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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
What does AB afferent fibers lead to in nerve injurt/nerve sensitization
leads to allodynia (light touch hurt) as a result of increased AMPA and NMDA expression and sensitivity
26
What is the pain circulatory system in the brain
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
27
What does activation of Mu opioid in brain do?
alter mood Produce sedation Reduce emotional rxn
28
What does Mu opioid receptor in brainstem do?
increases activity of descending fibers
29
What does Mu opioid receptor in brain do?
-alter mood -produce seation -reduce emotional rxn
30
What does Mu opioid receptor in spinal cord do?
Inhibit vesicle release hyperpolarize post synaptic membrane
31
What does Mu opioid receptor in periphery do?
-reduce activation of primary afferent neurons -modulate immune activity
32
What are the two types of alkaloids contained in opioids
-Phenanthrenes -Benzylisoquinalones
33
What are the types of phenanthrenes? Types of benzylisoquinolones?
Phenanthrenes- Morphines codeine Thebaine Benzylisoquinolone- Noscapine Papaverine
34
What are the opioids that occur naturally called?
Opiates
35
Explain the SAR pf phenanthrenes
3 position substitution ester or esther products decrease potency (codeine) 6 position increases activity (hydromorphone or hydrocodone) 14 position OH has increased potency (oxycodone)
36
What are the names of some peptides active endogenously
Pro-opiomelanocortin (POMC) Preproenkephalin preprodynorphin Nociceptin/orphanin
37
What is pro-opiomelanocortin (POMC) cleaved to? What does it then act on?
Cleaved to B endorphin and acts on Mu opioid receptor
38
What is preproenkephain cleaved to? What does it then act on?
Preproenkephalin is cleaved to 1)leu-enkephalin- which ats on delta opioid receptor 2)Met-enkephalin- which acts on Mu and delta receptors
39
What is preprodynorphan cleaved to? What does it act on?
cleaved to Dynorphan which acts on Kappa opioid receptors
40
What are the main opioid receptors
Mu Opioid receptors Kappa Opioid receptors Delta opioid receptors They are all GPCR Gi coupled
41
What are the endogenous compounds that act on the Opioid receptors
Mu-endorphin Kappa- dynorphin Delta- enkephalin nociceptin- nociceptin
42
How do opioids work at a molecular level to reduce firing of pain signals
Action of opioids open K channels to hyperpolarize membrane and close calcium channel. This makes it harder for neurons to fire.
43
opioid receptor of sigma molecule
does not exisyt
44
Presynaptic and post synaptic action of opioid receptors
Presynaptic- inhibits Ca channel, decrease in neurotransmitter release Postsynaptic- activate GIRK channel. efflux of K+, leading to hyperpolarization
45
Where do B-endorphins come from?
B endorphins are the endogenous opioids that work on Mu opioid receptors. Come from pro-opiomelanocortin
46
What is the therapeutic use of Mu opioid receptor
Analgesia Sedation Antitussive
47
What type of analgesis is My opioid receptors involved in?
Not as effective for chronic pain, useful for acute pain. Can be used for cancer pain, palliative pain and PCA.
48
Opioid induced side effects are mostly
ON TARGET effects
49
What does it mean that Mu opioid side effects are mostly on target
This means that they are a result of action of mu opioid receptor activation
50
What are the side effects associated with opioids
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
can we use some opioids as antidiarrhea meds
Yes, Some opiods do not cross BBB
52
Kappa opioid natural ligand? Effect on body? therapeutic use?
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
Delta opioid receptor natural ligand? adverse effects in body?
Enkephalin is natural ligand Role in hypoxia, ischemia, stroke. Hypernation also includes release of enkephalin opioid.
54
Use of Delta Opioid receptors
reduce anxiety and depression Treat alcoholism Relieve hyperalgesia, chronic pain NO FDA approved delta opioid (seizure is side effect)
55
What are opioid sites of action ion the brain. Uses of these areas
Nucleus accumbens and ventral tegmental area (VTA) both important for reward. Linked to addiction. All substances of abuse have connection in this circuit.
56
How do opioids affect VTA and nuc acc and GABA
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
Can depressants cause opioid release
Yes
58
How addiction happens in opioids
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
Administration routes of opioids
IV IM oral Topical epidermal
60
PK of the different routes of administration of opioids
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
PK of morphine? Fentanyl?
Morphine has slow rise Fentanyl has rapid peak
62
Explain the metabolism and bioavailability of morphine
Readily absorbed, significant 1st pass metabolism Bioavailability 25%
63
Enzymes for morphine absorption
Hepatic- 2D6 and 3A4
64
Excretion of morphine
glomerular filtration (kidney)
65
What are some opioids that are prodrugs
Heroin, Codeine, tramadol
66
Which opioids do not produce active metabolites
Fentanyl and methadone
67
How does lipophilicity influence onset/duration of opioids? Give examples
Morphine- low lipophilicity, slower passage, prolonged duration of action Fentanyl- high lipophilicity, rapid onset, short durationC
68
Codeine is metabolized to
Morphine and hydrocodone
69
Heroin is metabolized to
Morphine
70
What is the enzyme that transforms codeine to morphine
2D6
71
Which enzyme is responsible for making the Nor- metabolites (norhydrocodone, noroxymorphone)
CYP3A4
72
Mnemonic to remember 3A4 and nor
Four=Nor=less active
73
Which enzymes play an important role in drug-drug interaction in opioids
2D6 and 3A4
74
What are the types of metabolizers of oipioids
PM-poor metabolizer IM- intermediate metabolizer EM- extensive metabolizer UM- ultra rapid metabolizer
75
Which phenotype causes more side effects
ultra rapid metabolizer
76
Which phenotype has no therapeutic effect from codeine
PM
77
How potent is fentanyl? What is it used for?
100x more than morphine 50x more than heroine used for palliative care and breakthrough pain
78
What are some opioid agonists that are used in hospital procedures
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
What are some non-phenanthrene opioids
Tramadol Maperidine Methadone
80
What kind of drug is tramadol? What is it used for?
Tramadol is a drug with SNRI like properties that is used as a painkiller
81
What is Meperidine used for? Toxic metabolite name? What does this toxic metabolite lead to?
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
What is an opioid that is an NMDA antagonist
Methadone
83
WHat is methadone used for? Side effects?
Methadone- primarily used for opioid dependence. Causes prolonged QTc.
84
Why would we want to block NMDA receptors?
NMDA is important for the conduction of pain signals. Blocking this leads to blocking pain signals.
85
What are some opioids used as antitussives
Codeine Dextromethorphan- limited opioid activity
86
What are some anti-diarrheal opioids? How do they act?
Diphenoxylase Loperamide Eluxadone Slow GI tract and lower diarrheal
87
What are some opioids that act in MOR (Mu) and KOR (kappa) that are used for moderate pain
1. Pentazocine and butorphanol 2. Nalbuphine 3, Buprenorphine
88
How do Pentazocine and butorphanol act? Side effects?
K agonist and partial agonist/antagonist at Mu side effects- Less dysphoria Hallucinations increased HR and BP
89
How does Nalbuphine work?
Full agonist at K, antagonist at Mu
90
How does buprenorphine work? What is it used for?
Partial Mu agonist, weak K agonist and gamma antagonist. Primarliy used in opioid replacement therapy
91
Preventative and acute management of constipation
Senna PEG Sodium docusate
92
Biggest risk of death in opioid withdrawn patients
Respiratory depression
93
What is opioid induced hyperalgesia?
Occurs when there is a prolonged exposure to opiates and a secondary pain pathway begins to form.
94
What is opioid induced hyper algesia linked to neurotransmitter wise
Glutamate
95
will giving more opioid give an analgesic effect in opioid induced hyperalgesia
Giving more opioid will not give analgesic effects because of the glutamate pathway
96
Symptoms with limited/no tolerance
Constipation Itching Miosis
97
Treatments for opioid dependence
1. methadone- full agonist 2. Buprenorphine- partial agonist 3. Naltrexone/Narcan- antagonist
98
How does Methadone treat opioid dependence
Provides relief from withdrawal. Slow acting (reduced risk of high) 2-4 hrs Slow PK- accumulates with repeated doses NMDA antagonist
99
How does Buprenorphine treat opioid dependence
Blocks full agonist effect of heroin as an antagonist provides some activation as agonist to prevent withdrawal subutex- Some abuse potential
100
How does Naltrexone treat opioid dependence?
Antagonist taken once month IM inj Decent oral bioavailability.
101
Are Naloxone and Naltrexone interchangeable?
Naloxone- antidote for OD, limited oral bioavailability, rapid onset, short t1/2 Naltrexone- Decent oral bioavailability, medium half life Not interchangeable
102
How often to give naloxone to a patient that has overdosed and is going through respiratory depression
Repeat every 2-5 minutes if not conscious (short half life and rapid onset)
103
Effect of opioid abuse on neonates?
Causes serious withdrawal lasting 4-6 months and may even cause seizures
104
How to treat neonatal abstinence syndrome non pcol
Swaddling, hypercaloric formula, frequent feedings, observation (sleep, weight gain/loss, temperature), Rehydration
105
How to treat neonatal abstinence syndorme Pcol
Morphine sulphate Buprenorphine sublingua Methadone Morphine and buprenorphine linked with shorter hospital stay than methadone
106
summary for opioid receptors
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 >> 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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