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SRNAPharmacology II > OPIOID Agonist /Anta > Flashcards

OPIOID Agonist /Anta Flashcards

1
Q

Opioid, Greek word for

A

Juice

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2
Q

Narcotic

A

Greek work for Stupor

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3
Q

Term opioid include

A

opioid agonists
opioid antagonists
opioid agonist-antagonists.

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4
Q

Opioid- unique

A

Provide analgesia without loss of touch, proprioception or consciousness

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5
Q

Antagonists

A

Binds to a receptors site and blocks and agonists from binding

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6
Q

One opioid associated with loss of touch

A

lidocaine

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7
Q

Semisynthetic opioids

A
  • From modified Morphine molecule
  • Codeine
  • Heroin
  • Hydromorphone
  • Oxycodone
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8
Q

Hydropmorphone is _____times more potent than morphine

A

EIGHT

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9
Q

Synthetic Opioids

A 
Fentanyl
Sufentanil
Alfentanil
Remifentanil
Methadone
Meperidine
Tramadol
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10
Q

Mechanism of action

A

• Opioids in ionized state bind strongly at the
anionic opioid receptor site
• Only levorotary forms of the opioid exhibit
agonist activity

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11
Q

Mechanism of action (read)

A

Opioids- agonists at stereospecific opioid receptors
Presynaptic and post synaptic sites (inhibit
neurotransmitters)
In CNS-
Principally the brainstem and spinal cord
In peripheral tissues
Opioid receptors on primary afferent neurons

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12
Q

These opioid receptors on primary afferent neurons are

activated by 3 endogenous peptide opioid receptor ligands:

A

Enkephalins
Endorphins
Dynorphins

Opioids mimic these endogenous ligands & bind to opioid
receptor and modulate pain

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13
Q

Mechanism of opioid Principle effect

A

Principle effect of opioid receptor activation is ⇩
neurotransmission

Decrease largely due to presynaptic inhibition of
Ca++ channels= ⇩ neurotransmitter release
Acetylcholine
Dopamine
Norepinephrine
Substance P
Serotonin
Postsynaptic inhibition of evoked activity may
also occur

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14
Q

Presynaptic opioid receptors

A

G coupled protein receptor
• Leads to ⇩intracellular cAMP concentration, ⇩ Ca+
+ ion influx and inhibits the release of excitatory neurotransmitters (Glutamate,substance P)

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15
Q

Mu 1 receptors

A
  • Mu1 – produces analgesia (Supraspinal & spinal)
  • Euphoria
  • Low abuse potential
  • Miosis
  • Urinary retention
  • Hypothermia
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16
Q

Agonists of Mu 1

A

Endorphins
Morphine
Synthetic opioids

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17
Q

Antagonists of Mu 1

A

Naloxone

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18
Q

• Mu2 –responsible for

A
  • Analgesia (spinal)
  • Hypoventilation
  • physical dependence (addiction)
  • Constipation- marked
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19
Q

Mu2 Agonists

A

Endorphins
Morphine
synthetic Opioids

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20
Q

Mu2 antagonists

A

Naloxone

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21
Q

Receptors

A

Mu, Delta and Kappa
• All 3 classes couple to G proteins and
subsequently inhibit adenyl cyclase, ⇩
conductance of voltage gated calcium channels or
open potassium channels
• All of these effects = ⇩ neuronal activity
• Mu or morphine receptors are principally
responsible for supra spinal and spinal analgesia

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22
Q

POSTSYNAPTIC OPIOID RECEPTORS

A

• G protein coupled receptor- all opioid receptors
• Antagonize Adenyl cyclase
• ⇩ cAMP
⇧ K channels
resting membrane potential is more negative
Makes it more difficult for the neuron to propagate a
signal

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23
Q

Kappa receptors responsible for ?

A 
Kappa Receptors
• Analgesia (supraspinal & spinal)
• Sedation
• Dysphoria
• Low abuse potential
• Miosis
• Diuresis
Antagonist
Naloxone
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24
Q

Kappa agonists

A

Agonists
Dynorphins- cause inhibition of neurotransmitter release via type N calcium channels which results in analgesia
• Less respiratory depression, but may cause diuresis and dysphoria
• High intensity painful stimulation may be resistant to the analgesic
effect of kappa receptors
• Opioid agonist-antagonists often act principally on kappa receptors

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25
Q

Kappa antagonist

A

Naloxone

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26
Q

• Delta Receptors

A 
Analgesia (supraspinal & spinal)
• Antidepressant effects
• Physical dependence
• Ventilatory depression
• Constipation- minimal
• Urinary retention
• May modulate the activity of the Mu receptor
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27
Q

Delta agonists

A
  • Responds to the endogenous ligand enkephalin

* No Delta selective agents, but several are being researched

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28
Q

Neuraxial Opioids

A

Epidural or subarachnoid/spinal/intrathecal

space

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29
Q

• Opioid receptors (principally Mu) are in

A

substantia gelatinosa of the spinal cord

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30
Q
  • Opioids given neuraxial, rather than IV or
    regional local anesthetics injection, are
    not associated with _______
A

sympathetic nervous system denervation
skeletal muscle weakness
Loss of proprioception

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31
Q

Epidural dose is __________times ____dose

A

Analgesia is dose related and specific for visceral rather than somatic pain is 5-10 times subarachnoid dose
⇩ MAC for volatile anesthetics
Clinicians must evaluate patient for contraindications to epidural injection

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32
Q

Duramorph ______– epidural

Duramorph_______—spinal

A

3-5 mg

0.1-0.3mg

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33
Q

Know Coagulation status

A

To prevent epidural hematomas

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34
Q

Epidural administration

A

• <1mm from spinal cord, separated by 2 meninges
• Dura and Arachnoid
•

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35
Q

• Opioids placed in the epidural space undergo

A

uptake into the epidural fat, systemic absorption (epidural
veins), or diffusion across the Dura (mu receptors on
spinal cord)into the CSF

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36
Q

What penetrates the Dura mater faster?

A

Highly lipid soluble and low molecular weight

penetrate Dura faster

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37
Q

CSF concentration of sufentanyl (1000xx more lipid soluble)peaks in about ____, fentanyl in about ______
Morphine only _____cross the dura to the CSF
If drugs is poorly lipid soluble

A

• CSF concentration of Sufentanil peaks in about 6
minutes, fentanyl in about 20
• Morphine peaks in 1-4 hours in CSF
• Morphine only 3% crosses the Dura to the CSF
• Poorly lipid soluble will have slower onset and longer
duration of action

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38
Q

LUMBAR INJECTION

A

Most common location for epidural is in lumbar
spine
• Epidural space largest in the lumbar region
• Spine is most perpendicular in lumbar region
• Spinal cord ends at L-1

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39
Q

LUMBAR EPIDURAL

A

Most common location for epidural is in lumbar
spine
• Epidural space largest in the lumbar region
• Spine is most perpendicular in lumbar region
• Spinal cord ends at L-1

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40
Q

NEURAXIAL OPIOIDS
After epidural injection fentanyl blood levels peak
________
_________ peaks faster
• Morphine blood levels peak in _________

A

After epidural injection fentanyl blood levels peak
in 5-10 minutes
• Sufentanil peaks faster
• Morphine blood levels peak in 10-15 minutes
• Epidural administration of morphine, fentanyl and
sufenta produce opioid blood levels similar to
blood levels by IM injection of equal dose
• Epinephrine with opioid will decrease systemic
absorption but won’t decrease diffusion of
Morphine into the CSF

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41
Q

• Epidural administration of morphine, fentanyl and
sufenta produce opioid blood levels similar to
blood levels by IM injection of equal dose
• Epinephrine with opioid will

A

decrease systemic absorption but won’t decrease diffusion of Morphine into the CSF

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42
Q

Subarachnoid (intrathecal) lipid soluble opioids

fentanyl

A

• Rapidly absorbed in spinal cord

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43
Q

Subarachnoid (intrathecal) morphine + epinephrine

A
  • Increase the block density
  • Decreases intravascular absorption
  • Prolongs duration of action of lipid soluble local anesthetics
  • doesn’t alter duration of highly protein bound LA
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44
Q

Subarachnoid (intrathecal) water soluble (morphine)

A
  • Doesn’t get absorbed intravascular
  • Floats in CSF –movement to brainstem
  • May cause delayed apnea
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45
Q

• Side effects of neuraxial ( Epidural and Spinal)

opioids

A
  • Pruritus
  • Nausea/vomiting
  • Urinary retention
  • Depression of ventilation
  • Sedation
  • CNS excitation
  • Viral reactivation
  • Neonatal morbidity
  • Sexual, ocular, GI, and Thermoregulation dysfunction
  • Water retention
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46
Q

PRURITUS

A

MAY GIVE BUPRENEX< (WILL TREAT PRURITIS AND NOT REVERSE ANALGESIA EFFECT)

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47
Q

• Side effects are caused by the opioid in the CSF
or systemic circulation
• Side effects are

A

dose dependent

Pruritus
• Nausea/vomiting
• Urinary retention
• Respiratory depression

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48
Q

Most common SE with neuroaxial opioids

A

Pruritus-
usually localized-face, neck, upper thorax
Usually within a few hours of injection
Likely R/T cephalad migration in CSF
Can relieve with opioid antagonist (BUPRENEX)

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49
Q

URINARY RETENTION

A

Urinary Retention
• Most common with young males, R/T interaction
of opioid receptors in the sacral spinal cord
• This interaction promotes inhibition of sacral
parasympathetic nervous system outflow and
causes detrusor muscle relaxation and ↑ in max
bladder capacity -> bladder retention

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50
Q

• Morphine can cause marked

A

detrusor relaxation in 15 min and can last up to 16 hours

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51
Q

• Most serious side effect OF OPIOIDS

OCCURS IN _____PATIENTS

A 
Respiratory Depression
• Occurs in about 1% of patients
• May occur within minutes or hours later
Early depression occurs within 2 hours
Most likely due to systemic absorption
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52
Q

Respiratory Depression
Late depression occurs > ______ after injection
due to ___________
All reports of clinically significant delayed depression is due to morphine
No respiratory depression after 24 hours

A

Late depression occurs > 2 hours after injection
due to cephalad migration of opioid in CSF and
interaction with receptors in the ventral medulla
All reports of clinically significant delayed depression is due to morphine
No respiratory depression after 24 hours

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53
Q

Increases risk of Respiratory depression

A

• Respiratory depression
• Increased risk with concomitant use of IV opioid or
sedative
• Coughing may affect movement of CSF and ↑risk of
depression of ventilation

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54
Q

Ventilatory depression risk is increased with:

A 
High opioid use
low lipid solubility of opioids
Concomitant IV opioid/
sedative use, lack of opioid tolerance, advanced age,
Increased intrathoracic pressure
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55
Q

Diagnosis of respiratory depression
What does it decrease
All leads to ______eventual _______

A 
• Decreasing RR
• Decreasing MV
• Causes decreased SpO2 reading
- Increased somnolence (hypercarbia)
- May see increased Blood pressure
- All leads to apnea
- Eventual cardiopulmonary arrest
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56
Q

Opioids Side effects sedation

A

Sedation
• Dose related with all opioids especially sufentanil
• Mental status changes i.e. paranoid psychosis, catatonia,
hallucinations can occur- reversible with Naloxone

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57
Q

Opioids side effects CNS excitation

A

Most likely due to cephalad migration in CSF->
interaction with non-opioid receptors in brainstem and
basal ganglia-> block glycine or GABA inhibition
Tonic skeletal muscle rigidity is rare with neuraxial

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58
Q

Opioids side effects: Viral Reactivation

A

Link between OB patients and reactivation of herpes

virus with epidural morphine use

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59
Q

Miscellaneous side effects

A

• PRESERVATIVE FREE OPIOIDS (and Local Anesthetics) ONLY

  • Sustained erection
  • Miosis, nystagmus and vertigo- (after morphine)
  • Delayed gastric emptying
  • Inhibiting shivering- may cause ↓ temp
  • Oliguria, water retention leading to peripheral edema
  • Spinal cord damage
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60
Q

Duramorph is good because it is

A

PRESERVATIVE FREE

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61
Q 
MORPHINE Intro
Produces?
Better for what type of pain? 
Works best if\_\_\_\_\_\_
In absence of pain may cause 
\_\_\_\_\_\_\_
A

Opioid that all other opioids are compared to
• Produces- analgesia, euphoria, sedation and ↓
concentration
• Morphine is better for dull pain than sharp
• Works best if given prior to painful stimulus
• In absence of pain may cause dysphoria rather than
euphoria
• Effective against visceral as well as skeletal muscles and
joints
• Water soluble molecule

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62
Q

• Morphine peak effect
• _________– rapid onset
• IM for peak effect
Oral morphine-

A

IV-15-30 minutes
45-90 minutes

absorption from GI tract is limited

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63
Q

For morphine, plasma does not correlate with

A

Clinical effect.

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64
Q

Morphine Pharmacokinetics

A

• Only a small percentage gains access into the
CFS (<0.1%)
• Reasons of poor penetration into the CNS include:
poor lipid solubility, high ionization at
physiological pH, protein binding, rapid
conjugation with glucuronic acid
• Hyperventilation will make the blood more
alkaline and ↑ non-ionized fraction and ↑ passage
into the CNS

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65
Q

• Respiratory acidosis (hypoventilation) will do what?

A

decrease non ionized portion but may lead to
higher CNS concentrations due to ↑ cerebral blood
flow due to the ↑ carbon dioxide levels

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66
Q

Morphine accumulates

A

accumulates rapidly in the kidneys, liver
and skeletal muscles and unlike fentanyl does not
undergo significant first pass effect into the lungs

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67
Q

Principle pathway is

A

Conjugation with glucuronic acid

in hepatic and extra hepatic sites, mainly the kidneys

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68
Q

• Principle metabolites of Morphine

A

• Morphine -3-glucuronide (75-80%)Pharmacologically
inactive
• Morphine-6-glucuronide (5-10%)-pharmacologically activemore potent and longer duration of action than morphine

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69
Q

MAO inhibitors and Morphine

A

Inhibit formation of glucuronide metabolites

Leads to exaggerated effects(morphine doesn’t break down)

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70
Q

ELIMINATION ON MORPHINE

A

• Elimination of morphine glucuronide may be
impaired in renal failure, leading to
accumulation of metabolites and unexpected
respiratory depression with small doses

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71
Q

Formation of glucuronide conjugates may be

impaired by

A

MAOI’s, which may cause exaggerated effects of morphine

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72
Q

Morphine elimination half time
________in plasma concentration of morphine after _______Is principally due to ________
Amount in urine?

A

Decrease in plasma concentration of morphine
after initial distribution is principally due to
metabolism
• Only a small amount of unchanged drug is
excreted in urine
• Plasma concentrations are higher in the elderly

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73
Q

• Clearance of morphine is

A

↓ in the first 4 days of life making neonates more sensitive to respiratory depression

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74
Q

Morphine in women vs men

A

Greater analgesic potency and slower speed of
onset in women
• Higher postoperative opioid consumption in men

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75
Q

CV and morphine

•

A

high doses (1mg/kg IV) to supine
normovolemic patient is unlikely to cause a direct
myocardial depression or hypotension

76
Q

Morphine and position changes

what is it caused by?

A

Change from supine to standing may cause hypotension and syncope
• Caused by impairment of compensatory sympathetic
nervous system response
• Decrease in vasomotor tone leads to decreased preload,
cardiac output and blood pressure

77
Q
  • CV

* ↓ BP can occur due to morphine induced______or _________

A

bradycardia or histamine release

78
Q

Bradycardia with morphine due to

A

↑ activity over vagal nerves, stimulation of vagal nuclei in the medulla, also depressant effect on SA node and slowed conduction through AV node

79
Q

• Opioids given prior to induction _______heart rate during exposure to volatile anesthetics (VA) with/without surgical stimuli
• Histamine release and hypotension can be minimized by
limiting the rate of administration to_____

A

may slow
5mg/minute IV,
maintain pt supine and well hydrated

80
Q 
Morphine \_\_\_\_\_\_\_\_\_\_\_\_produces
substantial histamine release and a ↓ in BP &amp; SVR
• Response varies among patients
•\_\_\_\_\_\_\_\_\_\_\_\_\_minutes does not
cause histamine release, neither does
A

1mg/kg over 10 minutes
Fentanyl 50mcg/kg over 10

sufentanil

81
Q

Give ______ AND*** _______to prevent

changes in BP and SVR ? Does it prevent histamine release?

A

Pretreatment with H1, H2 blockers does not

prevent histamine release but does

82
Q

CV and morphine

• Morphine does not sensitize the heart

A

to catecholamines or predispose to dysrhythmias as long as hypercarbia or
arterial hypoxemia doesn’t result from ventilatory
depression

83
Q

Rise CO2

A

is a stiumulus to breathe

Patient with narcotics does not respond

84
Q

All opioids cause a dose dependent depression of
ventilation
• Primarily due to_________
• Depression of ventilation characterized

A
  • agonist effect at Mu 2 receptor leading to a direct depressant effects on brainstem ventilation centers
  • by ↓ responsiveness to CO2.
85
Q

• Opioids depress cough by effects on the

A

medullary cough centers, codeine greatest effect

86
Q

Ventilation and morphine

3 things increase

A 
Dose dependent depression of ciliary activity
• ⇧ airway resistance
• ⇧ bronchial smooth
muscle contraction
• ⇧ Histamine release
87
Q

Hypoventilation =

A

⇧ CBF & ⇧ ICP

88
Q

Opioids in absence of ___________decrease ____and _____
Caution in head injury pt due to effects on
wakefulness, producing miosis, ventilation depression
and associated __________

A

Opioids in absence of hypoventilation ⇩ CBF ⇩ICP
Caution in head injury pt due to effects on
wakefulness, producing miosis, ventilation depression
and associated ↑ in ICP, also BBB integrity could be
impaired resulting in ↑ sensitivity to opioids

89
Q

Rapid IV administration of opioids can cause

• Risk greatest with _____then ___then

A

skeletal muscle rigidity, especially the abdomen and thoracic area- leading to difficult ventilation
Fentanyl then remifentanil, then morphine

90
Q

Sufentanil may cause ______-and ________

A

Laryngospasm & ⇧ difficulty to ventilate

91
Q

• Opioids can cause

Equal analgesic doses of opioids ↑ bile duct pressure
above pre drug levels
• Fentanyl 99%
• Morphine 53%
• Meperidine 61%
A

spasm of biliary smooth muscle,
resulting in ↑ intrabiliary pressure associated with
epigastric distress and biliary colic

92
Q

a. During cholangiogram spasm may be misdiagnosed as a stone- __________may reverse opioid induced biliary smooth muscle spasm
b) Naloxone may _________

A

Glucagon (2mg IV)

b)also reverse spasm but will also reverse
analgesia

93
Q

Opioids can produce spasms of the___________
• Delayed passage =
• Morphine was once used to treat diarrhea

A

GI tract, causing constipation, biliary colic & delayed
gastric emptying
↑ water absorption = ↑ constipation

94
Q

• Morphine ____peristaltic contraction _____tone of pyloric sphincter, ileocecal valve and _____sphincter

A

↓ propulsive peristaltic contraction and ↑ tone of pyloric sphincter, ileocecal valve and anal sphincter

95
Q

What causes opioids induced N/V/D? (most important)

A

Opioid induced N/V are caused by direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle

96
Q

Morphine may also cause N/V by

A

↑ GI secretions and delaying passage of intestinal contents

97
Q

Morphine can cause urinary retention by

A

↑the tone and peristaltic activity of the ureter
• Giving an anticholinergic can reverse these effects
• Urinary retention

98
Q

Morphine and skin

A

• Morphine causes cutaneous blood vessels to dilate,
causing skin of the face, neck and upper chest to become flushed and warm
• Changes in cutaneous circulation are in part caused by
histamine release

99
Q

• Histamine is responsible for_____and_____ at the injection site

A

urticaria and erythema

100
Q

Chronic opioid use by the mom may result

A

in physical dependence (intrauterine addiction)

101
Q

Administration of naloxone may cause life

threatening

A

neonatal abstinence syndrome

102
Q

IMPORTANT: Drugs interactions with some opiods? what exaggerates ventilatory depression?

A 
Ventilatory depression effects of some opioids
may be exaggerated by:
• amphetamines
• phenothiazine
• MAOI
• TCA’s
103
Q

Cross tolerance develops between all opioids
• Tolerance can occur without physical dependence but
the reverse does not seem to occur
• Tolerance usually takes _____with analgesia
doses of Morphine
• Repeated use causes compulsive desire
(psychological) and continuous need (physiologic) for
drug

A

2-3 weeks

104
Q

• Tolerance develops to_____, ______, ________, _____ and ______ but not to effects on______and _______

A

analgesia, euphoric, sedative,
depression of ventilation and emetic effects
Miosis and constipation

105
Q

WITHDRAWAL of opioids
• Initial symptoms include (6)
and Later symptoms include

A

• Yawning, diaphoresis, lacrimation, or coryza, insomnia
and restlessness
Abdominal cramps, nausea, vomiting and
diarrhea reach their peak in 72 hours and decline
over the next 7-10 days

106
Q

Abrupt withdrawal of opioids leads to_______

Prevention?

A

increases in sympathetic nervous system
Prevention
Clonidine diminishes transmission in sympathetic pathways in the CNS and may help prevent withdrawal symptoms

107
Q

What is the Principal manifestation of OVERDOSE?
_________ which may lead to apnea

• Pupils are______ and ______ unless severe
hypoxemia is present which results in mydriasis

Skeletal muscles are may occur

• Pulmonary edema commonly occurs

A

depression of ventilation

Slow breathing frequency

symmetric and miotic

flaccid and airway obstruction

108
Q

• Triad of ______. _______ and _______should

suggest opioid overdose

A

Miosis, hypoventilation and coma

109
Q

Treatment of Overdose Treatment
- Ventilation?
• Opioid antagonist

• If no response after______- question diagnosis
• Continuous infusion for adults __________
Caution- opioid antagonist to treat opioid
overdose may cause

A

Mechanical ventilation
Naloxone 0.4-2mg every 2-3 minutes as needed

10mg

Adults up to 0.8mg/kg/hr

acute withdrawal

110
Q

MEPERIDINE is a ______Agonist at

A

• Synthetic opioid agonist at mu and kappa opioid
receptors
• Structurally similar to atropine and produces a
mild atropine like antispasmodic effect

111
Q

What are analogues of Meperidine?

A

• Fentanyl, Sufentanil, alfentanil and remifentanil

112
Q

• Principle pharmacologic effects of Meperidine resemble

A

morphine

113
Q

Meperidine pharmacokinetics

A

1/10 as potent as morphine
Duration of action 2-4 hours, which is shorter
then morphine

114
Q

In equal doses causes as much

A

sedation, euphoria, depression of ventilation, nausea and

vomiting as morphine

115
Q

Meperidine Metabolism

A

Hepatic metabolism is extensive, 90% metabolized to normeperidine (demethylation) and meperidinic acid (hydrolysis)
• More acidic urine can speed elimination
• Decreased renal function-⇧ risk for seizure

116
Q

Primary route of elimination of Meperidine? what is dependent on ?

A

Urine excretion ; pH

117
Q

If urinary pH <5 than up to

A

25%of meperidine is eliminated unchanged in the urine

118
Q

_______can lead to accumulation of normeperidine–> increase risk of ______

A

Decrease renal function : Seizures

119
Q

Only narcotic to cause Mydriasis

A

Demerol (because of anticholinergic side effect)

120
Q

Metabolite Normeperidine what is the half time

A

Elimination Half time of 15 hours

• Pt with renal failure half life may be >35 hoursc

121
Q

Normeperidine is ______as potent as meperidine as an

analgesi

A

½

122
Q

Normeperidine causes CNS stimulation-

A

toxicity manifests as myoclonus and seizures- most likely during prolonged meperidine administration as during PCA, especially with renal function

123
Q

Meperidine half time

A

3-5 hours

124
Q

Meperidine protein binding and elderly

A

PB 60%
• Elderly have decreased protein binding and
increased plasma concentrations of free drug and
increased sensitivity to the opioid

125
Q

Meperidine may be effective in suppressing post

operative

A

shivering that may cause increases in metabolic o2 consumption

126
Q

IV meperidine causes a massive

A

release of histamine

therefore is usually given IM

127
Q

• Anti-shivering effects of meperidine may be due

to

A

stimulation of kappa receptors (10% of drugs activity)

128
Q

Meperidine is a potentt

• Not useful to treat diarrhea, no antitussive effects

A

alpha 2 agonist-this might contribute to the anti-shivering effect

129
Q

• Clonidine is more effective at

A

reducing post op shivering

130
Q

Side effects of meperidine

A

Orthostatic Hypotension

131
Q

Hypotension _______, ______and ________ than with morphine

A

more frequent and more profound, more ventilatory depression

132
Q

• Meperidine given to pts on antidepressants

(MAOI, fluoxetine) may cause

A

Serotonin syndrome aka serotonin toxicity

133
Q

Serotonin Syndrome Symptoms are-

A

Autonomic instability with htn, tachycardia, diaphoresis, hyperthermia,
confusion, agitation, hyperreflexia
• Severe cases- coma seizures, coagulopathy and
metabolic acidosis may develop

134
Q

Fentanyl Structurally related to______________

A

meperidine

100 times more potent than morphine

135
Q

75% of initial fentanyl dose undergoes_______

• Effect site equilibration time is

A

first pass pulmonary uptake- limits the initial amount of
drug that reaches the systemic circulation
6.4 minutes

136
Q

• If multiple Iv doses or continuous infusion are

given inactive sites

A

become saturated

137
Q

FENTANYL METABOLISM

A

• Metabolized by N-demethylation, producing
norfentanyl, which is structurally related to normeperidine
• <10% fentanyl is excreted unchanged in urine

138
Q

Norfentanyl is excreted in the_____and

detectable for

A

urine ; 72 hours after a single IV dose

139
Q

• Fentanyl metabolites–_________pharmacological

action

A

minimal

140
Q

• Elimination half time of Fentanyl is _____than morphine and reflects a _________due to__________

A

Greater; larger Vd due to greater lipid solubility

141
Q

Fentanyl in elderly

A

↑ elimination half time is D/T a ↓ in clearance, due to ↓ hepatic blood flow, ↓ albumin production and ↓ hepatic enzyme activity

142
Q

FENTANYL CONTEXT SENSITIVE HALF

TIME

A

As duration of continuous infusion ↑ past 2 hours, the
context-sensitive half time of fentanyl becomes greater
then sufentanil

143
Q

All opioids show a __________with initiation of CPB

• ↓ in plasma concentration is greater with fentanyl d/t a

A

↓ in plasma concentration; significant portion of the drug will adhere to the cardiopulmonary bypass circuit

144
Q

• The ↓ is least with opioids with

A

a large Vd (alfentanil, sufentanil) and have a more stable

plasma concentration

145
Q

Fentanyl Clinical Uses

Analgesia

A

Low dose 1-2 mcg/kg IV for analgesia
• 2-20 mcg/kg IV as an adjunct to inhaled anesthetics to blunt tachycardia and htn associated with laryngoscopy or sudden change in level of surgical stimulation

146
Q

**Hallmark of fentanyl

A

STABLE HEMODYNAMICS profile
Lack of Histamine release
Lack myocardial depression effects

147
Q

High dose of fentanyl

A

• High dose 50-150mcg/kg have been used alone

to produce surgical anesthesia

148
Q

• CV effects of fentanyl

A

• No histamine release-no dilation of venous vessels to
cause hypotension
• Carotid sinus baroreceptor reflex control of heart rate is
depressed by fentanyl
• Bradycardia more prominent than with morphine

149
Q

Fentanyl and muscle

A

CHEST WALL RIGIDITY

Difficult to differentiate myoclonus from muscle rigidity.

150
Q

Analgesic doses potentiates the effects of ________and _______the dose requirements of _______

A

Analgesic doses potentiate the effects of midazolam and decrease the dose requirements of propofol
• Marked synergism with opioid- benzodiazepine
combination with respect to hypnosis and
depression of ventilation

151
Q

SUFENTANIL- SUFENTA

A

Structurally related to fentanyl
• 5-10 times more potent than fentanyl
• Greater affinity for opioid receptors than fentanyl
• Dose that produces seizures is 1000 times the
analgesic dose

152
Q

Fentanyl vs sufenta on post op analgesia

A

• Less ventilatory depression than Fentanyl with

longer postoperative analgesia

153
Q

SUFENTANIL PHARMACOKINETICS

Vd, Elimination half time

A

• Elimination half time is between fentanyl and alfentanil
• Vd and elimination half-time are ↑ in obese pt- r/t
highly lipid soluble
• <1% unchanged in urine

154
Q

Effect site equillibration is

A

6.2 min similar to fentanyl

155
Q

Protein binding of Sufentanyl

A
  • Highly protein bound (92.5%) =low Vd
  • Undergoes significant first pass pulmonary effect
  • Undergoes significant liver metabolism
156
Q

• Termination of action of Sufentanyl
• Context sensitive half time
• Lower than alfentanil for infusions up to 8 hours
• Sufentanil has a larger Vd than alfentanil
• May have a more favorable recovery profile than
alfentanil for longer procedures

A

redistribution

• Can accumulate over time

157
Q

Clinical uses of Sufentanyl

A

More rapid induction, earlier emergence and earlier
extubation when compared to higher doses of fentanyl or
morphine
• Causes chest wall rigidity, N/V and bradycardia similar to
fentany

158
Q 
Alfentanyl: ALFENTA
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
•\_\_\_\_\_\_\_\_\_\_potent than fentanyl
• 1/3 the duration of action of fentanyl
• onset of action\_\_\_\_\_\_\_\_
A

Analogue of fentanyl
1/5-1/10 less
Rapid 1.4 min

159
Q

For alfentanyl: Rapid effect site equilibration due

A

to low pKa90% of drug is non-ionized at physiologic pH

160
Q

Pharmacokinetics of Alfentanyl

A

• Vd is 4-6 times smaller then fentanyl- lower lipid
solubility, higher protein binding than fentanyl
• Metabolized in liver by cytochrome P-450 3A
• Hepatic clearance of 96% from plasma in 60 min

161
Q

• Clinical uses of Alfentanyl

A

• Rapid onset of action is useful when noxious
stimuli is acute but transient (laryngoscopy, retro
bulbar block)
• Useful for outpatient procedures
• Less N/V than fentanyl and sufentanil
• General anesthesia adjunct 5-15 mcg/kg IV q
5-20 minutes

162
Q

• Caution with Parkinson’s pt in using ______ may cause

A

Alfentanyl; acute dystonia

163
Q

Remifentanyl Selective_______________
• Similar potency to fentanyl
• 15-20 times more potent than alfentanil
• Effect site equilibration similar to alfentanil
• Only opioid not metabolized in the liver
• Not affected by renal failure

A

mu receptor opioid agonist

164
Q

Only narcotic not eliminated by the liver

A

REMIFENTANYL (ALTIVA)

165
Q

REMIFENTANYL Structurally unique- metabolism

A

ester linkage makes drug susceptible to hydrolysis by nonspecific plasma and tissue esterase’s

166
Q

• Unique metabolism causes the following

characteristics of REMIFENTANYL

A

• Brevity of action
Rapid onset and short duration of action = precise and titratable effect
Non-cumulative effects
Rapid recovery after discontinuation of infusion

167
Q

Pharmacokinetics of REMIFENTANYL

Onset, clearance, offset

A

• Very potent
Small Vd
Rapid onset (similar to alfentanil)
Reaches steady state in 10 minutes of infusion start
Rapid clearance (3L/min)
Low variability compared to other IV anesthetics relationship between infusion rate and opioid
concentration is less variable

168
Q

Offset of Remifentanyl

A

Complete offset in 6-8 minutes after stopping infusion

169
Q

Clinical use of REMIFENTANYL

A

Case where profound analgesic effect is desired
transiently (retro bulbar block)
• Long procedures when a quick recovery is desirable
• Short duration of action may be a disadvantage for
surgery with considerable post op pain
• Care must be taken not to stop infusion accidentally
• N/V, ventilation depression, ↓ HR and BP may occur

170
Q

Anesthesia induction with remifentanyl?

A

• Anesthesia induced with 1mcg/kg IV over 60-90 seconds
or with gradual initiation of infusion at 0.5-1.0 mcg/kg IV
for about 10 minutes, before a hypnotic prior to tracheal
intubation

171
Q

OPIOID AGONIST USED POST OP
Half life _________
Mg dose = _______of aspirin
120mg IM

A 
Codeine- similar to morphine
Half life 3-3.5 hours
• Effective anti-tussive at 15 mg dose
• 60mg oral = to 650 mg of aspirin
• 120 mg IM codeine = to 10mg morphine
• Limited first pass hepatic effect due to methyl
group for hydroxyl group- accounts for efficacy of
oral codeine
172
Q

Remifentanyl IV not recommended because

A

Significant histamine release

Hypotension

173
Q

Codeine converts to

A

Morphine

174
Q

Derivative of morphine

Remifentanyl

A
  • 8 times more potent then morphine
  • Shorter duration of action than morphine
  • Used similar to morphine
  • Side effects similar to morphine
175
Q

TRAMADOL Centrally acting analgesic with a moderate affinity for the ______, ______ and________
• 5-10 times less potent analgesic than morphine

A

mu receptor, weak kappa and delta opioid receptor affinity

176
Q

Tramadol actions

A

• Enhances function of spinal descending inhibitory
pathways by inhibition of neuronal reuptake of
nor epinephrine and serotonin and presynaptic
stimulation of serotonin release
• Dose 3mg/kg to treat moderate to severe pain
• Seizures reported with epilepsy and drugs that
lower the seizure threshold-antidepressants

177
Q

Opiods agonist-antagonists

A

Bind to mu receptor and produce limited response
(partial agonist) or no effect (competitive
antagonist)•
Partial agonist at kappa and delta receptors
• Side effects- similar to opioid agonist- may cause
dysphoria

178
Q

OPIOD AGONIST-ANTATONIST adv and disadv.

A

• Advantages- analgesia with low risk of depressed
ventilation, and physical dependence
• Disadvantage- has a ceiling effect

179
Q

• Antagonist effects can attenuate

A

efficacy of subsequent doses of opioid agonist

180
Q

Clinical use of OPIOID AGONIST and ANTAGONIST

A

• Used independently to produce limited level of analgesia
• Ceiling effect on analgesia and respiratory depression, ↑
dose has less profound effect
• Can use in combo with other agents- nitrous oxide,
benzodiazepines
• These combinations are NOT sufficient for surgical
anesthesia

181
Q

Clinical use

•

A

Partially reverse an agonist
• Reverse unwanted effect of opioid without reversing all the analgesic properties
• Opioid agonist-antagonist will not remove all the analgesic properties

182
Q

• Can result in onset of sudden pain which can evoke a severe sympathetic response leading to ↑ BP and HR

A
  • Butorphanol-Stadol

* Nalbuphine-Nubain

183
Q

OPIOD ANTAGONIST Naloxone- Narcan

A

• High affinity for opioid receptor which results in
displacement of agonist from receptor
• Antagonist does not activate receptor but
prevents an agonist from binding to it

184
Q

Uses of Narcan

•

A

Treat opioid respiratory depression present in the
postoperative period
• Treat opioid respiratory depression in neonate
due to maternal administration of opioid
• Treat deliberate opioid overdose
• Treat side effects of itching associated with
neuraxial opioids- agonist-antagonist Nalbuphine
works well for this also

185
Q

Dose of Narcan

A

Dose 1-4mcg/kg IV produces prompt reversal of
opioid induced analgesia and ventilation
depression
• Short duration of action so supplemental doses
may be needed or continuous infusion
• Metabolized in liver (high first pass effect)

186
Q

Side effects of Narcan
what is related to dose and rte?
Administration over?

A

• N/V appear to be related to rate and dose given
• Administration over 2-3 minutes = ↓ N/V
• Fortunately vomiting occurs simultaneously with
awakening which allows for pt to protect their
airway

SRNAPharmacology II (32 decks)

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