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Duke Pharmacology- Hannah > Opioids lecture part 2 > Flashcards

Opioids lecture part 2 Flashcards

1
Q

What is the most widely used opioid analgesic in anesthesia?

A

fentanyl

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2
Q

What is significant about the structure of fentanyl?

A

phenlypiperdine ring

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3
Q

What is the potency of fentanyl?

A

75-125 times more potent than morphine

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4
Q

What is the liphophilicity of fentanyl?

A

Fentanyl is liphophilic b/c of its chemical structure

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5
Q

What is the pKa of fentanyl?

A

8.4

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6
Q

What is the pKa of morphine?

A

7.9

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7
Q

Discuss the pharmacokinetics of fentanyl?

A

rapid onset and shorter duration of action (1-3 minute onset)
lipid soluble
redistribution terminates effect of single dose

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8
Q

What is the elimination half-time of fentanyl?

A

longer than that of morphine

Large Vd- more than 80% leaves the plasma in less than 5 minutes

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9
Q

How is fentanyl metabolized?

A

N-dealkylation and hydroxylation

no active metabolites

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10
Q

Name 3 drugs that have a large first pass uptake in the lungs.

A

Propofol, fentanyl, & lidocaine

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11
Q

True or false: cirrhosis prolongs elimination half-time of fentanyl.

A

false

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12
Q

What is the context sensitive half-time like with fentanyl?

A

increases exponentially with infusions >2 hours
reflects redistribution and saturation into inactive
tissue sites

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13
Q

What patient population has implications with fentanyl?

A

elderly- prolonged elimination time due to decreased clearance
age-related decreases in hepatic blood flow, microsomal enzyme activity, and albumin production (highly protein bound)

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14
Q

What are the dosages for fentanyl?

A

induction/intubation: 1-3 mcg/kg
analgesia: 1-3 mcg/kg IV provide analgesia
sole anesthetic: 50-150 mcg/kg to produce surgical analgesia

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15
Q

What are the risks/benefits of fentanyl as sole anesthetic?

A

stable hemodynamics, lack of cardiac depressant effect, no histamine
recall?, respiratory depression post op, lack of response to surgical stim at any dose

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16
Q

Transdermal fentanyl

A

leave patch in place- reduces IV requirements

stable concentration for 3 days

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17
Q

Side effects of fentanyl:

A

similar profile to morphine
“secondary peaks” may reflect release from pulmonary uptake
Does NOT evoke histamine release; hypotension unlikely
bradycardia more prominent- carotid sinus baroreceptor control
Associated with modest increases in ICP
vasodilatory?
Seizure activity; myoclonus
Inhibition of inhibitory neurons

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18
Q

What does fentanyl have synergism with?

A

propofol and versed

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19
Q

What is the chemical structure of sufentanil?

A

Thienyl analogue of fentanyl

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20
Q

What is the potency of sufentanil?

A

potency is 5-10 times that of fentanyl

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21
Q

What are the clinical uses and dosages of sufentanil?

A

0.1-0.4 mcg/kg produces longer analgesia and less respiratory depression than fentanyl
induction-doses required for laryngoscopy may cause chest wall rigidity

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22
Q

Protein binding for sufentanil

A

significantly more than fentanyl
alpha 1 glycoprotein
enhanced effects in neonates

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23
Q

Comment on the Vd of sufentanil.

A

rapid distribution terminates effects- highly lipid soluble, increased Vd

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24
Q

Sufentanil has:

A

significant first pass pulmonary uptake

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25
Q

How is sufentanil different then fentanyl?

A

more potent, may contribute to chest wall rigidity, d/t high lipid solubility may see increased effects with liver disease

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26
Q

How is sufentanil metabolized?

A

rapidly metabolized by N-dealkylation and O-demethylation
N-dealylation metabolites are inactive
O-demethylation- desmethyl sufentanil- has activity and must be conjugated to be eliminated so renal function is important

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27
Q

Sufentanil clearance is sensitive to

A

hepatic blood flow

normal renal function is essential for clearance

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28
Q

What is the potency of alfentanil?

A

Alfentanil is less potent than fentanyl; shorter duration of action

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29
Q

What is the onset of alfentanil?

A

rapid onset after IV administration (redeeming quality)

high fraction of unionized drug (90% of the drug exists in nonionized form at physiological pH

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30
Q

What is the pKa of alfentanil?

A

6.5

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31
Q

What is the volume of distribution of alfentanil?

A

small Vd; less than that of fentanyl

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32
Q

What is alfentanil principally bound by?

A

alpha 1 glycoproteins

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33
Q

How is alfentanil metabolized?

A

metabolized by two independent pathways: piperdine N-dealkylation to noralfentanil & amide N dealkylation to N-phenyylpropionamide

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34
Q

What are the dosages of alfentanil?

A

15 ug/kg IV- blunts stimulation of laryngoscopy
30 ug/kg IV-catecholamine response to noxious stimulation
150-300 ug/kg IV- produces unconsciousness (induction)
combo w/ inhaled anesthetic 15-150 mcg/kg/hr

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35
Q

What are side effects associated with alfentanil?

A

decreased BP, diminished incidence of N/V

acute dystonia so avoid in pt’s with Parkinson’s

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36
Q

What is the mechanism of action of remifentanil?

A

selective mu agonist
potent like fentanyl
blood brain equilibration like alfentanil

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37
Q

What is significant about the structure of remifentanil?

A

it has an ester linkage so it allows for it to be broken down by nonspecific plasma esterases in the blood

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38
Q

What is remifentanil good for?

A

Good for surgeries where we can’t paralyze because it is very synergistic with propofol

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39
Q

What are the benefits of remifentanil

A

brief action, titratable, does not accumulate, rapid recovery

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40
Q

What are the dosages of remifentanil?

A

analgesia: 0.5-0.2 mcg/kg/min
anesthesia induction: 1 mcg/kg bolus followed by infusion of 0.1-0.3 mcg/kg/min for 10 minutes prior to induction agent
sedation: 0.05-0.1 mcg/kg/min in combination with midazolam 2 mg

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41
Q

What is a negative aspect of remifentanil?

A

it is abrupt–> can get hyperdynamic responses if you don’t give some type of long term coverage

42
Q

What is the Vd of remifentanil?

A

small Vd

43
Q

What is the context sensitive half-time of remifentanil?

A

4 minutes

44
Q

What is significant about the metabolism of remifentanil?

A

metabolized by non-specific plasma esterases- no active metabolites, not affected by pseudocholinesterase deficiency, pK unchanged by renal or hepatic failure

45
Q

What are side effects of remifentanil?

A

can induce “seizure like” activity, N/V, depress ventilation, decrease BP, hyperalgesia secondary to acute opioid tolerance (can give ketamine or mag to block this)

46
Q

Discuss hydromorphone

A

main long-acting opioid
consistent, reliable, 5x more potent than morphine, shorter duration of action than morphine
less hydrophillic than morphine so faster onset, more sedation, less euphoria
can cause agitation and myoclonus

47
Q

What is methadone?

A

synthetic opioid used in chronic pain settings
attractive for withdrawal and drug suppression
long terminal half-life- 12 hours so need to be prepared for long-term management
need to go to pulse ox floor

48
Q

Side effects of methadone

A

similar to morphine: depression of ventilation, miosis, constipation, biliary tract spasm
sedative and euphoric effects less

49
Q

Opioid withdrawal use of methadone dose

A

can substitute for morphine at 1/4th the dosage

20 mg IV, produces postop analgesia >24 hours

50
Q

Methadone is used to treat chronic pain because

A

low abuse potential
NMDA antagonist activity may be beneficial for neuropathic pain
disadvantage is prolonged and unpredictable half-life
drug can accumulate and cause depression of
ventilation

51
Q

What is tramadol?

A

synthetic codeine analog
given PO, IM, or IV
weak moderate Mu agonist
less potent than morphine
useful for chronic treatment-less addictive
enhances function of descending inhibitory pathways

52
Q

What is the metabolism of tramadol?

A

CYP 450 in the liver

active metabolite O-desmethlytramadol has modest analgesic effects

53
Q

What are the disadvantages of tramadol?

A

interacts with coumadin anticoagulants
drug-related seizures (may lower seizure threshold and not in a good way)
high incidence of N/V
Zofran may interfere with analgesic component d/t reuptake of 5-hydroxytryptamine

54
Q

What is heroin?

A

synthetic opioid
differs from morphine in that it rapidly penetrates the CNS where it is hydrolyzed to active metabolites
monacetylmorphine, morphine
Compared to morphine: more rapid onset, less nausea, greater liability for physical dependence

55
Q

Opioid agonist-antagonist

A

these bind to mu receptors but produce limited responses or no effect

56
Q

What are the advantages of opioid agonist-antagonist?

A

produce analgesia
limited depression of ventilation
Have a ceiling effect- reserved for patients who can’t tolerate a pure agonist

57
Q

What is butorphanol?

A 
limited intraoperative use
agonist-antagonist so not 100% efficacy 
affinity for kappa receptors
given for analgesia and anti-shivering 
resembles pentazocine
        agonist effects are 20x greater
        antagonist effects are 10-30x greater
low affinity for mu receptors
        produces antagonism
58
Q

Where is butorphanol metabolized?

A

metabolized in liver and excreted primarily in the bile

inactive metabolite-hydroxybutorphanol

59
Q

What is the half-time of butorphanol?

A

2.5-3 hours

60
Q

What are the side effects of butorphanol?

A

sedation, nausea, diaphoresis, dysphoria, depression of ventilation, increase in catecholamine response (increased HR, BP, PAP, CO), mild biliary and GI tract symptoms, limits effects of concomitant opioid agonists, withdrawal following acute discontinuation in chronic therapy

61
Q

What drug classification is nalbuphine?

A

agonist-antagonist

62
Q

What is significant about the chemical structure of nalbuphine?

A

it’s related to oxymorphone and naloxone

63
Q

Where is nalbuphine metabolized and what is the elimination half time?

A

liver

3-6 hours

64
Q

Where does antagonism occur with nalbuphine?

A

mu receptors
if given before an opioid it may diminish effects of morphine-like drugs preop
if given after opioid it can reverse (2-3 hours) depression of ventilation effects but maintain analgesia

65
Q

When is the best time to give nalbuphine?

A

after an opioid because it can reverse depression of ventilation while maintaining analgesia

66
Q

What are the side effects of nalbuphine?

A

sedation
less dysphoria than pentazocine & butorphanol
depression of ventilation has ceiling effect (30 mg)
catecholamine stimulation effects
may be beneficial in cardiac patients needing
sedation and analgesia (doesn’t produce
hypotension or bradycardia)

67
Q

What is buprenorphine derived from?

A

derived from thebaine

potent analgesic

68
Q

What is the dosing of buprenorphine and its relationship to morphine?

A

0.3 mg IM= 10 mg morphine so very potent

69
Q

What are the clinical uses of buprenorphine?

A

postop pain related to cancer, renal colic and MI

70
Q

What are the side effects of buprenorphine?

A

drowsiness, n/v, and depression of ventilation- similar to morphine but may be prolonged, resistant to antagonism by naloxone
pulmonary edema
dysphoria unlikley
low abuse risk
can precipitate withdrawal in patient taking morphine

71
Q

What is the chemical structure of an opioid antagonist like?

A

opioid agonists with mild structural changes to the substitution of an alky group for a methyl group

72
Q

What are examples of opioid antagonists?

A

pure Mu antagonist receptors include: naloxone, naltrexone, nalmefene

73
Q

What is the dosage of naloxone?

A

dose 1-4 mcg/kg IV; don’t ever give a whole vial typically will se 40 mcg given
5 mcg/kg/hr can fix depression of ventilation without affecting analgesia

74
Q

What is naloxone used for?

A

opioid induced hypoventilation, depression of ventilation in the neonate d/t maternal administration, treat deliberate drug overdose, detect suspected physical dependence

75
Q

What is the half-life of naloxone?

A

30-45 minutes

76
Q

the oral route of naloxone is

A

1/5th as potent due to first pass hepatic metabolism

77
Q

How is naloxone metabolized?

A

by liver conjugation with glucoronic acid

naloxone-3-glucuronide

78
Q

What are side effects of naloxone administration?

A

reversal of analgesia (can be possible to titrate to maintain analgesia and reverse hypoventilation)
N/V
increased sympathetic nervous system activity- sudden onset of pain, tachycardia, hypertension, pulmonary edema, cardiac dysrthythmia- vfib
administration to the opioid dependent parturient may result in fetal withdrawal

79
Q

Role of naloxone in shock

A

in animals large doses of naloxone (>1 mg/kg) have shown to improve myocardial contractility and outcomes

80
Q

What is naltrexone and when is it used?

A

opioid antagonist

used in treatment of alcoholism; has sustained effects >24 hours

81
Q

What is nalmefene?

A

pure opioid antagonist

82
Q

What is the dosing for nalmefene?

A

15-25 mcg IV until effect achieved (max dose 1 mcg/kg)

83
Q

What is the potency of nalmefene?

A

Equally potent to naloxone

84
Q

If nalmefene is given prophylactically,

A

it decreases N/V and pruritis in patient with IV PCA

85
Q

What is the primary advantage of nalmefene?

A

longer duration of action than naloxone so doesn’t need to be re-dosed in 30 minutes

86
Q

How is nalmefene metabolized?

A

metabolized in the liver by hepatic conjugation

87
Q

What are the side effects of nalmefene?

A

pulmonary edema

88
Q

What is methylnaltrexone?

A

quaternary opioid receptor agonist
doesn’t penetrate the CNS b/c it is highly ionized
attenuates morphine induced delayed gastric emptying
decreases incidence of nausea

89
Q

True or false: If you have an allergy to fentanyl, you’re allergic to morphine.

A

False they do not cross-react

also true opioid allergies are very rare- mostly histamine release, orthostatic hypotension, and N/V

90
Q

Opioid immune modulation

A

chronic opioid use can compromise immune function
opioid receptors are present on immune cells & allows for immunosuppression-depression of NK cell
following prolonged exposure or abrupt withdrawal
pain itself can also impair immune function

91
Q

Opioids are shown to decrease

A

the amount of anesthetic gas required

92
Q

What are the advantages of PCAs?

A

decreased healthcare provider workload, increased patient satisfaction, lower opioid consumption, inherent safety

93
Q

What PCA in the first stage of labor has been shown to provide good analgesia while minimizing neonate effects?

A

remifentanil

94
Q

Post surgery we tell moms to

A

dump for 24 hours even though concentration of fentanyl & sufentanil is negligible in breast milk

95
Q

Where do neuraxial opioids target?

A

placed intrathecally to target Mu receptors in the substantia gelatinosa in the spinal cord

96
Q

Unlike local anesthetics, neuraxial opioids

A

do not result in sympathectomy, sensory block or weakness

97
Q

epidural placement of opioids results in:

A

Mu receptors and systemic absorption
offers minimal to no over IV administrtion
uptake into fat, systemic absorption, and diffusion across dura

98
Q

With neuraxial opioids,

A

epinephrine can enhance intrathecal effects of morphine

99
Q

Epidural injection of neuraxial opioids results in

A

similar blood concentrations produced by IM injection

100
Q

Pharmacokinetics of neuraxial opioids:

A

uptake into fat, systemic absorption or diffusion across dura
dependent on liphophilicity, only 3% of epidural
morphine crosses the dura to enter the CSF
Less lipid soluble drugs more likely to stay in CSF
morphine movement can result in delayed
depression of ventilation
coughing and straining can facilitate this
lumbar to cisterna magna (1-2 hours) 4 and lateral
ventricles (3-6 hours)

101
Q

What are the side effects of neuraxial opioids?

A

Dose dependent
Pruritis- related to cephalad migration and interaction with trigeminal nucleus
N/V
urinary retention- common in young males d/t interaction of opioid with spinal cord receptors in the sacrum
depression of ventilation- CSF migration and interaction with ventral medulla (morphine)
pulse ox, oxygen

102
Q

Additional side effects of neuraxial opioids

A

sedation
myoclonus rare
reactivation of herpes virus (trigeminal nucleus)
miosis, nystagmus, and vertigo (reversible with naloxone), delay in gastric emptying, priapism
spinal cord damage (needs to be preservative free!)

Duke Pharmacology- Hannah (14 decks)

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