causes serious withdrawal lasting 4-6 months and may even cause seizures

104
Q

How to treat neonatal abstinence syndrome non pcol

A

Swaddling, hypercaloric formula, frequent feedings, observation (sleep, weight gain/loss, temperature), Rehydration

105
Q

How to treat neonatal abstinence syndorme Pcol

A

Morphine sulphate
Buprenorphine sublingua
Methadone

Morphine and buprenorphine linked with shorter hospital stay
than methadone

106
Q

summary for opioid receptors

A

μ (Mu) Opioid

  • Analgesia, euphoria and mood
    effects, respiratory depression,
    miosis, neuroendocrine
    regulation, decreased GI motility,
    autonomic regulation, tolerance
    and withdrawal

Endorphins > Enkephalins >
Dynorphins

κ (Kappa) Opioid

Analgesia, diuresis, sedation,
dysphoria and psychotomimetic,
less miosis, less respiratory
depression, little dependence

Dynorphins&raquo_space; Endorphins and
Enkephalins

δ (Delta) Opioid

Analgesia, mood, reduced anxiety,
ischemic protection, little
dependence

Enkephalins > Endorphins and
Dynorphins

Orphanin Opioid-Receptor-Like
Subtype 1 (ORL1), Nociceptin
cntroversy actions
opposes classic μ effects,
mediate pain
Nociceptin /Orphanin FQ
40

Therapeutics (38 decks)

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