This document provides information on opioids including their classification, mechanism of action, receptors, and effects. It discusses specific opioids like morphine, fentanyl, and sufentanil. Morphine is naturally occurring and has a duration of action of 3-4 hours. Fentanyl is 75-125 times more potent than morphine. Sufentanil has an analgesic potency 5-10 times that of fentanyl. All three opioids can cause respiratory depression, the most serious adverse effect. Their use requires monitoring to prevent this.

1. OPIOIDS
Presenter - Dr Tess Jose
PG resident anesthesia

2. CLASSIFICATION OF OPIOIDS

5. MECHANISM OF ACTION
• By GPCR binding- Gi/o type
• • Decrease presynaptic neurotransmitter release and
neuronal transmission
• • Receptor types- mu, kappa, delta
• • Receptor location- at spinal (substantia gelatinosa
at dorsal horn) and supraspinal levels (locus cerulus,
PAG, rostral ventral medulla)
• • Ligand binding site of receptor- anionic, thus, drug
should be in ionized state for effective binding.

6. OPIOID RECEPTORS
• Though opioid receptors are found scattered in CNS
and peripheral tissues, their high densities occur in
five areas of CNS.

10. MECHANISM OF OPIOID INDUCED
ANALGESIA
• •At spinal cord level- receptor in substansia
gelatinosa, abolish afferent pain impulses at the
level of dorsal horn
• At supraspinal level- descending
modulation,neurons in PAG synapse with
interneurons inspinal cord and inhibit pain impulse
generation
• Local site- regionally located opioid receptors

11. NEUROPHYSIOLOGICAL EFFECTS
OF OPIOID
• Analgesia- Excellent analgesic for nociceptive pain,
without loss of consciousness
• Consciousness- Unconsciousness at high doses only,
not suitable as sole anaesthetic since unpredictable,
cause dose dependent MAC reduction, synergistic
effect with hypnotics to cause sedation.
• CBF and metabolic rate- No significant effect on CBF,
decrease cerebral metabolic rate modestly
• ICP- Minimally affected under controlled ventilation

12. Common Opioid Side Effects
• CARDIOVASCULAR SYSTEM
• Hypotension –due to peripheral arterial and venous
dilation depression of vasomotor centre release of
histamine.
• Bradycardia –increased activity of vagal nerves.

13. • RESPIRATORY DEPRESSION
• Inhibiting brainstem respiratory mechanism.
• Opioids induced depression of ventilation is
characterized by decreased respone of these
ventilation centre to carbon dioxide as reflected by
an increse in the resting Paco2.
• Opioids agonist also interfere with pontine and
medullary ventillary centre that regulate rhythm of
breathing, leading to prolong pause between
breaths and periodic breathing.

15. • CENTRAL NERVOUS SYSTEM EFFECTS
• Miosis is due to an excitatory action of opioids on
the Edinger westphal nucleus of occulomotor
nerve.
• In the absence of hypoventilation, opioid decrese
cerebral blood flow and ICP.
• These drugs must be used with caution in patient
with head injury.

16. • CHEST WALL RIGIDITY
• Due to inhibition of striatal release of gamma
aminobutyric acid and increased dopamine
production.
• Majority of resistance to ventilation is due to
laryngeal musculature contraction.
• Treatment is muscles relexation with
neuromuscular blocking drugs or opioid
antagonism with naloxone.

17. • SEDATION
• post operative titration of morphine frequently
induces sedation that precedes the onset of
analgesia.
• Morphine induced sedation should not be
considered as an indicator of appropriate analgesia.

18. • BILIARY TRACT
• Sphincter of oddi may constrict
• Contract biliary smooth muscle
• Result in billary colic

19. • GASTROINTESTINAL TRACT
• constipation effects of the opioids are mediated
through an action of the enteric nervous system and
cns.
• Propulsive peristaltic waves are diminished.
• Tone is increased.
• This delay passage of the fecal mass and allow
increased absorption of water,which leads to
constipation.
• So used in management of diarrhea .

21. • GENITOURINARY SYSTEM
• Ureteral and bladder tone are increased.
• Ureteral colic caused by a renal calculus is made
worse by opioid induced increase in ureteral tone
• Decreased renal plama flow.
• Urine urgency is produced by opioids induced
augumentation of detrusor muscle tone, but, at the
same time, the tone of urinary sphincter is enhanced,
making voiding difficult.

22. • COUGH SUPPRESSION
• Opioids depress cough by effects on the medullary
cough centre.
• The greatest cough suprression occurs with
codeine.
• One useful property of dextrorotatory isomer such
as dextromethorphan is that they can supress
cough but do not produce analgesia or depression
of ventilation.

23. • NAUSEA AND VOMITING
• Opioids stimulate the chemoreceptor trigger zone
in the area postrema of the medulla through delta
receptor.
• Stimulation of dopamine receptor as a mechanism
for opioids induced nausea and voimiting.
• Intraoperative use of opioids is a well known risk
factor for post operative nausea and vomiting.

24. • CUTANEOUS CHANGES
• Morphine causes cutaneous blood vessels to dilate.
• The skin of face,neck and upper chest frequently
become flushed and warm due to release of
histamine.
• Morphine induced histamine release probably
account for conjuctival erythema and pruritus

25. • HORMONAL CHANGES
• Increase prolactin.
• Decreased LH, FSH ,testosterone and estrogen .
• PLACENTAL TRANSFER
• Opioids are readily transported across the
placenta.
• Depression of neonate can occur as a
consequence of administer of opioids to the
mother during labor.

26. • OVERDOSE OF OPIOIDS
• the triad of miosis, hypoventilation and coma
should suggest overdose of opioid.
• Hypotension and seizures develop if arterial
hypoxemia persits.
• Pulmonary edema, upper airway obstruction
occurs.
• Treatment is mechanical ventilation and
administration of an opioids antagonist

28. Morphine
• Chemical Structure
• Naturally occurring opioid which is a phenanthrene
derivative.
• Formulation and Administration
• Clear colourless solution containing 10/15/ 30 mg/ml of
Morphine sulphate
• Tablets containing 5/10/30/60/100/200 mg of Morphine
• Syrup containing 2/10/20 mg/ml
• Suppositories containing 15/30 mg of drug
• Administered IV, IM, PO, rectal, epidural, intrathecal, or SC

29. • Mechanism of Action
• Morphine is an agonist at the u and k- opioid receptors
• Opioids cause their effects by:
• Interaction with pre-synaptic Gi-protein receptors
causing an increase in the K+
• conductance resulting in hyperpolarization of the cell
membrane
• Closure of voltage gated calcium channels by inhibition of
adenylate cyclase (resulting in reduced production of
cAMP)

30. • Pharmacokinetics
• Onset: 5 min (IV), 15-30 min (IM), 20 min (PO)
• Peak Effect: 15-30 min (IV), 45-90 min (IM)
• Duration of Action: 3-4 hours
• Protein Binding: 20-40%

31. • Absorption:
• Oral bioavailability is only 20-25% due to extensive
first pass metabolism.
• Distribution:
• Morphine has a Vd of 3.4-4.7 L/Kg.
• Due to low lipid solubility of the drug, it
equilibrates slowly between the plasma and CSF,
and there is poor correlation between the plasma
levels and effect of the drug.

32. • Metabolism:
• Primarily undergoes hepatic and extra-hepatic
(primarily renal) glucuronidation
• to Morphine-3-glucuronide (75-85%), and
Morphine-6-glucuronide (5-10%), apart from
demethylation to normorphine (5% ). Morphine-3-
glucuronide is pharmacologically inactive.

33. • Morphine-6-glucuronide binds to µ receptors with
the same affinity as Morphine and has 650 times
more analgesic potency as compared to Morphine.
• It is possible that most of the analgesic activity
attributed to Morphine is actually due to
Morphine-6-glucuronide.

34. • Elimination Half Life: 1.7-4.5 hours
• Excretion:
• Primarily in the urine as Morphine glucuronide
conjugates. 10-15% is excreted in the faeces as
conjugated Morphine.

35. Pharmacodynamics
• Analgesic effect:
• Brain: It is well established that the analgesic
effects of opioids arise from their ability to inhibit
directly the ascending transmission of nociceptive
information from the spinal cord dorsal horn and to
activate pain control circuits that descend from the
midbrain, through the rostral ventromedial medulla
(RVM) and periaqueductal grey, to the spinal cord
dorsal horn.

36. • Spinal Cord: Analgesic actions of systemic morphine
are in part mediated by a net inhibitory effect from
the PAG and RVM on nociceptive processing in the
spinal dorsal horn.
• Peripheral mech: Opioids may also produce analgesia
through the peripheral mechanism.
• Immune cells infiltrating the inflammation site may
release endogenous opioid-like substances, which act
on the opioid receptors located on the primary
sensory neuron

37. • CVS:
• Contractility: Morphine produces little or no change
in myocardial contractility
• Cardiac Rhythm Conduction: Morphine may depress
cardiac conduction by a mechanism mediated by
direct membrane actions, as opposed to opioid
receptor interactions
• Myocardial Ischaemia: Opioids have antiarrhythmic
and anti-ischemic action with central and peripheral
opioid receptor
• Circulatory Reflexes: Baroreceptor reflexes were
well preserved by moderate doses.

38. • CNS:
• Effect of opioids on consciousness: Opioids can
reduce the MAC of isoflurane at skinincision in
patients by at least 80%.
• Hallucination: Opioid-induced hallucination is an
uncommon yet significant adverse effect of opioid
treatment, frequently attributed to underlying
psychiatric disease or personality disorder rather
than a direct neurobiological effect of opioids

39. • Cerebral Blood flow & CMR: Opioids generally
produce modest decreases in cerebral metabolic
rate and intracranial pressure (ICP), although the
changes are influenced by the concomitant
administration of other agents and anaesthetic
drugs.
• Opioids also decrease cerebral blood flow (CBF)
when they are combined with nitrous oxide (N₂O).

40. • Muscle Rigidity: Opioids can increase muscle tone
and may cause muscle rigidity.
• Pupil Size: Opioids and most μ- and K-agonists
cause constriction of the pupil by an excitatory
action on the parasympathetic nerve innervating
the pupil.

41. • Respiratory System
• Effects on airway: The antitussive actions of opioids are
well known and central in origin.
• Opioids blunt or eliminate somatic and autonomic
responses to tracheal intubation. They allow patients to
tolerate endotracheal tube placement without coughing or
"bucking."
• Respiratory Depression: Opioids cause dose dependent
respiratory depression, representing the most feared
adverse effect. The incidence of opioid induced respiratory
depression varies from 0.1% to 37%

42. • Uses and Dosage
• Intraop analgesia: 0.05-0.1 mg/Kg IV
• Analgesia :0.05 -0.1 mg/Kg IV, 0.1-0.2 mg/kg IM/SC, 5-20
mg PO, 15-30 mg rectally repeated 3-4 hourly)
• In the management of left ventricular failure/Acute
coronary syndrome 2-4 mg IV repeated every 15 min
• Used along with kaolin in the symptomatic management
of diarrhoea
• Neuraxial anaesthesia: Epidural 30-100mcg bolus /Caudal
0.2-0.4 µg/kg /Intrathecal 300µg in adults

43. • Adverse Effects
• Late respiratory depression, Abuse potential,
Nausea and vomiting
• Pruritis, urinary retention in neuraxial use
• Histamine release-hypotension, urticaria,
bronchospasm
• • Bradycardia
• Hypothermia

44. • Contraindications
• COPD, asthma, and obesity hypoventilation
syndrome (Pickwickian syndrome), Hepatic or renal
failure, Known allergy

45. Fentanyl
• phenylpiperidine-derivative synthetic opioid
agonist that is structurally related to meperidine.
• fentanyl is 75 to 125 times more potent than
morphine.

46. • Pharmacokinetics
• A single dose of fentanyl administered IV has a more
rapid onset and shorter duration of action than
morphine.
• Despite the clinical impression that fentanyl has a short
duration of action, its elimination half-time is longer
than that for morphine because of large vd.
• The larger Vd of fentanyl is due to its greater lipid
solubility and thus more rapid passage into tissues
compared with the less lipidsoluble morphine.

47. • Uses and Dosage
• Fentanyl, 2 to 20 mg/kg IV, may be administered as
an adjuvant to inhaled anesthetics in an attempt to
blunt circulatory responses to
• (a) direct laryngoscopy for intubation of the trachea,
or
• (b) sudden changes in the level of surgical
stimulation
• To provide the analgesic component in general
anaesthesia (1-2mcg/Kg)
• Post-operative pain management
• Analgo-sedation in intensive care unit.

48. • As an adjunct in neuraxial anaesthesia/ for
neuraxial analgesia (50-100 mcg epidurally/ 5-
25mcg intrathecally)

49. • As a transdermal patch for cancer pain management.75
to100 mg per hour result in peak plasma fentanyl
concentrations in about 18 hours that tend to remain
stable during the presence of the patch,
• Each transdermal patch contains a depot of fentanyl that
provides adequate drug to produce stable plasma
fentanyl concentrations for 3 consecutive days.
• Transdermal fentanyl systems applied before the
induction of anesthesia and left in place for 24 hours

50. • Fentanyl may be administered as a transmucosal
preparation (oral) in a delivery device designed to
deliver 5 to 20 mg/kg of fentanyl.
• The goal is to decrease preoperative anxiety and
facilitate the induction of anesthesia, especially in
children.
•

51. • Cardiovascular Effects :Unlike morphine, fentanyl,
even in large doses (50 mg/kg IV), does not evoke
the release of histamine As a result, dilatation of
venous capacitance vessels leading to hypotension
is unlikely

52. • Adverse Effects
• Early Respiratory depression (rarely, it may cause
late respiratory depression due to elution of drug
from muscle)
• Abuse potential
• Nausea and vomiting
• Contraindications
• Known allergy to fentanyl

54. SUFENTANIL
• sufentanil is a thienyl analogue of fentanyl The
analgesic potency of sufentanil is 5 to 10 times that
of fentanyl.
• Sufentanil undergoes significant first-pass
pulmonary uptake (approximately 60%) after rapid
IV injection
• The extensive protein binding of sufentanil (92.5%)
compared with that of fentanyl (79% to 87%)
contributes to a smaller Vd, which is characteristic
of sufentanil.

55. • A single dose of sufentanil, 0.1 to 0.4 μg/kg IV, produces
a longer period of analgesia and less depression of
ventilation than does a comparable dose of fentanyl (1 to
4 μg/kg IV).
• Compared with large doses of morphine or fentanyl,
sufentanil, 18.9 μg/kg IV, results in more rapid induction
of anesthesia, earlier emergence from anesthesia, and
earlier tracheal extubation.
• Sufentanil causes a decrease in cerebral metabolic
oxygen requirements and cerebral blood flow is also
decreased or unchanged.
• Bradycardia produced by sufentanil may be sufficient to
decrease cardiac output. As observed with fentanyl,
delayed depression of ventilation has also been
described after the administration of sufentanil.

56. • large doses of sufentanil (10 to 30 μg/kg IV) or
fentanyl (50 to 150 μg/kg IV) produce minimal
hemodynamic effects in patients with good left
ventricular function, the systemic blood pressure
and hormonal (catecholamine) responses to painful
stimulation such as median sternotomy are not
predictably prevented

57. Alfentanil
• Alfentanil is an analogue of fentanyl that is less
potent (one-fifth to one-tenth) and has one-third
the duration of action of fentanyl.
• A unique advantage of alfentanil compared with
fentanyl and sufentanil is the more rapid onset of
action (rapid effect-site equilibration) after the IV
administration of alfentanil.
• Cirrhosis of the liver, but not cholestatic disease,
prolongs the elimination half-time of alfentanil.
• Renal failure does not alter the clearance or
elimination half-time of alfentanil.

58. • The rapid effect-site equilibration characteristic of
alfentanil is a result of the low pKa of this opioid
such that nearly 90% of the drug exists in the
nonionized form at physiologic pH. It is the
nonionized fraction that readily crosses the blood–
brain barrier.

59. Uses
• Alfentanil has a rapid onset and offset of intense
analgesia reflecting its very prompt effect-site
equilibration.
• administration of alfentanil, 15 μg/kg IV, about 90
seconds before beginning direct laryngoscopy is
effective in blunting the systemic blood pressure
and heart rate response to tracheal intubation

60. • The catecholamine response to this noxious
stimulation is also blunted by alfentanil, 30 μg/kg.
• Alfentanil, 150 to 300 μg/kg IV administered
rapidly, produces unconsciousness in about 45
seconds. lower incidence of postoperative nausea
and vomiting.

61. Remifentanil
• Remifentanil is a selective μ opioid agonist with an
analgesic potency similar to that of fentanyl
• Fast onset and fast offset
• The most salient pharmacokinetic feature of
remifentanil is the extraordinary clearance of nearly 3L
per minute, which is about eight times more rapid than
that of alfentanil.
• Remifentanil has a smaller Vd than alfentanil.
• The combination of rapid clearance and small Vd
produces a drug with a uniquely transient effect

62. Undergoes ester hydrolysis
• One additional benefit during labor would be rapid
clearance from the neonatal circulation as well, thus
reducing the risk of neonatal depression.
• Anesthesia can be induced with remifentanil, 1 μg/kg IV
administered over 60 to 90 seconds, or with a gradual
initiation of the infusion at 0.5 to 1.0 μg/kg IV for about
10 minutes, before administration of a standard
hypnotic prior to tracheal intubation.

63. • Remifentanil can be used as the analgesic component of a general
anesthetic (0.25 to 1.00 μg/kg IV or 0.05 to 2.00μg/kg/minute IV)
or sedation techniques with the ability to rapidly recover from
undesirable effects such as opioid-induced depression of
ventilation or excessive sedation.
• Remifentanil, 0.05 to 0.10μg/kg/minute, in combination with
midazolam, 2 mg IV, provides effective sedation and analgesia
during monitored anesthesia care in otherwise healthy adult
patients.
• Remifentanil, 100 μg IV, attenuates the acute hemodynamic
responses to electroconvulsive therapy and does not alter the
duration of electroconvulsiveinduced seizure activity.

64. TRAMADOL
• Name: Tramadol hydrochloride
• Availability: It is available as 1 ml ampoule
containing 50 mg/ml
• Mechanism of action: It stimulates the µ, δ and k
type of opioid receptors and produces analgesia. It
is a weak opioid.

65. • Uses, dose and route: It can be given intravenously,
intramuscularly, epidurally or orally.
• Analgesia: Tramadol is given in a dose of 1 – 2
mg/kg, given intravenously for providing
postoperative pain relief. It may be repeated 8th
hourly

66. • Onset: More than one arm-brain circulation time (1
– 2 minutes) when given IV,
• Duration: Four to six hours
• Elimination: It is metabolized by liver and excreted
by the kidn

67. • Central nervous system (CNS): Initially it causes
euphoria and then sedation. It is a good analgesic.
Later, it produces dose-dependent depression of
the CNS. The pattern of respiratory depression is
similar to morphine.
• Cardiovascular system: It causes less histamine
release and produces less hypotention.

68. • Respiratory system: It produces dose-dependent
reduction in respiratory rate and in large doses,
apnoea. The tidal volume is well-maintained till
late. Minute ventilation reduces causing
hypercarbia. It obtunds the airway reflexes well. It
can cause bronchospasm through histamine
release.

69. • Gastrointestinal system: It has emetic properties
(high incidence), delays gastric emptying and
produces constipation

70. • Uses and Dosage
• Dose: Oral 3 mg/kg & IV 1 mg/Kg Intra-op & post op
analgesia for moderate to severe pain
• Part of 2nd step of WHO analgesic ladder
• Dose-100-400mg/day, Age>75 yrs (300mg/day)
• Post op Shivering - 2mg/kg IV
• Regional Block - 100 mg as adjuvant
• Tramadol has dose & time dependant bactericidal
activity against E coli, S epidermidis. S aureus

71. • Adverse Effects
• Nausea, Vomiting
• Dizziness (>10%)
• Constipation (1-10%)
• Fatigue and Headache
• Palpitations, hypotension, tachycardia after rapid IV
injection
• Anxiety, Hallucinations (Rare, 0.01 to 0.1%)

72. • Cautions: To be used with caution in patients with
respiratory failur

73. Opioid Agonist–Antagonists

74. Pentazocine
• opioid agonist actions as well as weak antagonist
actions.
• agonist effects at Delta and k receptors
• Prolonged use of it can lead to physical
dependence.

75. • Clinical use
• Pentazocine 10-30mg iv is used most often for the
relief of moderate pain .
• Placement in the epidural space produces a rapid
onset of analgesia.
• It has been shown to be an effective treatment for
pruritis after cesarean delivery under spinal
anesthesia with opioids.

76. • Side effects
• most common side effect of pentazocine is
sedation, followed by diaphoresis and dizziness.
• Dysphoria, including fear of impending death is
associated with high doses.

77. Butorphanol
• Butorphanol is an agonist-antagonist opioid that
resembles pentazocine.
• Butorphanol has :
• (a) low affinity for μ receptors to produce antagonism,
• (b)moderate affinity for κ receptors to produce
analgesia and antishivering effects,
• (c) minimal affinity for σ receptors, so the incidence of
dysphoria is low.
• Butorphanol is rapidly and almost completely absorbed
after IM injection, onset of effect is rapid, peak
analgesia occur within one hour.

78. • The elimination half life of butorphanol is 2.5-3.5
hour.
• Transnasal butorphanol is effective in reliving
migraine and post operative pain.

79. • Side effects
• sedation
• Nausea
• diaphoresis.
• Depression of ventilation is similar to that produced
by simmilar dose of morphine.
• increase systemic blood pressure
• pulmonary artery blood pressure,
• cardiac output.

80. Buprenorphine
• Buprenorphine is an agonist-antagonist opioid
derived from the opium alkaloid thebaine.
• After IM administration, the onset of buprenorphine
effect occurs in about 30 minutes, and the duration
of action is at least 8 hours.
• Buprenorphine is effective in relieving moderate to
severe pain such as that present in the postoperative
period and that associated with cancer, renal colic,
and myocardial infarction.

81. • A sublingual combination tablet composed of
buprenorphine and naloxone in a fixed 4:1 ratio
may provide pain releif in chronic pain

82. • The side effects of buprenorphine include
• drowsiness
• nausea
• vomiting
• depression of ventilation

83. Opioids antagonist

84. Naloxone
• Naloxone is a nonselective antagonist at all three opioid
receptors.
• Naloxone is selective when used to
• (a) treat opioid-induced depression of ventilation as may
be present in the postoperative period,
• (b) treat opioid-induced depression of ventilation in the
neonate due to maternal administration of an opioid,
• (c) facilitate treatment of deliberate opioid overdose
• (d) detect suspected physical dependence.

85. • Naloxone, 1 to 4 µg/kg IV, promptly reverses
opioidinduced analgesia and depression of
ventilation.
• The short duration of action of naloxone (30 to 45
minutes) is presumed to be due to its rapid removal
from the brain.
• The elimination half-time is 60 to 90 minutes

86. • Naloxone is metabolized primarily in the liver by
conjugation with glucuronic acid to form naloxone-
3-glucuronide.
• The elimination half-time is 60 to 90 minutes.
• Naloxone is absorbed orally, but metabolism during
its first pass through the liver renders it only one-
fifth as potent as when administered parenterally

87. • SIDE EFFECTS
• Cardiovascular stimulation after administration of
naloxone manifests as increased sympathetic nervous
system activity, presumably reflecting the abrupt
reversal of analgesia and the sudden perception of pain.
• This increased sympathetic nervous system activity may
manifest as tachycardia, hypertension, pulmonary
edema, and cardiac dysrhythmias.
• Even ventricular fibrillation has occurred after the IV
administration of naloxone and the associated sudden
increase in sympathetic nervous system activity

88. • Nausea and vomiting appear to be closely related
to the dose and speed of injection of naloxone.
Administration of naloxone slowly over 2 to 3
minute

89. Role in Treatment of Shock
• Naloxone produces dose-related improvement in
myocardial contractility and survival in animals
subjected to hypovolemic shock and, to a lesser
extent, in those subjected to septic shock.
• The beneficial effects of naloxone in the treatment of
shock occur only with doses >1 mg/kg IV, suggesting
that the beneficial effects of this drug are not opioid
receptor–mediated or, alternatively, are mediated by
opioid receptors other than µ receptors—possibly δ
and κ receptors.

90. Naltrexone
• Naltrexone, in contrast to naloxone, is highly
effective orally, producing sustained antagonism of
the effects of opioid agonists for as long as 24
hours.
• It has found a role in the treatment of alcoholism,
possibly by reducing the pleasure associated with
ethanol intoxication

91. Nalmefene
• The recommended dose is 15 to 25 mg IV
administered every 2 to 5 minutes until the desired
effect is achieved, with the total dose not
exceeding 1 mg/kg.
• The primary advantage of nalmefene over naloxone
is its longer duration of action, which might provide
a greater degree of protection from delayed
depression of ventilation due to residual effects of
the opioid as the antagonist is cleared.

92. • the half-time of nalmefene is about 10.8 hours.
• This longer duration of action is likely due to the
slower clearance of nalmefene compared with
naloxone.
• Nalmefene is metabolized by hepatic conjugation,
with ,5% excreted unchanged in the urine.
• As with naloxone, acute pulmonary edema has
occurred after the IV administration of nalmefene

93. Drug Interactions
• The combination of meperidine and MAO inhibitor
may result in hemodynamic instability, hyperpyrexia,
coma, respiratory arrest, or death.
• Propofol, barbiturates, benzodiazepines, inhaled
anesthetics, and other CNS depressants can have
synergistic cardiovascular, respiratory, and sedative
effects with opioids.
• The clearance of alfentanil may be impaired and the
elimination half-life prolonged following treatment
with erythromycin

94. Biotransformation
• all opioids depend primarily on the liver for
biotransformation and are metabolized by the
cytochrome P (CYP) system, are conjugated in the
liver, or both.
• Because of the high hepatic extraction ratio of
opioids, their clearance depends on liver blood flow

95. • Morphine and hydromorphone undergo conjugation
with glucuronic acid to form, in the former case,
morphine 3-glucuronide and morphine 6-
glucuronide, and in the latter case, hydromorphone
3-glucuronide.
• Meperidine is N-demethylated to normeperidine, an
active metabolite associated with seizure activity,
particularly with very large meperidine doses.
• The end products of fentanyl, sufentanil, and
alfentanil are inactive.

96. • Codeine is a prodrug that becomes active after it is
metabolized by CYP2D6to morphine.
• Tramadol similarly must be metabolized by CYP to
O-desmethyltramadol to be active. Hydrocodone is
metabolized by CYP2D6 to hydromorphone (a more
potent compound) and by CYP3A4 to
norhydrocodone (a less potent compound).
• Oxycodone is metabolized by CYP2D6 and other
enzymes to series of active compounds that are less
potent than the parent one.

97. • The ester structure of remifentanil makes it
susceptible to hydrolysis by nonspecific esterases in
red blood cells and tissue yielding a terminal
elimination half-life of less than 10 min.
• Hepatic dysfunction requires no adjustment in
remifentanil dosing.

98. Reference
• Stoeltings
• Morgan