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Duke Pharmacology- Hannah > Opioid analgesics lecture part 1 > Flashcards

Opioid analgesics lecture part 1 Flashcards

1
Q

Who was the first individual to hypothesize that perception of pain comes from the brain instead of the heart as previously believed?

A

Renee de Clarks with his drawing of Treatsy of Man

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2
Q

In general, where are opioid receptors located?

A

Centrally (brain & spinal cord)

can be located in periphery but not primary location!

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3
Q

What happens to pain receptors in patients with chronic pain?

A

pain receptors can be located peripherally at the site of pain and pain can be initiated anywhere along the pathway thus opioids are not best drugs for chronic pain

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4
Q

Why wouldn’t we inject an opioid at the surgical site?

A

there’s nowhere for the opioid to work on because our opioid receptors are not located there

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5
Q

What substances are released that send a pain signal when we have destruction of cells?

A

Substance P, calcitonin gene related peptide, serotonin, histamines; these cause neuroelectrical stimulation which create a nerve impulse

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6
Q

Why do we have endogenous pain modulation?

A

It is a survival benefit

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7
Q

Describe the transmission of pain/ pain pathway

A

we have injury to the phospholipid bilayer and substances are released (substance P, calcitonin gene related peptide, serotonin, & histamines)–> these substances create a nerve impulse along first order neuron–> synapse in the spinal cord at second order neuron in the dorsal root ganglion–> transmission to midbrain (3rd order neuron)–> brain sends signal to part of brain that is experiencing the pain via the 4th order neuron
Additionally have spinal reflex arc

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8
Q

What substances does the body release to modulate pain?

A

Endorphins, enkephalins, dynorphins, norepinephrine

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9
Q

What are the distinct classes of opium?

A

Phenanthrenes (morphine, codeine, & thebaine)

Benzlisoquinolines (papaverine, noscapine)

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10
Q

What is the role of opioid agonists (and what do they not do)?

A

Produce analgesia! analgesia is the lack of perception of pain
They do not produce loss of touch, loss of proprioception, or loss of consciousness (in appropriate dosages)

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11
Q

Semi-synthesized opioids are:

A

Modifications to the morphine molecule which result in heroin

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12
Q

What are naturally occurring opiates?

A

morphine & codeine

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13
Q

What is a synthetic opioid?

A

Not modified from a naturally occurring drug; created in a lab
-they do contain a phenanthrene nucleus but they are created rather than modified

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14
Q

What are the most common synthetic opioids?

A

Methadone (recent resurgence due to prolonged half-life) and phenylpiperidine- meperidine, fentanyl, sufentanil, alfentanil, and remifentanil

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15
Q

Where are our pain fibers located?

A

Rexed lamina 1, 2, and sometimes 5 in the dorsal horn

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16
Q

What is the mechanism of action for opioids?

A

Opioid receptors are G-protein-coupled receptors
Their principle effect is to decrease
neurotransmission
Mimic the actions of endogenous ligands- such as
enkephalins, endorphins, dynorphins, and
norepinephrine

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17
Q

Where do endogenous substances work to prevent pain?

A

They were pre-synaptically to inhibit release of acetylcholine, dopamine, norepinephrine, and substance P
they include: enkephalins, dynorphins, and endorphins

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18
Q

Where do exogenous substances work to modulate pain?

A

Endogenous substances work postsynaptically by attaching to GCPRs in which the second messenger causes increased K+ conductance and decreased function

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19
Q

What is another site of action for opioids?

A

NMDA receptors

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20
Q

In regards to their mechanism of action, opioids do not…

A

block nerve impulses (only way to do this is with LA)

alter responsiveness of afferent nerve endings to noxious stimulation

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21
Q

Where specifically in the brain are opioid receptors found?

A

periaqueductal gray- recognizes pain and tells body to limit it endogenously
locus coeruleus- related to alertness (dex also acts on this)
rostral ventral medulla

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22
Q

Where specifically in the spinal cord are opioid receptors found?

A

Primary afferent and interneurons of the dorsal horn

target rexed lamina 1, 2, and 5

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23
Q

What are the names of the opioid receptors?

A

Kappa, Sigma, Mu, & Delta

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24
Q

What do the Mu1 receptors cause?

A

BEAMU

Bradycardia, euphoria, analgesia (spinal & supraspinal), miosis, and urinary retention

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25
Q

What do the Mu2 receptors cause?

A

ALL THE BAD THINGS… ventilatory depression, physical dependence, constipation, analgesia (spinal)

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26
Q

What do the Kappa receptors cause?

A

activation results in the inhibition of neurotransmitter release
analgesia (supraspinal & spinal), dysphoria, sedation,
miosis, diuresis, lesser extent (hypoventilation & high-
intensity pain), agonist-antagonist often act principally
on K receptors (low abuse potential)

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27
Q

If we wanted to give an opioid that resulted in the least amount of respiratory depression and was less likely to cause urinary retention, what receptor would this opioid be acting on?

A

Kappa receptors…. kappa receptors also cause the least amount of pain control

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28
Q

Why don’t Kappa receptors have full efficacy when modulating pain?

A

Because they are agonist-antagonists

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29
Q

What do the Delta receptors cause?

A

it’s your typical opioid: physical dependence, reduced ventilation, constipation, analgesia (supraspinal & spinal) & urinary retention
Delta receptors respond to endogenous ligands known as enkephalins & they may also serve to modulate Mu receptor activity

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30
Q

What opioids are not metabolized in the liver?

A

All of them except remifentanil are metabolized in the liver

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31
Q

Opioids are primarily excreted ______

A

by the kidneys

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32
Q

Small dose effects of opioids are terminated by ____ whereas effects of multiple doses and infusions are terminated by ____

A

redistribution; metabolism

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33
Q

Pharmacogenetics

A

we have genetic variation in each one of us which determines our responsiveness to opioids

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34
Q

What are common CV side effects of opioids?

A

-In healthy patients, bradycardia w/ sustained BP
-Impairment of SNS response (orthostatic hypotension)… venous pooling & histamine release
-Does not sensitize the heart to catecholamines
does not affect hearts ability to be affected by
endogenous substances

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35
Q

Opioids are _____ with these drugs____ to cause myocardial effects

A

synergistic; with benzodiazepines & nitrous oxide

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36
Q

What is a positive CV side effect of opioids?

A

Sigma & Kappa receptors produce a cardiac protectant effect by enhancing myocardial resistance to oxidative and ischemic stresses

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37
Q

How do opioids affect the oxyhemoglobin curve?

A

They shift the curve to the right by making us less responsive to changes in CO2

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38
Q

Opioids act on Mu and Delta receptors in the brainstem…

A

to produce a dose-dependent depression of ventilation

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39
Q

What are common respiratory effects of opioids?

A

-interfere with pontine & medullary ventilatory centers- regulate rate and rhythm of breathing
-decreased responsiveness to CO2
by decreasing acetylcholine release in the medullary
center of the brain
Shift the CO2 response curve to the right
-Produce a dose-dependent depression of ventilation

40
Q

What are additional respiratory effects of opioids?

A
  • decreased RR accompanied by compensation in TV (think slow, deep breaths)
41
Q

What are some bronchial effects of opioids?

A

Decreased ciliary action
Increased airway resistance
bronchial smooth muscle & histamine release

42
Q

Factors that affect depression of ventilation:

A

advanced age or extremes in age
Natural sleep
amount of and tolerance to pain

43
Q

What opioid is used for cough suppression?

A

Codeine is used for depression of medullary cough centers

Dextromethorphan- also has cough suppression component without analgesia or respiratory depression

44
Q

What are common CNS effects?

A
  • awareness possible
  • sedative and euphoric effects; a sedated patient is not pain free
  • decreased cerebral blood flow & possibly ICP
45
Q

Opioids are most effect for what kind of pain?

A

acute, visceral, and dull

46
Q

Anesthetic effects of opioids are two fold:

A

Inhibit ascending transmission of nociceptive information

activate descending pathways

47
Q

Why would we use opioids cautiously with head trauma patients?

A

Opioids alter wakefulness, cause miosis, depression of ventilation, and increased sensitivity when BBB is compromised

48
Q

Why do opioids cause miosis?

A

they act on autonomic nervous system component of Edinger-Westphal nucleus of oculomotor nerve
this can be antagonized by atropine

49
Q

Muscle rigidity

A

-Opioids have no effect on nerve conduction (can’t cause muscle contraction)
-skeletal muscle hypertonus “truncal rigidity”
following large doses of opioid
related to mu receptors acting on dopamine &
GABA channels
evidence supports resistance due to laryngeal
musculature contracture (treat with naloxone or
NMB)

50
Q

If you give an induction dose of a drug & you go to ventilate & cannot…

A

1st- stick in an oral airway (rules out masking issues)

2nd- If it’s an airway issue based on the drug, give a drug to combat the issue

51
Q

In up to 60% of patients, morphine….

A

induces sedation that precedes analgesia

assumption that sleep occurs when pain is relieved

52
Q

What do opioids do to the biliary tract?

A

Opioids cause spasm of biliary smooth muscle and the sphincter of Oddi
-Morphine can contract pancreatic ducts which can increase amylase and lipase levels and mimics acute pancreatitis

53
Q

How would you reverse the smooth muscle spasm that opioids can cause in the biliary tract?

A

Give 2 mg Glucagon IV

It will not antagonize analgesic effects

54
Q

How do opioids affect the GI tract?

A

-cause decreased gastric motility, propulsive activity, and emptying time
can increase risk of aspiration or delay drug
absorption
-Opioid-induced constipation

55
Q

What can antagonize GI effects?

A

Methylnaltrexone is an opioid antagonist that only works in the gut

56
Q

Why do opioids cause nausea & vomiting?

A
  • stimulation of chemoreceptor trigger zone in the medulla (serotonin type 3 receptors & dopamine type 2 receptors)
  • Increased GI secretions and delayed gastric emptying
57
Q

What types of patients have reduced NV?

A

recumbent patients

58
Q

What causes the genitourinary side effects of opioids?

A

opioid induced augmentation of detrusor muscle tone results in urgency but tone of urinary sphincter is enhanced making voiding difficult

59
Q

Why might people receiving opioids have cutaneous changes?

A 
Histamine release (not an allergy) which results in conjunctivial erythema & pruritis 
Morphine causes blood vessels to dilate resulting in warm, flushed skin
60
Q

What opioid is the biggest culprit that causes pruritis?

A

Intrathecal morphine

61
Q

Given the hydrophilicity of opioids, how does this effect placental transfer?

A

opioids readily cross the placenta which results in neonatal depression
-morphine has a greater effect than meperidine (think about potency)
Chronic use can cause neonatal physical dependence & naloxone may precipitate neonatal abstinence syndrome

62
Q

Ventilatory effects of opioids act synergistically with which drugs?

A

benzodiazepines, amphetamines, phenothiazines, MAO’s, tricyclics

63
Q

What effect does physostigmine and atropine have on opioids & why?

A

physostigmine- enhances & atropine-antagonizes b/c cholinergic system is a positive modulator of opioid analgesia

64
Q

What is the triad of an overdose?

A

miosis, hypoventilation, coma (hypotension & seizures develop if arterial hypoxemia persists)

65
Q

What is the treatment for an opioid overdose?

A

Mechanical ventilation, supplemental oxygen, antagonist

66
Q

What opioids cause reflex coughing?

A

seen more so with fentanyl, sufentanil, and alfentanil

-not seen with morphine or hydromorphone

67
Q

What are the two thoughts behind reflex coughing with administration of fentanyl, sufentanil, and alfentanil?

A
  • imbalance of sympathetic and vagal nerve innervation

- Stimulation of juxtacapillary irritant receptors

68
Q

Explain the relationship with tolerance & dependence?

A

We can develop tolerance without physical dependence but we cannot develop physical dependence without tolerance

69
Q

What kind of tolerance can develop between all opioids?

A

Cross-tolerance b/c they are chemically related/act on similar receptors

70
Q

Describe what happens with pharmacodynamic tolerance.

A

Since opioids are agonists we have desensitization and down-regulation; up regulation of cAMP
-can develop in 2-3 weeks… much quicker with more potent drugs

71
Q

What are some s/s that don’t go away even when we develop a tolerance?

A

Constipation & miosis

72
Q

What is a consideration with ketamine use in long-term chronic opioid abusers?

A

long-term opioid use activates NMDA receptors down regulating spinal glutamate receptors which may make them less responsive to ketamine

73
Q

What are the symptoms of withdrawal abstinence syndrome?

A

Initial symptoms: yawning, diaphoresis, lacrimation, insomnia, & restlessness
Cramps, N/V, diarrhea peak at 72 hours then decline in 7-10 days
Tolerance is quickly lost

74
Q

What is the onset of morphine?

A

15-30 minutes which is slow compared to other opioids making it not as useful in anesthesia

75
Q

Describe the pharmacokinetics of morphine related to lipid solubility

A

only a small portion reaches the CNS d/t poor lipid solubility, high degree of ionization at physiologic pH, protein binding, and rapid conjugation in the liver

76
Q

What does morphine do?

A

Produces analgesia, euphoria, sedation, and decreased concentration, nausea, body warmth, pruritis (nose), dry mouth, extreme heaviness

77
Q

When should you give an opioid?

A

Preemptively before the pain pathway is activated

78
Q

What kind of pain is morphine best for?

A

Slow, dull pain

79
Q

Describe the metabolism of morphine

A

Morphine is primarily metabolized through conjugation with glucuronic acid via both the liver & kidneys; ok to give in liver patients but has significant renal metabolism so be careful

80
Q

Due to Co2 changes…

A

there is increased cerebral blood flow b/c of vasodilation

81
Q

What active metabolite of morphine are we concerned with?

A

morphine 6-glucuronide b/c it is more potent than morphine itself & has a longer duration of action
other metabolites include morphine 3-glucuronide (inactive), normorphine, and codeine

82
Q

With morphine impaired renal function can result in

A

accumulation and unexpected respiratory depression

83
Q

What is the clinical use of meperidine (demerol)?

A

anti-shivering postoperatively through activation of kappa receptors

84
Q

Meperidine is structurally similar to

A

atropine & produces mild antispasmodic effects

85
Q

Meperidine acts on what receptor site?

A

Mu-receptor agonist & kappa receptors

86
Q

Meperidine’s potency related to morphine is

A

1/10th as potent

87
Q

The duration of action of meperidine is

A

2-4 hours

88
Q

Extensive first pass metabolism by the liver limits the oral usefulness of

A

meperidine

89
Q

Meperidine has extensive metabolism to

A

Normeperidine (active metabolite) & meperidinic acid

90
Q

What is the primary route of elimination for meperidine?

A

Renal excretion- pH dependent so the more acidic, the greater fraction of drug excreted unchanged
decreased renal function can result in accumulation of metabolites

91
Q

What are side effects of meperidine?

A

may cause increase in heart rate, mydriasis (atropine like effects d/t structural similarity), high doses decrease myocardial contractility
delirium & seizures
can elicit serotonin syndrome in patients taking MAOI or fluoxetine
Crosses the placenta
less biliary tract spasm
withdraw develops more rapidly & is shorter in duration

92
Q

Pearls of Meperidine:

A

structurally related to atropine & the implications of this are increased HR & mydriasis, clinical use 4.5 mg for shivering, don’t give in 80 year old pts. on dialysis

93
Q

What is the elimination half-time of normeperidine?

A

15 hours and can exceed 30 hours in renal failure

94
Q

Why are elderly patients more sensitive to normeperidine?

A

decreased plasma protein= increased circulating volume= exaggerated response

95
Q

How is normeperidine excreted?

A

eventually undergoes hydrolysis to meperidinic acid

Duke Pharmacology- Hannah (14 decks)

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