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PHS 931 > Block 3 Lecture 4 -- Pain Pathways and Non-opioid Analgesics, and Lecture 5 Opioids > Flashcards

Block 3 Lecture 4 -- Pain Pathways and Non-opioid Analgesics, and Lecture 5 Opioids Flashcards

1
Q

When is amantadine preferred?

A

new patients with mild symptoms

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2
Q

What are the chemical mediators of pain?

A

1) bradykinin
2) 5-HT
3) neuropeptides
4) ATP, K+
5) chemokines
6) PGE2
7) Na, Ca, Glu ion channels
8) ASICs
9) TRPV1

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3
Q

What neuropeptides mediate pain?

A

CGRP: calcitonin-gene-related peptide– especially in migraine

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4
Q

What is TRPV1?

A

transient receptor potential vanilloid-1 channel– Ca-permeable ionotrope activated by protons

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5
Q

Where are protons as a source of pain produced?

A

1) tumor
2) heat
3) inflammation
4) capsaicin
5) gaseous anesthetics

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6
Q

What are the 3 important factors to treating pain?

A

1) site of drug action
2) timing
3) nature of pain

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7
Q

What drugs target the site of pain initiation?

A

1) methylene blue

2) ASA, NSAIDs

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8
Q

What drugs target the transmission pathway of pain?

A

local anesthetics

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9
Q

What is methylene blue?

A

neurotoxicant; injection destroys nerve endings

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10
Q

What drugs target the spinal cord?

A

1) topical counterirritants

2) transcutaneous electrical nerve stimulation

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11
Q

What is capsaicin’s MoA? Any counseling points?

A

TRPV1 agonist

2-4 weeks for max efficacy

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12
Q

How do topical counterirritants work?

A

reduce referred pain in same dermatome

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13
Q

What things act on the spinothalamic tract fibers to reduce pain?

A

1) EtOH (kill fiber)

2) anterolateral cordotomy

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14
Q

What things act on the spinal cord and brain to reduce pain?

A

opioids

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15
Q

What are the benefits of pre-emptive acute pain treatment?

A

decreases risk of progression from acute to chronic pain

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16
Q

What things are known pruritogens?

A

1) histamines

other chemicals, drugs

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17
Q

What mediates itch?

A

MrgrprA3 (mas-related GPCR)

    • not a sub-modality of pain
    • ALST
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18
Q

Differentiate COX-1 vs. COX-2 structure.

A

COX-2 has 523 Val (allows larger side chain)

COX-1 has Ile 523

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19
Q

What are prostanoids?

A

all the products of COX pathway

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20
Q

What are eicosanoids?

A

20C metabolites of arachidonic acid

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21
Q

What are the effects of PGE2?

A

1) pain
2) inflammation
3) inhibit acid secretion
4) increase GI mucous, bicarb
5) maintain renal blood flow; increase Na/H2O excretion

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22
Q

What are the effects of TXA2?

A

1) vasoconstriction

2) platelet aggregation

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23
Q

What are the effects of PGI2?

A

1) vasodilation, esp. mucosal
2) increase GI mucous, bicarb
3) inhibit GI acid secretion
4) maintain renal blood flow; increase Na/H2O excretion
5) platelet disaggregation

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24
Q

What are the major COX-1 products?

A

PGE2 + TXA2

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25
Q

What are the major COX-2 products?

A

PGE2 + PGI2

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26
Q

What are the beneficial effects of inhibiting COX?

A

1) Analgesia
2) antipyresis
3) platelet disaggregation
4) anti-inflammatory
5) reduced cancer risk
6) reduced dysmenorrhea symptoms

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27
Q

What are the bad effects of inhibiting COX?

A

1) GI
2) uncoupled oxidative phosphorylation
3) decreased renal blood flow
4) erythema

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28
Q

What forms of cancer does COX inhibition reduce risk of?

A

1) colorectal
2) gastric
3) lung
4) breast
5) ovarian
6) prostate
7) skin

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29
Q

How does COX inhibition decrease cancer risk?

A

1) decreased inflammation
- - decreased cell turnover
2) +apoptosis
3) decreases angiogenesis
4) decreases cell proliferation

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30
Q

What are adjuncts to reduce GI side effects?

A

1) H2RAs
2) PPIs
3) PGE analog misoprostol
4) anti-H. pylori
5) antacids
6) acid-barriers

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31
Q

What are acid-barriers for GI adjunct?

A

sucralfate

– no evidence of efficacy

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32
Q

What are risk factors for GI ADRs?

A

1) h. pylori
2) h/o GI bleed
3) oral anticoag
4) long-term NSAID tx
5) hi NSAID dose
6) smoking
7) EtOH
8) CVD

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33
Q

How do NSAIDs compare to ASA in decreasing renal blood flow?

A

NSAIDs more effective

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34
Q

How does ASA differ from other salicylates and NSAIDs?

A

ASA irreversibly inhibits COX-1

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35
Q

What are topical forms of salicylates?

A

methyl salicylate
triethanolamine salicylate
bismuth subsalicylate

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36
Q

What are the secondary MOAs of salicylates?

A

1) increases endocannabinoids
2) inhibits spinal nociceptive processing by 5-HT, NE, ACh
3) decreases NO production

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37
Q

What’s the usual ASA dose for kids and adults?

A 
kids = 10 mg/kg
adults = 10-15 mg/kg
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38
Q

What defines ASA intolerance? What’s the prevalence compared to hypersensitivity?

A

intolerance = proven hypersensitivity or severe indigestion after low-dose ASA
6-20% vs. 0.6-2.5% hypersensitivity

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39
Q

Are salicylates cross-reactive in allergy to NSAIDs?

A

Yes – altered eicosanoid metabolism

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40
Q

What are the ADRs of salicylates?

A

1) fecal occult blood loss
- - 1.2 g/day = 4.5 mL
- - 3.6 g/day = 11.2 mL
- - menses = 1-2mL
2) acute GI hemorrhage
- - dose, not duration-related

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41
Q

What are ASA interactions?

A

1) GI irritants (EtOH)
2) PPB
- - sulfonylureas, valproate, oral anticoag
3) drugs competing for URAT1

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42
Q

Where is URAT1 located?

A

proximal tubule

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43
Q

What is the pregnancy category of ASA?

A

C – no evidence

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44
Q

What are the recommendations of ASA during pregnancy?

A
    • avoid 2 weeks prior to delivery

- - lo-dose daily ASA in 1st trimester lowers preeclampsia risk in hi-risk women

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45
Q

What is the current pre-eclampsia cure?

A

premature delivery

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46
Q

What are the effects of ASA on pregnancy?

A

1) not effective in preventing further pregnancy losses
2) increases duration of labor
3) increases complicated deliveries and still-births
4) increases bleeding in newborn and during elivery

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47
Q

How is ASA poisoning treated?

A

1) lavage, charcoal
- - if EC, whole body irrigation
2) hydrate
3) alkalinize urine with bicarb to 7.8-8

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48
Q

What nomogram for ASA poisoning?

A

Done

– no indication of severity until 6h

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49
Q

What are the symptoms of ASA poisoning?

A

1) 20 mg/dL = tinnitus
2) 35 = respiratory alkalosis
3) 50-80 = n/v, fever, lethargy/excitability
4) severe = medullary depression, metabolic acidosis

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50
Q

Why does metabolic acidosis occur in ASA OD?

A

1) medullary depression
2) accumulation of metabolic acids and decreased renal fx
3) fat catabolism = ketoacids
4) inability to buffer

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51
Q

What is the toxic level for child/adult?

A

160mg/dL

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52
Q

What are the uses of ASA?

A

1) mi/stroke/vascular prophylaxis in those with CVD
2) daily ASA to decrease cancer mortality 16%
- - efficacy increases after 5 years
- - GI, colorectal, esophageal best

53
Q

What are contraindications to NSAID use?

A

1) ASA-associated asthma
2) hypersensitivity to asthma
3) 3rd trimester

54
Q

What are the ADRs of NSAIDs?

A

1) non-selective CV risk (VT)
2) GI (stomach more than duodenal)
3) nephrotoxicity
4) renal cell cancer
5) hepatotoxicity

55
Q

Why can NSAIDs be hepatotoxic?

A

metabolites form covalent adducts with proteins

– form immunogen

56
Q

What are the forms of nephrotoxicity from NSAID use?

A

1) acute renal failure
- - reversible, dose- and duration-dependent
2) renal papillary necrosis
- - hypoxia
3) nephrotic syndrome with acute interstitial nephritis
- - hypersensitivity, days to develop
- - reversible

57
Q

What are signs of nephrotoxicity?

A

hyperNa, hyperK, hyperCl; edema

58
Q

When should you use NSAIDs with caution due to potential nephrotoxicity?

A

1) low GFR
2) low Na
3) heart failrue
4) liver disease
5) diabetes
6) ACE inhibitors

59
Q

What are the tNSAIDs selective for COX-2?

A

meloxicam
diclofenac
etodolac

60
Q

What does APAP stand for?

A

acetyl-para-amino phenol

61
Q

What are the ADRs of celecoxib?

A

1) increased MI risk
2) sulfa allergy
3) HA, GI
- - but fewer GI ulcers than tNSAIDs

62
Q

How is celecoxib metabolized?

A

2C9

– inhibits 2D6

63
Q

What are the CV ADRs of NSAIDs?

A

1) increased CV risk in cardiac patients
- - least=naproxen; most=diclofenac
2) bleeding risk doubled for anti-coag patients

64
Q

How to limit CV risk in cardiac NSAID patients?

A

most COX-1 selective
min dose
min duration

65
Q

What is the MoA of APAP?

A

1) selective COX-2 inhibitor mainly in brain
2) stimulates descending serotonergic pathways
- - inhibits afferent pain fibers
3) CB1r agonist

66
Q

Describe A for APAP.

A

1) good oral F
2) interpatient variability for rectal
3) IV available

67
Q

Describe metabolism of APAP?

A

80% metabolized in liver

    • most via UGT (60%) or SULT (30%)
    • 10% via CYP2E1 to yield imine
    • imine detox by GST

can inhibit 3A4
half-life = 2h

68
Q

What are ADRs of APAP?

A

1) INR increase
- - if warfarin metabolized by 3A4 and 2C9
2) increased asthma risk in kids exposed to APAP in utero

69
Q

What’s the APAP toxicity level?

A

7.5-10g in adults

150 mg/kg in kids

70
Q

What is used to evaluate APAP toxicity?

A

Rumack-Matthew Nomogram

71
Q

How is APAP toxicity treated?

A

N-acetylcysteine

– effective if given in 8-10h

72
Q

Describe toxicity symptoms of APAP.

A

6-14 h
– non-specific flu-like sxs
3-5 days
– acute liver and/or renal failure

73
Q

Why can’t you use alcohol with APAP?

A

EtOH induces 2E1 (imine metabolism)

    • toxicity with less than 2-4g/day
    • concurrent EtOH use increases renal risk 2x
74
Q

How do opioids generally compare to non-opioids?

A

1) greater efficacy
2) good for visceral pain
3) central action
4) structurally homogeneous

75
Q

How do the opioids vary?

A

source and structure

– C3, 6, 17

76
Q

What is the structure of endorphins?

A

31aa w/ met-enkephalin

77
Q

What is the structure of dynorphins?

A

13-17aa w/ leu-enkephalin

78
Q

What is structure of enkephalins?

A

5aa: Tyr-Gly-Gly-Tyr +leu or met

79
Q

What are the effects of mu1 agonism?

A

1) supraspinal analgesia
2) sedation
3) euphoria
4) physical dependence

80
Q

What are the effects of mu2 agonism?

A

1) spinal analgesia
2) sedation
3) respiratory depression
4) GI immobility

81
Q

What are the effects of delta1/2 agonism?

A

1) analgesia
2) anti-depressant
3) dependence
4) respiratory depression
5) fewer GI effects

82
Q

What are the effects of kappa1/2/3 agonism

A

1) GI immobility
2) sedation
3) diuresis
4) DYSPHORIA

83
Q

How do kappa receptors vary?

A

1 is spinal

2, 3 are supraspinal

84
Q

Describe A of morphine.

A

Fpo,rectal = 25%
– first pass
Finj = 50%

85
Q

Describe PPB of morphine

A

35%

86
Q

Describe M for morphine

A

t1/2 = 2 hr
UGT2B7
– 90% yields M3G
– 10% yields M6G

87
Q

What is morphine-6-glucuronide?

A

active morphine metabolite

    • 100x more affinity
    • can be formed and trapped in brain
88
Q

What morphine isomers are active for antitussive? What do these isomers lack?

A

D-isomers of HC, DM, codeine

– lack analgesia, respiratory depression, tolerance, drowsiness

89
Q

Opioid tolerance does not occur to…

A

1) miosis
2) GI
3) smooth muscle tone

4) kappa agonists/mu antagonists

90
Q

What are the effects of morphine opioids?

A

1) euphoria
2) satiation
3) sedatoin
4) analgesia
5) respiratory depression
6) antitussive
7) hypothermia
8) miosis
9) n/v
10) decreased cardiac work
11) increased sm tone
12) histamine release

91
Q

What are symptoms of opioid-induced, non-allergic histamine release?

A

1) pruritis
2) flushing
3) hypotension
- - no hives, bronchoconstriction, edema

92
Q

How do opioids cause respiratory depression?

A

1) decreased neurogenic drive

2) decreased CO2 response

93
Q

How do opioids act as analgesics?

A

1) increase pain threshold

2) change pain perception (limbic connection)

94
Q

What are morphine’s effects on CV system?

A

1) decreased left ventricular diastolic pressure
2) decreased cardiac work
3) decreased venous return

no HR/CO effect
not with mixed agents

95
Q

What is fibromyalgia?

A

chronic disorder mainly affecting females characterized by chronic, non-malignant pain, fatigue, and sleep problems

96
Q

How is fibromyalgia treated?

A

muscle relaxants
anticonvulsants
antidepressants

Opioid efficacy lacking

97
Q

How is low-back pain treated?

A

1) acute: NSAIDs/APAP, muscle relaxants, PT
2) chronic: strengthening

not opioids
– increases time from work and medical expenses

98
Q

How does codeine compare to morphine?

A

more complete absorption

lower abuse potential

99
Q

What is the WHO model for pain treatment?

A

Step 1: mild-moderate
Step 2: mild-moderate or Step 1 failure
Step 3: moderate-severe or step 2 failure

100
Q

What is Step 1 in the who model?

A

non-opioid +/- adjuvant

101
Q

What is Step 2 in the who model?

A

short-acting prn
+/- non-opioid ATC
+/- adjuvant

102
Q

What is step 3 in the who model?

A

SR opioid ATC
+/- short-acting
+/- adjuvant

103
Q

What is the MoA of caffeine?

A

1) A2 antagonist
- - cerebrovasoconstriction
2) increases rate and extent of drug absorption
3) increases analgesic activity

104
Q

MoA of buprenorphine

A

partial mu agonist

kappa antagonist

105
Q

MoA of butorphanol

A

kappa agonist

mu antagonist

106
Q

MoA of pentazocine

A

kappa agonist

mu antagonist

107
Q

MoA of tramadol

A

weak mu agonist

NET, SERT inhibition

108
Q

How is hydrocodone metabolized?

A

1) 2D6 O-demethylation (hydromorphone, 2D6 variability)

2) 3A4 N-demethylation (norhydrocodone, weak active)

109
Q

How is methadone used?

A

1) analgesic
2) opioid detox
3) maintenance of detox

110
Q

How is fentanyl metabolized?

A

3A4, 2.5-12h half-life

111
Q

How is meperidine used?

A

moderate acute pain for 24-48h max

– active metabolite accumulates in brain

112
Q

Diphenoxylate MoA

A

synthetic meperidine-like opioid with poor CNS penetration

113
Q

Loperamide MoA

A

synthetic meperidine-like opioid with poor CNS penetration

114
Q

What are the synthetic opioids?

A

meperidine

fentanyl

115
Q

What are the semi-synthetic opioids?

A

hydros and oxys

heroin

116
Q

What are the natural opioids?

A

morphine, codeine

117
Q

What are ADRs of tramadol?

A

1) seizure
2) anaphylactoid
3) hypoglycemia

118
Q

How is tramadol metabolized?

A

2D6 to active metabolite
– higher affinity
3A4

119
Q

What is suboxone?

A

buprenorphine + naloxone SL film

120
Q

MoA of pentazocine

A

kappa agonist, mu antagonist

121
Q

MoA of butorphanol

A

kappa agonist, mu antagonist

122
Q

ADRs of pentazocine?

A

use-limiting psychotomimesis

123
Q

What opioids require REMS?

A

1) ER & LA for moderate-severe chronic pain
2) transmucosal IR fentanyl
3) buprenorphine transmucosal for opioid dependence

124
Q

What are the reasons for interpatient variability to opioids?

A

1) OPRM1 (mu receptor1 gene) SNP
2) kids have poorly developed BBB and more H2O
- - hydrophilics eliminated slower
3) geriatrics less sensitive, reduced cardiac and hepatic fx

125
Q

What are contraindications to opioid use?

A

1) hypersensitivity
2) acute bronchial asthma
3) head injury

126
Q

In what opioids is renal insufficiency an issue?

A

morphine, meperidine

127
Q

What are common co-analgesics?

A

1) antidepressants
2) SERT/NET inhibitors
3) anticonvulsants
3) hydroxyzine, phenothiazines
4) corticosteroids
5) clonidine

128
Q

MoA naloxone

A

full mu antagonist
kappa antagonist
delta antagonist

129
Q

MoA naltrexone

A

full mu, kappa antagonist

partial delta antagonist

PHS 931 (29 decks)

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