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ACEM Primary Written > Anaesthetics: Pharmacology - Opioids > Flashcards

Anaesthetics: Pharmacology - Opioids Flashcards

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1
Q

Four examples of natural opioids (opiates)

A
  1. Morphine
  2. Codeine
  3. Thebaine
  4. Papaverine
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2
Q

Three endogenous opioids

A
  1. Endorphins
  2. Enkephalins
  3. Dynorphans
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3
Q

What are the three endogenous opioid precursor molecules?

A
  1. Proopiomelanocortin (POMC)
  2. Preproenkephalin (proenkephalin A)
  3. Preprodynorphan (proenkephalin B)
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4
Q

What are the three opioid receptor subtypes?

A

Mu, delta and kappa

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5
Q

Five functions of mu opioid receptor

A

Supraspinal and spinal analgesia
Sedation
Respiratory depression
Slowed GI transit
Modulation of hormone and neurotransmitter release

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6
Q

Two functions of delta opioid receptor

A

Supraspinal and spinal analgesia
Modulation of hormone and neurotransmitter release

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7
Q

Three functions of kappa opioid receptor

A

Supraspinal and spinal analgesia
Psychomimetic effects
Slowed GI transit

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8
Q

Relative affinities of endogenous opioids for the three opioid receptor subtypes

A

Mu: endorphins > enkephalins > dynorphans
Delta: enkephalins > endorphins, dynorphans
Kappa: dynorphans&raquo_space; endorphins, enkephalins

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9
Q

What kind of receptors are the opioid receptors?

A

GPCRs

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10
Q

Describe the cellular mechanism of action of opioid receptors

A

Close voltage-gated Ca2+ channels on presynaptic terminal to reduce transmitter release (has been demonstrated for glutamate, ACh, NA, 5HT, substance P)
Open K+ channels and hyperpolarise synaptic neurons (thus inhibitory)

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11
Q

How do opioids produce analgesia?

A

Bind GPCRs in brain and spinal cord regions involved in pain transmission and modulation

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12
Q

At which opioid receptor do the majority of currently available opioid analgesics act?

A

Mu

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13
Q

What receptor is responsible for the euphoria and physical dependence seen with opioid use?

A

Mu

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14
Q

How does opioid tolerance and dependence occur?

A

Mechanism unclear but thought to be due to persistent mu receptor activation (as seen in severe chronic pain), which may be mediated by:
- Upregulation of cAMP system
- Failure of “receptor recycling” (mu receptors not endocytosed for recycling post-activation)

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15
Q

What is the proposed mechanism of opioid-induced hyperalgesia?

A

Occurs via spinal dynorphan and activation of bradykinin and NMDA receptors

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16
Q

Describe the pharmacokinetics of opioids

A

Absorption: most are well-absorbed via subcut, IV and oral routes (although oral dose may need to be much higher than parenteral due to first-pass metabolism); other administration methods include intranasal, oral mucosal (lozenge), and transdermal
Distribution: all bind plasma proteins with varying affinity and rapidly leave the intravascular space, localising in highly perfused tissues e.g. brain, lungs, liver, kidney, spleen); due to its bulk, skeletal muscle is main drug reservoir despite having lower drug concentrations
Metabolism: converted in large part in liver to polar metabolites (mostly glucuronides, with limited ability to cross BBB)
Elimination: primarily by kidneys with small amount unchanged, some enterohepatic circulation

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17
Q

Two opioids with reduced first-pass metabolism (effective orally)

A

Codeine
Oxycodone

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18
Q

What makes it difficult to predict the effective oral dose for a patient?

A

There is considerable interpatient variability in the rate and extent of first-pass metabolism of opioids

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19
Q

How is heroin metabolised?

A

By plasma esterases, with morphine as metabolite

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20
Q

What are two of the main morphine metabolites and their respective effects?

A

M3G: neuroexcitatory and can cause seizures if accumulates
M6G (10%): 4-6x analgesic potency of morphine

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21
Q

How is fentanyl metabolised? What active metabolites are produced?

A

Via hepatic oxidative metabolism (CYP3A4)
No active metabolites

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22
Q

What enzyme is responsible for the metabolism of codeine, oxycodone and hydrocodone? Why is there often a variable response to these medications?

A

CYP2D6
CYP2D6 shows significant genetic polymorphism which alters response to dose

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23
Q

How are opioids excreted?

A

Primarily by the kidneys, with small amount unchanged
Small amount in bile, enterohepatic circulation

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24
Q

Nine CNS effects of opioids

A
  1. Analgesia
  2. Euphoria (or dysphoria)
  3. Sedation
  4. Respiratory depression
  5. Cough suppression
  6. Miosis
  7. Truncal rigidity
  8. Nausea and vomiting
  9. Change in temperature (hyperthermia with mu receptor agonism)
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25
What is the mechanism of opioid-induced respiratory depression?
Inhibits brainstem respiratory mechanisms Causes blunted response to hypercarbia
26
Is opioid-induced respiratory depression dose-related?
Yes
27
Which opioid is particularly effective at suppressing cough?
Codeine
28
What complications may arise as a result of opioid-induced cough suppression?
Accumulation of secretions Airway obstruction Atelectasis
29
Does tolerance develop to miosis with continued opioid use?
No
30
What is the mechanism of opioid-induced miosis?
Mediated via parasympathetic pathways
31
Do opioid antagonists block miosis?
Yes
32
Which opioid typically produces truncal rigidity?
Fentanyl
33
What are the complications of truncal rigidity seen with high doses of fentanyl?
Reduced thoracic compliance leading to decreased ventilation
34
What is the mechanism of opioid-induced nausea and vomiting?
Activation of chemoreceptor trigger zone in brainstem
35
What is the effect of opioids on the cardiovascular system?
No significant direct effects on heart or cardiac rhythm Hypotensive effect due to peripheral arterial and venous dilation, mediated via histamine release and central depression of vasomotor stabilising mechanisms
36
Does tolerance develop to opioid-induced constipation?
No
37
What effects do opioids have on the biliary tract?
Constriction of smooth muscle, which may cause biliary colic
38
What effects do opioids have on the kidneys?
Decreased renal function (likely due to decreased renal plasma flow) Antidiuretic effect seen with mu opioids
39
What effects do opioids have on the genitourinary tract?
Prolong labour Increase ureteral and bladder tone (may cause urinary retention, worsen pain of ureteric colic)
40
What effects do opioids have on neuroendocrine function?
Stimulates ADH, prolactin and GH release Inhibits LH release
41
What is the mechanism of opioid-induced pruritis?
CNS effect and due to peripheral histamine release
42
What effect do opioids have on the immune system?
Effects on lymphocyte proliferation, antibody production, and chemotaxis
43
What three opioid effects are not impacted by tolerance?
1. Miosis 2. Constipation 3. Convulsions
44
What opioid effect is moderately impacted by tolerance?
Bradycardia
45
To what eight opioid effects does a high degree of tolerance develop?
1. Analgesia 2. Euphoria/dysphoria 3. Sedation 4. Mental clouding 5. Respiratory depression 6. Antidiuresis 7. Nausea and vomiting 8. Cough suppression
46
Does cross-tolerance develop between full mu-receptor agonists and opioids with mixed receptor effects?
No
47
Does cross-tolerance develop between different mu-receptor agonists? How does opioid rotation work?
Yes, but it may be partial or incomplete which is why opioid rotation can produce improved analgesia with an equal or lesser dose
48
Nine symptoms of opioid withdrawal syndrome
1. Rhinorrhoea 2. Yawning 3. Chills, pilorection 4. Hyperventilation 5. Hyperthermia 6. Mydriasis 7. Myalgias 8. Vomiting, diarrhoea 9. Anxiety, hostility
49
What is the timing of morphine/heroin withdrawal symptoms relative to last dose? When do these symptoms peak and when do they resolve? How does withdrawal from methadone compare?
Morphine/heroin withdrawal: starts 6-10hrs post last dose, peaks at 36-48hrs, most symptoms resolve after 5 days Methadone: longer withdrawal period (up to 2 weeks) but less intense immediate syndrome
50
Seven contraindications/precautions for opioid use
1. Use of full with partial agonist: causes reduced analgesia and may precipitate withdrawal syndrome 2. Head injuries: respiratory depression increases CO2 and induces cerebral vasodilation, raising ICP 3. Pregnancy: chronic maternal use causes physical dependence in foetus 4. Decreased lung function: may precipitate acute respiratory failure 5. Hepatic or renal impairment: prolonged half-life, accumulation of active metabolites 6. Endocrine disease: prolonged/exaggerated effects with adrenal insufficiency and hypothyroidism 7. Use with other sedative-hypnotics, antipsychotics, and MAOIs
51
Four adverse effects of opioids
1. Tolerance 2. Dependence 3. Addiction 4. Overdose (respiratory and CNS depression etc)
52
What is the risk of using MAOIs with opioids?
May cause hyperpyrexic coma (also reports of HTN)
53
Ten adverse effects of acute use of opioids
1. Respiratory depression 2. Nausea and vomiting 3. Pruritis 4. Urticaria 5. Constipation 6. Urinary retention 7. Delirium 8. Sedation 9. Myoclonus 10. Seizures
54
Nine adverse effects of chronic use of opioids
1. Hypogonadism 2. Immunosuppression 3. Increased feeding 4. Increased GH secretion 5. Withdrawal effects 6. Tolerance, dependence 7. Abuse, addiction 8. Hyperalgesia 9. Impairment while driving
55
List five phenanthrene opioids. Which are strong agonists, which are mild to moderate agonists, and which have mixed receptor actions?
Morphine, heroin (strong agonists) Codeine, oxycodone (mild to moderate agonists) Buprenorphine (mixed receptor actions)
56
What structural class of opioid is methadone?
Phenylheptylamine
57
Name two phenylpiperidines. Which is a strong agonist and which is a mild to moderate agonist?
Fentanyl (strong agonist) Loperamide (mild to moderate agonist)
58
Describe the pharmacokinetics of morphine, including the oral bioavailability, half-life and duration of action
Absorption: oral bioavailability 20-40% Metabolism: t1/2 = 2-3hrs, duration of action 4-5hrs, 90% hepatic metabolism (produces active metabolite hydromorphone) Elimination: 90% renal, 10% biliary
59
Describe the pharmacokinetics of heroin, including the oral bioavailability and half-life
Absorption: oral bioavailability <35% Metabolism: hepatic metabolism produces morphine, t1/2 = 2-3mins Elimination: 90% renal, 10% biliary
60
What is the mechanism of action of methadone?
Strong mu-receptor agonist NMDA blockade Blockade of monoaminergic reuptake transporters
61
Describe the pharmacokinetics of methadone, including oral bioavailability and half-life
Absorption: well-absorbed from GIT (oral bioavailability exceeds morphine, 44-90% Metabolism: long t1/2 = 25-52hrs, hepatic metabolism (with high interpatient variability) Elimination: renal and biliary
62
Name two clinical uses for methadone and briefly explain the rationale for each
1. Difficult-to-treat pain (e.g. cancer, neuropathic) - May succeed whether other opioids have failed (at 10-20% of the morphine-equivalent daily dose) due to additional non-opioid mechanisms of action - Should be given 8-hrly for this purpose 2. Opioid misuse (detoxification and maintenance) - Tolerance and dependence develop more slowly - Withdrawal syndrome is more prolonged but milder
63
How is methadone prescribed for purposes of opioid detoxification vs maintenance therapy?
Detoxification: given 2-3x per day for 2-3 days then ceased (milder withdrawal) Maintenance: given daily (deliberately produces cross-tolerance to prevent addiction-reinforcing effects of using other opioids)
64
Describe the pharmacokinetics of fentanyl including oral and transdermal bioavailability and duration of action
Absorption: oral bioavailability 33%, transdermal bioavailability 92% Metabolism: hepatic metabolism with no active metabolites (so preferred in renal impairment), duration of action 1-1.5hrs Elimination: 60% renal (<10% unchanged)
65
What structural class of opioid is methadone?
Phenylpiperidine
66
Why is meperidine (pethidine) no longer widely used?
Due to risk of adverse effects, including: - Antimuscarinic effects (e.g. tachycardia) - Negative inotropic effects - Seizures caused by active metabolite normeperidine (which accumulates with high doses +/- renal impairment)
67
Describe the pharmacokinetics of meperidine, including oral bioavailability and metabolism
Absorption: 50-60% oral bioavailability Metabolism: t1/2 = 2-3hrs, 90% hepatic metabolism (produces active metabolite normeperidine) Elimination: renal
68
What structural class of opioid is codeine?
Phenanthrene
69
What is one possible adverse effect of codeine?
Can antagonise strong agonists (e.g. morphine)
70
Does metabolism of oxycodone produce active metabolites?
Yes, oxymorphone
71
What structural class of opioid is oxycodone?
Phenanthrene
72
What structural class of opioid is buprenorphine?
Phenanthrene
73
What structural class of opioid is loperamide?
Phenylpiperidine
74
What is the mechanism of action of loperamide and what is its clinical use?
Acts on peripheral (not central) mu-receptors Controls diarrhoea with limited potential for misuse
75
What structural class of opioid is buprenorphine?
Phenanthrene
76
What is the mechanism of action of buprenorphine?
Partial mu-receptor agonist (high binding affinity but low intrinsic activity: antagonises stronger opioids) Delta- and kappa-receptor antagonist Also binds ORL1 (orphanin receptor)
77
Describe the pharmacokinetics of buprenorphine
Absorption: sublingual administration preferred to avoid first-pass metabolism, transdermal also available Distribution: long duration of action due to slow dissociation from mu-receptors (renders it resistant to naloxone and to displacement by other opioids)
78
Why is buprenorphine resistant to naloxone?
Slowly dissociates from mu-receptors
79
What is the major clinical use of buprenorphine and why?
Opioid dependence due to decreased risk of respiratory depression (compared with e.g. methadone) Often combined with naloxone to prevent illicit IV misuse
80
Adverse effects of buprenorphine
Psychomimetic effects reported (hallucinations, nightmares, anxiety)
81
What is papaverum?
Mixed of opiate alkaloids (codeine, morphine, papaverine)
82
What is the mechanism of action of tramadol?
Centrally-acting analgesic Major mechanism of action is related to blockade of 5HT and NA reuptake transporters Also demonstrates low-affinity binding to mu-receptors (only partially antagonised by naloxone)
83
Two adverse effects of tramadol
Risk of seizures and serotonin syndrome
84
Two adverse effects of tapentadol
Risk of seizures and serotonin syndrome
85
What is the mechanism of action of tapentadol?
Modest mu-receptor agonist Significant blockade of NA reuptake
86
Describe the chemical structure of the opioid antagonists
Morphine derivatives with bulkier substituents at the N17 position
87
What is the mechanism of action of opioid antagonists?
Strong mu-receptor antagonist, with lower delta- and kappa-receptor antagonism (but can still reverse agonists at these sites) Acts as competitive antagonist and is inert in the absence of agonist drug
88
Three examples of opioid antagonists and give a brief overview of their unique properties and typical use
Naloxone: IV, short-acting, for opioid reversal Naltrexone: oral, longer-acting, maintenance drug in heroin addiction and reduces cravings in alcohol addiction (also combined with bupropion for weight loss) Nalmefene: IV, for opioid reversal but longer half-life than naloxone
89
What effect does naloxone have on an opioid-depressed patient vs a conscious opioid-dependent patient?
Opioid depression: rapid reversal (within 1-3mins) of respiration, consciousness, pupil size, bowel activity, and pain awareness Opioid-dependent: precipitates acute withdrawal
90
Do tolerance and dependence develop to opioid antagonists?
No
91
What is the clinical significance of naloxone's short duration of action?
Severely depressed patient may recover with a single dose of naloxone, only to relapse into coma 1-2hrs when dose wears off
92
What is the usual initial vs maintenance dose of naloxone for opioid-induced life-threatening respiratory/CNS depression?
Initial: 0.1-0.4mg IV Maintenance: 0.4-0.8mg IV as needed
93
What are the clinical uses of naloxone and naltrexone?
Naloxone: opioid reversal (overdose, opioid-induced respiratory or CNS depression) Naltrexone: maintenance drug for opioid addiction, reduces cravings in alcoholism, combined with bupropion for weight loss
94
What is the mechanism of action of naltrexone for its use in alcoholism?
Reduces alcohol cravings by increasing baseline B-endorphin release
95
Describe the pharmacokinetics of naloxone
Absorption: given IV Metabolism: short duration of action (1-2hrs), glucuronide conjugation in liver Elimination: renal
96
Describe the pharmacokinetics of naltrexone
Absorption: well-absorbed orally, may undergo rapid first-pass metabolism Metabolism: t1/2 = 10hrs
97
What is the effect of a single oral 100mg dose of naltrexone on heroin effects?
Blocks heroin effects for up to 48hrs
98
Six clinical uses of opioid agonists
1. Analgesia (severe constant pain - less effective for sharp intermittent) 2. Acute pulmonary oedema 3. Antitussive 4. Antidiarrhoeal 5. Anaesthesia 6. Shivering
99
What are the two uses of opioid agonists in anaesthesia?
Premedication for sedative, anxiolytic and analgesic effects Regional anaesthetic (e.g. epidural, subdural)
100
What are the three primary mechanisms of action of opioid agonists in acute pulmonary oedema?
1. Decreased perception of SOB, decreased anxiety 2. Decreased preload (due to decreased venous return) 3. Decreased afterload (due to decreased total peripheral resistance)
101
What is the equivalent dose of the following opioids to 10mg morphine: methadone, fentanyl, meperidine, codeine, oxycodone, buprenorphine
Morphine: 10mg Methadone: 10mg Fentanyl: 0.1mg Meperidine: 60-100mg Codeine: 30-60mg Oxycodone: 4.5mg Buprenorphine: 0.3mg
102
Duration of analgesic action of morphine
4-5hrs
103
Duration of analgesic action of fentanyl
1-1.5hrs
104
Duration of analgesic action of methadone
4-6hrs
105
Duration of analgesic action of meperidine
2-4hrs
106
Duration of analgesic action of codeine
3-4hrs
107
Duration of analgesic action of oxycodone
3-4hrs
108
Duration of analgesic action of buprenorphine
4-8hrs

ACEM Primary Written (150 decks)

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