- 1.OPIOIDS Dr.Khalid Al-Jonaieh Demonstrator Anesthesia
Department KKUH
2. Terminology
- used to refer to drugs derived from opium including
morphine.
- not useful in a pharmacologic or clinical context.
- the ability to bind a receptor to produce a stable complex and
intrinsic activity.
- the range in magnitude of an effect produced by a drug receptor
combination relative to the maximum possible effect.
- the relative dose required to achieve an effect which related
to receptor affinity.
3. Efficacy and Potency
- described by the dose-effect curve resulting from drug-receptor
combination
4. ENDOGENOUS OPIOIDS AND OPIOID RECEPTORS
- All of the endogenous opioids are derived from three
prohormones :
- Pro-opiomelanocortin ( POMC )
- All being with the pentapeptide sequences of {Leu} or
{Met}-enkephalin
5. Proenkephalin
- Widely distributed throughout the brain, spinal cord, and
peripheral sites, particularly the adrenal medulla.
6. The dynorphin
- All begin with the[ Leu ]- enkephalin sequence and are widely
distributed throughout the brain, spinal cord, and peripheral sites
.
7. Pro-opiomelanocortin
- The common precursor of - endorphin, ACTH, and melanocyte -
stimulating hormone.
- The termendorphinis reserved for peptides of the POMC
family.
- The major site of POMC synthesis is the pituitary, but it is
also found in the pancreas and placenta .
8. Receptors
- The initial classification by Martin of opioid receptors into
the three types
- Based on binding activity of the exogenous ligands
- Other Opioid receptors identified :
9. Selectivity
- Very few endogenous opioids exhibit great selectivity for a
single receptor type.
- Naloxone, the most commonly used opioid antagonist, is not
selective for opioid receptor type.
- Naltrindole( a - opioid receptor antagonist )
- Nor - binaltorphimine( a - opioid receptor antagonist ) .
10. Cellular Level
- Receptor binding initiates a series of physiologic functions
resulting in cellular hyperpolarization and inhibition of
neurotransmitter release, effects that are mediated by second
messengers .
- All opioid receptors appear to be coupled to G proteins, which
regulate the activity of adenylate cyclase among other
functions.
- G protein interactions, in turn, affect ion channels.
- Different ion may be involved at different opioid receptor
types.
11. Pharmacokinetics & Pharmacodynamic
- Pharmacokineticsdetermines the relationship between drug dose
and its concentration at the effect site(s).
- Pharmacodynamicvariables relate the concentration of a drug at
its site of action, in this case opioid receptors in the brain and
other tissues, and the intensity of its effects.
12. Pharmacokinetics
- The processes of absorption, redistribution, biotransformation,
and elimination .
- Compartmental models describe the time course of change in
plasma concentration.
- Opioids used in anesthesia are characterized by two -or three -
compartment models.
- Distribution phase: The early rapid decline in plasma
concentration after the peak.
- Elimination phase: The subsequent slower decline.
13. Pharmacokinetics
- Two main mechanisms are responsible for drug elimination
- Opioids are biotransformed in the liver by two types of
metabolic processes .
- Phase I reactionsinclude oxidative and reductive reactions,
such as those catalyzed by cytochrome P450 system, and hydrolytic
reactions .
- Phase II reactionsinvolve conjugation of a drug or its
metabolite to an endogenous substrate, such as D - glucuronic acid
.
- Remifentanil is metabolized viaester hydrolysis , which is
unique for an opioid .
- With the exceptions of theN -dealkylated metabolite of
meperidine and the 6- and possibly 3-glucuronides of morphine,
opioid metabolites are generallyinactive .
14. Pharmacokinetics
- Routes of opioid excretion:
15. Pharmacodynamic
- To reach its effector sites in the central nervous system( CNS
) , an opioid must cross biologic membranes from the blood to
receptors on neuronal cell membranes .
- The ability of opioids to cross this bloodbrain barrier depends
on such properties as
- Of these characteristics, lipid solubility and ionization
assume major importance in determining the rate of penetration to
the CNS .
16. Pharmacodynamic
- Lipid solubility is measured as an octanol :water or octanol
:buffer partition coefficient .
- Drug ionization is also an important determinant of lipid
solubility.
- Nonionized drugs are 1,000 to 10,000 times more lipid - soluble
than the ionized form .
- The degree of ionization depends on the pKa of the opioid and
the pH of the environment .
- Plasma protein binding also affects opioid redistribution
because only the unbound fraction is free to diffuse across cell
membranes .
- The major plasma proteins to which opioids bind are albumin and
1-acid glycoprotein.
17. Morphine
- Effect on MAC of Volatile anesthesia
- GIT Motility and Secretion
18. Analgesia
- Morphine analgesia results from complex interactions at a
number of discrete sites in the brain, spinal cord, and under
certain conditions, peripheral tissues.
- Involves both 1 and 2 opioid effects.
- Act selectively on neurons that transmit and modulate
nociception.
- Leaving other sensory modalities and motor functions intact
.
19. At the spinal cord level
- acts on primary afferent nociceptors to decrease the release of
substance P.
- hyperpolarizes postsynaptic neurons in the substantia
gelatinosa of the dorsal spinal cord to decrease afferent
transmission of nociceptive impulses.
- Spinal morphine analgesia is mediated by 2 - opioid receptors
.
20. At the Supraspinal level
- Opioid analgesia originates in
- the periaqueductal gray matter
- nuclei within the medulla
- notably the nucleus raphe magnus
- Primarily involves 1-opioid receptors
- Microinjections of morphine into any of these regions activate
the respective descending modulatory systems to produce profound
analgesia
- Coadministration at the level of the brain and spinal cord
increases morphine's analgesic potency nearlytenfold , an effect
mediated by 2 -opioid receptors
21. At Peripheral Level
- An action when acute inflammation is present.
- By activating peripheral opioid receptors
- Mediated by 3 - opioid receptors .
- In chronic pain conditions such as neuropathic pain or chronic
arthritis, spinal and peripheral receptors may be down - regulated,
a state that can decrease morphine analgesia.
22. Pain Relief
- The minimum effective analgesic concentration( MEAC )of
morphine
- For postoperative pain relief is 10 to 15 ng / mL
- For more severe pain, plasma morphine concentrations of 30 to
50 ng/mL are needed to achieve adequate analgesia
23. Effect on MAC of Volatile Anesthetics
- Decreases MAC of volatile anesthetics in a dose - dependent
manner.
- 1 mg / kg administered with 60% nitrous oxide( N2O) blocks the
adrenergic response to skin incision in 50% of patients, a
characteristic calledMAC-BAR
- Epidural morphine 4 mg given 90 minutes prior to incision
reduces halothane MAC by nearly 30%.
24. Other Central Nervous System Effects
- Cognitive and fine motor impairment
- Sleep disturbances including reduction in rapid eye movement
and slow-wave sleep.
- slowing of EEG, increased voltage and decreased frequency
.
- Pruritus appears to be a receptor-mediated effect produced at
the level of the medullary dorsal horn.
- Antipruritic effect mediated by receptors & not
histamine-mediated.
25. Hormonal Effects
- Affect the release of several pituitary hormones, both directly
and indirectly
- Inhibition of corticotropin - releasing factor
- Inhibition of gonadotropin - releasing hormone
- Which decreases circulating concentrations of:
- follicle - stimulating hormone
- Antidiuretic hormone release is inhibited
- Prolactin and growth hormone concentrations may be increased by
opioids.
26. Respiratory Depression
- Produce dose - dependent ventilatory depression.
- Primarily by decreasing the responsivity of the medullary
respiratory center to CO 2 .
- Similar for young and elderly patients.
- With increasing morphine doses, periodic breathing
resemblingCheyne-Stokesbreathing, decreased hypoxic ventilatory
drive, and apnea can occur.
27. Cautions
- Have been reported in asleep patients receiving morphine
infusions for postoperative analgesia.
28. Cough Reflex
- Depress by a direct effect on the medullary cough center .
- Receptors mediating this effect appear to be less
stereospecific and less sensitive to naloxone than those
responsible for analgesia .
29. Muscle Rigidity
- Ex. abdominal muscle rigidity and decrease thoracic
compliance
- Large doses of IV morphine (2 mg/kg infused at 10 mg/min)
- Increased by the addition of 70% N 2 O
- Mediated by receptors at supraspinal sites.
- These effects are reduced or eliminated by :
- drugs that facilitate GABA agonist activity such as thiopental
and diazepam
30. Nausea and Vomiting
- The incidence appears to be similar if you use it as
premedication or intraoperative.
- The incidence appears to be similar what ever the route of
administration.
- including oral, IV, intramuscular, subcutaneous, transmucosal,
transdermal, intrathecal, and epidural .
- Laboratory and clinical studies comparing the incidence or
severity of nausea and vomiting have found no differences among
opioids in equianalgesic doses.
- including morphine, hydromorphone, meperidine, fentanyl,
sufentanil, alfentanil, and remifentanil .
31. The vomiting center
- Receives input from the chemotactic trigger zone( CTZ ):
- the area postrema of the medulla
- The CTZ is rich in opioid, dopamine, serotonin, histamine, and(
muscarinic )acetylcholine receptors.
- The CTZ receives input from the vestibular portion of the
eighth cranial nerve .
32. Antiemetic
- At the level of the vomiting center:
- Studies suggests that antiemetic effects of morphine are more
short-lived than emetic effects.
- Possible explanation for this observation is that the active
metabolite morphine-6-glucuronide accumulates and worsens
nausea.
33. 34. Gastrointestinal Motility and Secretion
- Mediated by - , - , and - opioid receptors.
- Inhibit gastric secretion
- Decrease gastrointestinal motility and propulsion
- Decreases lower esophageal sphincter tone
35. Biliary Tract
- Increase the tone of the common bile duct and sphincter of Oddi
.
- Symptoms vary from epigastric distress to typical biliary colic
and may even mimic angina .
- Possibly via histamine release.
- Antagonism of morphine's biliary effects
bydiphenhydraminesupports this hypothesis.
36. Genitourinary Effects
- Results in dyssynergia between the bladder detrusor muscle and
the urethral sphincter because of a failure of sphincter relaxation
.
- Spinal morphine appears to causenaloxone - reversibleurinary
retention via -and / or - , butnot - opioid receptors .
37. Histamine Release
- From circulating basophils.
- From tissue mast cells in skin and lung.
- Morphine - mediated histamine release is dose - dependent.
- Not prevented by pretreatment with naloxone.
- Suggesting that histamine release is not mediated by opioid
receptors .
- The decrease in peripheral vascular resistance seen with high -
dose morphine( 1 mg / kg )correlates well with elevated plasma
histamine concentration . Fentanyl
38. Cardiovascular Effects
- arteriolar and venous dilation.
- decreased peripheral resistance.
- inhibition of baroreceptor reflexes.
- Lead to postural hypotension.
- morphine - mediated central sympatholytic activity.
- direct action on vascular smooth muscle.
- Caution : morphine's effect on vascular resistance is greater
under conditions of high sympathetic tone .
- Carefull with Severe Trauma & Cardiac Patients.
39.
- Does not suppress myocardial contractility.
- Produce dose - dependent bradycardia.
- In clinical anesthesia practice, opioids are often used to
prevent tachycardia and reduce myocardial oxygen demand .
- Patients undergoing cardiovascular surgery who received 1 to 2
mg / kg of morphine experienced minimal changes in heart rate, mean
arterial pressure, cardiac index, and systemic vascular resistance
.
- Cautiously in spontaneously breathing patients with head injury
or other conditions associated with elevated intracranial
pressure.
40. Disposition Kinetics
- After IV administration morphine undergoes rapid
redistribution
- Mean redistribution half - time between 1.5 and 4.4 min.
- Terminal elimination half - life between 1.7 and 3.3
hours.
- 35% protein bound, mostly to albumin .
- Its steady - state volume of distribution is large, the range
of 3 to 4 L / kg in normal adults .
- The MEAC is 10-15 ng / mL.
41.
- Morphine's major metabolic pathway is hepatic phase II
conjugation, to form morphine-3-glucuronide( M3G )and morphine-6 -
glucuronide( M6G ).
- The rate of hepatic clearance of morphine is high, with a
hepatic extraction ratio of 0.7
- Extrahepatic sites such as kidney, intestine, and lung.
- Unchanged morphine in the urine accounts for only about 10% of
the dose .
- A single IV dose, 40% of the dose are excreted in the urine as
M3G and and 10% as M6G.
42. Active Metabolites
- M6G possesses significant receptor affinity and potent
antinociceptive activity .
- Because morphine glucuronides are eliminated by the kidney,
morphine should be administered cautiously to patients with renal
failure .
43. Dosage and Administration of Morphine
- Used mainly as a premedicant and for postoperative
analgesia.
- For adults range from 0.01 to 0.20 mg / kg .
- When used in a balanced anesthetic technique with N2O, morphine
can be given in total doses of up to 3 mg/kg.
- When combined with other inhalation agents, it should not
exceed more than 1 to 2 mg / kg.
- The morphine dose associated with apparent cardioprotective
effect is a single dose of 40 mg, given before cardioplegia and
cardiopulmonary bypass .
44. Extra Info.
- Because of its hydrophilicity, morphine crosses the bloodbrain
barrier relatively slowly.
- Its onset can be observed within 5 minutes
- peak effects may be delayed for 10 to 40 minutes .
- This delay makes morphine more difficult to titrate as an
anesthetic supplement than the more rapidly acting opioids .
45. Meperidine
- A phenylpiperidine derivative.
- Was the first totally synthetic opioid .
- It was initially studied as an anticholinergic agent.
- Last comment about this opioid was
- Bad-Drug. 3 rdinternational anesthesia conference .
46. Analgesia and Effect on MAC of Volatile Anesthetics
- Potency is about one - tenth that of morphine's.
- Mediated by - opioid receptor activation mostly.
- Also has moderate affinity for -and - opioid receptors.
- The MEAC of meperidine is 200 ng / mL
- A dose - dependent reduction in the MAC of halothane .
47.
- Well - recognized weak local anesthetic properties .
- Alters nerve conduction and produces analgesia .
- Neuraxial meperidine may also produce sensory and motor
blockade as well as sympatholytic effects thatare not seen with
other opioids .
48. Side Effects
- Therapeutic doses can produce:
- sedation, pupillary constriction, and euphoria.
- Very high doses produce CNS excitement and seizures.
- In equianalgesic doses produce :
- delay in gastric emptying
- increase common bile duct pressure
49. Cardiovascular Effects
- Not associated with hemodynamic instability.
- 1 mg / kg in patients withcardiac diseasedecreased heart rate,
cardiac index, and ratepressure product.
- High dose depress contractility and significantly more
hemodynamic instability than morphine or fentanyl, partially
related to histamine release .
50. Shivering
- general and epidural anesthesia
- administration of amphotericin B
- Eliminates visible shiveringprevent the increase of O2
consumption.
51.
- Equianalgesic doses of fentanyl (25 g) and morphine (2.5 mg)
did not reduce postoperative shivering
- Not mediated by - opioid receptors .
- Butorphanol effectively reduces postoperative shivering in a
dose of 1 mg
- Mediated by - opioid receptors .
52.
- Low doses of naloxone, sufficient to block receptors, did not
reverse the antishivering effect of meperidine.
- High - dose naloxone, designed to block both andreceptors, did
reverse the antishivering effect.
- 1-adrenergic agonists (clonidine 1.5 g/kg), serotonin
antagonists, and propofol, can reduce postoperative shivering.
- Suggests that a nonopioid mechanism may be involved.
- Physostigmine 0.04 mg / kg can also prevent postoperative
shivering.
- Suggesting a role for the cholinergic system .
53. Disposition Kinetics
- Following IV administration, plasma concentration falls
rapidly.
- Redistribution half - life is 4 to 16 minutes.
- Its terminal elimination half - life is between 3 and 5
hours.
- Moderately lipid soluble.
- 40 to 70% protein bound mostly to albumin and 1-acid
glycoprotein.
- Large large Vd ss , range of 3.5 to 5 L/kg in adults.
54.
- High hepatic extraction ratio.
- The high clearance rate :10 mL / kg / min.
- It isN -demethylated in the liver to form normeperidine.
- Also hydrolyzed to meperidinic acid.
- Both metabolites may then be conjugated and excreted
renally.
- Normeperidine is pharmacologically active and potentially
toxic.
55. Active Metabolites
- Normeperidine : pharmacological active.
- Produce signs of CNS excitation.
- Mood alterations such as apprehension and restlessness.
- Neurotoxic effects such as tremors, myoclonus, and
seizures.
- The elimination half - life of the metabolite normeperidine( 14
to 21 hours ) .
- Mean plasma normeperidine concentration of 0.81 g / mLdeveloped
seizures even with patients without renal dysfunction.
56. Dosage and Administration of Meperidine
- A single IV dose is approximately one - tenth as potent as
morphine.
- IV : a shorter duration of action.
- IV analgesic doses for adults range from 0.1 to 1 mg / kg.
- IV doses of 12.5 to 50 mg are effective in reducing
postoperative shivering .
- The total daily dose should not exceed 1,000 mg in 24 hours
.
57. Methadone
- Pharmacologic properties that are similar to morphine .
- Chemical structure is very different from that of
morphine.
- Pseudopiperidine ring for opioid activity.
- Because of its long elimination half-life, mostly used for
:
- Long - term pain management
- Treatment of opioid abstinence syndromes .
58. Analgesia and Use in Anesthesia
- The onset of analgesia is rapid, within 10 to 20 minutes.
- After single doses of up to 10 mg, the duration of analgesia is
similar to morphine.
- Large or repeated parenteral doses, can reach up to 20
hours.
59. Side Effects
- Similar in magnitude and frequency to those of morphine .
- Did not appear to have clinically significant respiratory
depression .
- About 50% experienced nausea or vomiting, which was easily
treated with standard antiemetic therapy.
- Decreases intestinal propulsive activity
60. Disposition Kinetics
- Mean redistribution half - time is 6 min.
- Mean terminal elimination T 1/2is 34 hrs.
- Well absorbed after an oral dose with bioavailability 90%, and
peak plasma concentration at 4 hours.
- Extensive metabolism in the liver, mostlyN -demethylation and
cyclization to form pyrrolidines and pyrroline.
61. Dosage and Administration of Methadone
- To achieve prolonged postoperative analgesia
- 20 mg provide analgesia without significant post-OP respiratory
depression.
- Important note: that these long-acting opioids are not
currently approved for prophylaxis of postoperative pain.
62. Fentanyl
- Structurally related to phenylpiperidines.
- Clinical potency ratio 50 to 100 times that of morphine .
- Progressive EEG changes (slow) with a lag of 3 to 5
minutes.
- Resolution of EEG changes lagged by 10 to 20 minutes after stop
of fentanyl infusion.
63. Analgesia
- A - opioid receptor agonist.
- Dose - dependent analgesia.
- High doses produce unconsciousness.
- In post-OP patients, the mean fentanyl dose requirement was
55.8 g/hr.
- Mean plasma fentanyl concentration of 1.3 ng / mL reduced
experimental pain intensity ratings by 50%.
64. Use in Anesthesia
- Reduces the MAC of volatile anesthetics in dose - dependent
fashion.
- A single IV bolus dose of fentanyl 3 g / kg, given25 to 30
minprior to incision, reduced both isoflurane and desflurane MAC by
50% .
- 3 ng / mL provides a 59% reduction of sevoflurane MAC.
- Combining with propofol is a technique for providing general
anesthesia, (TIVA).
65.
- The potency index for TIVA is described as the plasma
concentration required to prevent a response in 50%( CP 50 ) or 95%
(CP 95 ) of patients to various surgical stimuli.
- Fentanyl reduces requirements for both volatile agents and
propofol by a similar proportion .
- Spontaneous ventilation returned when the fentanyl
concentration dropped to 1.5 to 2 ng / mL .
66. stress - free anesthesia
- Fentanyl has been used as the sole agent for anesthesia, a
technique that requires a large initial dose of 50 to 150 g /
kg.
- Significantly blunt the stress response that is, hemodynamic
and hormonal responses to surgical stimuliwhile producing only
minimal cardiovascular depression .
- fast - track techniques because of prolonged respiratory
depression
- intraoperative awareness and recall
67. Other CNS Effects
- Increase middle cerebral artery flow.
- Hypercarbia from fentanyl-induced respiratory depression
influence fentanyl ionization and cerebral blood flow and hence the
delivery brain tissue.
- Instructed to deep - breathe during fentanyl induction may
experience less rigidity.
- Seizurelike movements represent as myoclonus.
- Can activate epileptiform EEG activity in patients having
surgery for intractable temporal lobe epilepsy.
- Pruritus typically presents as facial itching.
68. Respiratory Depression
- Respiratory depression expressed as
- elevation in end-tidal CO 2
- a decrease in the slope of the CO 2response curve
- decrease minute ventilation at an end-tidal CO 2of 50 mm Hg (VE
50 )
- Greatly increased when it is given in combination with
midazolam.
- Blunts the hypoxic ventilatory drive to a greater extent than
the hypercarbic ventilatory drive .
69. Airway Reflexes
- Expiration, panting, and coughing decreased, the duration of
laryngospasm shortened, in a dose - dependent fashion .
- These protective reflexes return to baseline rapidly after
emergence.
70. Cardiovascular Effects
- Concentration - dependent negative inotropic effects.
- A very high concentration reduced contractility by 50%.
- In clinical practice up to 75 g / kg is associated with
hemodynamic stability.
- 7 g / kg at induction had a slight decrease in heart rate, but
no change in mean arterial pressure.
- 20 g / kg, decreases 15% in heart rate, MAP, systemic and PVR
seen in patients with CAD .
- Does not prevent the inflammatory effects associated with
cardiopulmonary bypass.
- Does not produce the apparent cardioprotective effects.
71. Extra Info.
- Hypertension in response to sternotomy is the most common
hemodynamic disturbance during high - dose fentanyl anesthesia and
occurs in 40 and 100% in patients receiving 50 to 100 g / kg .
- Unlike morphine and meperidine, which induce hypotension, at
least in part because of histamine release.
- The combination of fentanyl and diazepam produces significant
cardiovascular depression, increased central venous pressure
significantly.
- Adding 60% N2O to high-dose fentanyl produced a significant
decrease in cardiac output and increases in systemic and pulmonary
vascular resistance.
72. Endocrine Effects
- High - dose fentanyl( 100 g / kg ) prevented increases the
stress response during surgery
- but a lower dose of fentanyl did not .
- ( 5 g / kg followed by an infusion of 3 g / kg / h )
73. Smooth Muscle and Gastrointestinal Effects
- Fentanyl, significantly increases common bile duct pressure
(the highest)
74. Disposition Kinetics
- Fentanyl's extreme lipid solubility.
- Rapid crossing of biologic membranes.
- Rapid uptake by highly perfused tissue groups, including the
brain, heart, and lung.
- Thus, after a single bolus dose, the onset of effects is rapid
and the duration brief.
75.
- The onset within10 secondsand correlated with a rapid increase
inbrain tissuefentanyl concentration, which equilibrated
withplasmaby1.5 min .
- Recovery from fentanyl effects started within5 minand was
complete by60 min .
- Peak muscle concentration was seen at5 min .
- Fat concentration reached a maximum30 min , because of the
limited blood supply to that tissue .
- With prolonged administration of fentanyl, fat can act as a
reservoir of drug .
76.
- The terminal elimination half - time ranged from 3.1 to 6.6
hours.
- Significantly bound to red blood cells: 40%.
- Blood: plasma partition coefficient of 1.
- Highly protein bound, 79 to 87%. mostly1-acid glycoproteinwhich
is pH-dependent.
- Decrease in pH will increase the proportion of fentanyl that is
unbound.
- Thus, a patient with respiratory acidosis will have a higher
proportion of unbound( active )fentanyl, which could exacerbate
respiratory depression .
77.
- Clearance of fentanyl is primarily by rapid and extensive
metabolism in the liver .
- Indicate a high hepatic extraction ratio.
- Which dependent on liver blood flow .
- Metabolism is primarily byN -dealkylation to norfentanyl.
- By hydroxylation of both the parent and norfentanyl.
- 6% is excreted unchanged in the urine.
78. Dosage and Administration of Fentanyl
- Single bolus doseshort - acting opioid.
- Very large doses and multiple doses prolonged respiratory
depression and delayed recovery could occur.
- useful as a sedative / analgesic premedication : 25 to 50 g
IV.
- A transmucosal delivery system is effective premedicant for
pediatric and adult patients as well as an effective treatment for
breakthrough pain in chronic pain patients, should be administered
in a monitored environment .
79. Intubation Time
- Fentanyl blunt the hemodynamic response to laryngoscopy and
tracheal intubation, which can be particularly severe in patients
with hypertension or cardiovascular disease .
- Should be complete approximately3 minprior to laryngoscopy to
maximally blunt hemodynamic responses to tracheal intubation .
- Administration of up to3 to 5 g / kg / hrwill allow recovery of
spontaneous ventilation at the end of surgery . 0.5 to 2.5 g / kg
every 30 minutes .
80. cardiac surgery
- Prevents hemodynamic changes in response to noxious stimuli,
can be achieved with:
- a loading dose of 50 g/kg,
- followed by a continuous infusion of 30 g/kg/hr.
81. Sufentanil
- A thienyl derivative of fentanyl.
- Has a clinical potency ratio 2,000 to 4,000 times that of
morphine.
- Has a clinical potency ratio 10 to 15 times that of fentanyl
.
- EEG changes lagged behind plasma concentration changes by2 to 3
min , after 4-min sufentanil infusion.
- Resolution of the EEG changes lagged behind plasma
concentration changes by20 to 30 min .
82. Analgesia
- Highly selective - opioid receptor agonist.
- IV infusion rate to adequate postoperative analgesia, mean rate
of 8 to 17 g / hr was required during the first 48 hours .
83. Use in Anesthesia
- Decreases the MAC of volatile anesthetics in a dose - dependent
manner 70 to 90%.
- In cardiac surgery, high doses( 10 to 30 g / kg ) with oxygen
and muscle relaxants are needed.
- When used as the sole anesthetic agent, even high dosesmay
notcompletely block the hemodynamic responses to noxious
stimuli.
84. Other CNS Effects
- Equianalgesic doses of sufentanil and fentanyl produce similar
changes in the EEG.
- With 15 g / kg,activity became prominent within a few seconds,
and within 3 min, the EEG consisted almost entirely of slowactivity
.
- 1 to 2 g / kg, Rigidity and myoclonic activity reported during
induction, and on emergence.
- 0.5 g / kg was not associated with changes in cerebral blood
flow.
85. In patients with intracranial tumors
- 1 g / kg was associated with an elevation in spinal
cerebrospinal pressure, a decrease in cerebral perfusion pressure
and arterial pressure had dropped significantly.
86. Respiratory Depression
- In spontaneously breathing patients anesthetized with 1.5%
halothane and N2O, 2.5 g reduced mean minute ventilation by 50%,
and 4 g reduced mean respiratory rate by 50%.
- Changes in end - tidal CO2 were the same for fentanyl and
sufentanil
- the slope of the ventilatory response to CO2 was depressed to a
greater extent by fentanyl.
87. CVS Effects
- Produces vasodilation by :
- A sympatholytic mechanism.
- A direct smooth muscle effect .
- 15 g/kg, decrease in MAP which is used for induction of
anesthesia.
- Combining vecuronium and sufentanil can cause a decrease in MAP
during inductionand significant bradycardia and sinus arrest, but
not with pancuronium.
88. Endocrine Effects
- Sufentanil, like fentanyl, reduces the endocrine and metabolic
responses to surgery .
- However, even a large induction dose( 20 g / kg )did not
prevent increases in cortisol, catecholamines, glucose, and free
fatty acids during and after cardiopulmonary bypass .
89. Disposition Kinetics
- Smaller degree of ionization at physiologic Ph.
- Protein Binding 93% mostly to 1-acid glycoprotein.
- Vd ss smaller than fentanyl : 1.9 Kg/L.
- Elimination half - life shorter than that of fentanyl : 2.7
hrs.
- Plasma concentration drops very rapidly after an IV bolus
dose.
- 98% of the drug is cleared from plasma within 30 minutes after
IV bolus dose.
- Less red cell bound than fentanyl( 22 compared with 40% ).
90.
- As fentanyl high hepatic extraction ratio.
- Metabolism in the liver is by :
- Study show clearance and elimination half - life in patients
with cirrhosis are similar to controls.
91. Dosage and Administration
- Loss of consciousness is seen with total doses between 1.3 and
2.8 g / kg .
- Doses in the range of 0.3 to 1.0 g / kg given 1 to 3 minutes
prior to laryngoscopy can be expected to blunt hemodynamic
responses to intubation
- Balanced anesthesia is maintained with (A)intermittent bolus
doses or (B)a continuous infusion
- A:0.1 to 0.5 g / kg, mean maintenance requirements of 0.35 g /
kg / hr
- B:initial bolus of 0.5 g / kg followed by an infusion of 0.5 g
/ kg / hr
92. Cardiac Anesthesia
- Can be used as the sole agent.
- Much higher bolus doses( 10 g / kg )and / or infusion rates(
0.15 g / kg / min ) .
93. Alfentanil
- A tetrazole derivative of fentanyl.
- Alfentanil is a -opioid receptor agonist and produces typical
naloxone-reversible analgesia and side effectssuch assedation,
nausea, and respiratory depression.
- Its clinical potency is 10 times that of morphine.
- Its clinical potency one - fourth to one - tenth that of
fentanyl.
- Peak effect of EEG lagged behind peak plasma concentration by
1.0 g / kgproduce brief increases in systolic BP( 5 to 20 torr )
and heart rate( 10 to 25 beats / min ).
- In patients anesthetized, remifentanil( up to 5 g / kg
)produces dose - dependent decreases in systolic BP and heart rate
around 20% .
- Attenuated by premedication with glycopyrrolate 0.3 to 0.4 mg
and reversed with ephedrine or phenylephrine.
128.
- These hemodynamic effects were not mediated by histamine
release
- Transient and easily treated with fluids and downward titration
of propofol .
- Hypotension:12% with remifentanil 4% with fentanyl
- Bradycardia : 2% with remifentanil 1% with fentanyl
129. Coronary Artery Disease
- In a comparison of high - dose remifentanil( 2 g / kg / min )
and remifentanil0.5 g / kg / minplus propofol.
- Both techniques produced similar changes:
- 30% drop in mean arterial pressure
- 25% drop in cardiac index.
- 30% drop in myocardial blood flow
- 40% drop in oxygen consumption
130. Cardiac Surgery
- Rapid injection of remifentanil 1 g / kg followed by a
continuous infusion at 0.1 to 0.2 g / kg / min on induction
- Bradycardia( heart rate 2 g / kg can drop arterial pressure 20
to 30%.
- Hemodynamic changes in cardiac patients receiving high - dose
infusion are similar to remifentanil plus propofol .
138.
- Combined with a potent inhalation agent, a loading dose of1 g /
kggiven slowly( over 60 seconds ) can provide adequate intubating
conditions with hemodynamic stability.
139.
- The most commonly reported remifentanil - based regimen for
anesthetic induction and laryngoscopy consists of remifentanil0.5
to 1 g / kggiven over 60 seconds plus propofol1 to 2 mg / kg ,
followed by remifentanil infusion of0.25 to 0.5 g / kg / min .
140. Maintenance of General Anesthesia
- In combination with 70% N2O in O2, remifentanil 0.6 g/kg/min is
generally adequate.
- A lower infusion rate( 0.2 to 0.25 g / kg / min ) is needed
when remifentanil is combined with inhalation agents.
- For TIVA, maintenance infusion rates for remifentanil and
propofol are0.25 to 0.5 g / kg / minand75 to 100 g / kg / min ,
respectively .
- If N2O is added, remifentanil infusion rates as low as0.125
g/kg/minand propofol infusion of 50 to75 g/kg/mincan be used.
141.
- For elderly patients or those with cardiac disease, a reduction
in propofol by about 25% is recommended .
- Children require higher remifentanil doses to block responses
to skin incision.
142. Cardiac Surgery
- For high - dose opioid anesthesia for cardiac surgery, the
remifentanil infusion is maintained at 1 to 3 g / kg / min and
should be adjusted downward for hypothermia.
- Adding a low - dose propofol infusion of50 g / kg / minto this
high infusion rate effectively suppressed responses to skin
incision, sternotomy, and aortic cannulation .
143. A disadvantage of remifentanil
- Related to its short duration of action.
- Patients may experience substantial pain on emergence from
anesthesia .
- If moderate - to - severe postoperative pain is anticipated,
continuing the remifentanil infusion between0.05and0.15 g / kg /
min .
- The use of local and regional anesthetic techniques is also
effective .
- Mild postoperative pain is anticipated, intraoperative
administration of a NSAID 30 to 60 minutes before the end of
surgery.
144. Monitored Anesthesia Care
- Used for conscious sedation / analgesia.
- Used an adjunct for sedation or analgesia during regional
anesthesia, or for block placement.
- During colonoscopy, a continuous remifentanil infusion of0.2 to
0.25 g/kg/min , supplemented with small(10-mg)doses of propofol
provided good analgesia but mild respiratory depression was
common.
145. ESWT
- Patients who received low - dose( 12.5 to 25 g ) intermittent
bolus injection of remifentanil with or without infusion at0.05 g /
kg / minreported better analgesia than continuous infusion of0.1 g
/ kg / minalone .
146. Ophthalmologic Surgery
- Remifentanil 1 g / kg with or without a subsequent infusion of
0.2 g / kg / min administered 90 seconds prior to placement of
ophthalmologic block resulted in excellent analgesia.
- 14% of patients who received an infusion experienced
respiratory depression.
147. Regional Anesthesia
- When used as an adjunct to local or regional anesthesia, a much
lower maintenance infusion rate,0.05to0.1 g / kg / min , provides
adequate sedation and analgesia .
- Finally, the dose requirement of remifentanil for sedation /
analgesia is reduced 50% when combined with midazolam or propofol
.
- When 1 to 2 mg of midazolam premedication is given,0.01to0.07 g
/ kg / minremifentanil provides good sedation / analgesia.
148. Partial Agonists and Mixed AgonistAntagonists
- Structurally related to morphine .
- Characterized by binding activity at multiple opioid receptors
and their differential effects( agonist, partial agonist, or
antagonist ) .
- The clinical effect of a partial agonist at the - opioid
receptor is complex.
- Administered alone, a partial agonist has a flatter dose -
response curve and a lower maximal effect than a full agonist.
149.
- The observed effect of the combination of A and B is expressed
as a fraction of the maximal effect of the full agonist .As the
concentration of the partial agonist increases, the effect of the
combination converges on the maximum effect of the partial agonist
.When added to a low concentration( e . g . ,[ A ] =0.25 )of
agonist, the partial agonist increases the response; but when added
to a large concentration of the agonist, the response decreasesthat
is, B acts like an antagonist .
150.
- Combined with a low concentration of a full agonist, the
effects of the partial agonist are additive up to the maximum
effect of the partial agonist .
- Combined with increasing concentrations([ A ] =0.67 to 256 )of
full agonist, the partial agonist will act as an antagonist .
- These drugs mediate their clinical effects via and - opioid
receptors.
151.
- Nalbuphine and butorphanol have been reported to be antagonists
at the opioid receptor, they do cause respiratory depression, which
is not a function ofagonists .Thus, they appear to have at least
partial agonist activity at the - opioid receptor .
152. Receptors
153. The major role for using them
- To be in the provision of postoperative analgesia.
- Used for intraoperative sedation, as adjuncts during general
anesthesia.
- To antagonize some effects of full opioid agonists .
154. Nalbuphine
- Is a phenanthrene opioid derivative .
- Classified as aagonist and antagonist.
- It is more accurately described as a partial agonist at bothand
receptors .
- 0.5 mg / kg dose reduced enflurane MAC by 8%.
- This modest MAC reduction, compared with 65% for morphine,
suggests nalbuphine may not be a useful adjunct for general
anesthesia .
155. Study
- Combined with diazepam 0.4 mg / kg and 50% N2O in oxygen, a
loading dose of 3 mg/kg was followed by additional doses of 0.25
mg/kg as needed throughout surgery.
- No significant increases in blood pressure, stress hormones, or
histamine were seen.
- Emergence from anesthesia was uncomplicated.
156. Side Effects
- The most common side effect was drowsiness .
- Can precipitate withdrawal symptoms in patients who are
physically dependent on opioids .
157. Comparison with fentanyl
- Fentanyl was found to better attenuate hypertensive responses
to intubation and surgical stimulation .
- Significant respiratory depression was seen in 8 of 30 patients
who received fentanyl; compared with no respiratory depression in
the nalbuphine group.
- Postoperative sedation was common in the nalbuphine group.
158. Features
- The respiratory depression mediated by - opioid receptors.
- Has a ceiling effect equivalent to that produced by ~0.4 mg /
kg morphine .
- Analgesia is mediated by bothand receptors .
- Antagonize the respiratory depressant effects of full agonists
while still providing analgesic effects .
159.
- Have ceiling analgesic and respiratory depressant effects.
- Can be as effective as full agonists in providing postoperative
analgesia .
- Nalbuphine 5 to 10 mg has also been used to antagonize pruritus
induced by epidural and intrathecal morphine .
- The usual adult dose of nalbuphine is 10 mg as often as every 3
hours .
160. Butorphanol
- Has partial agonist activity at -and - opioid receptors.
- Produced dose - dependent sedation which mediated byreceptors
.
- Decreases enflurane MAC,11%, at 0.1 mg/kg. Increasing the
butorphanol dose 40-fold does not produce a further reduction.
- Butorphanol and morphine provided equally satisfactory
anesthesia .
161.
- Produces respiratory depression with a ceiling effect below
that of full agonists .
- 3 mg produces respiratory depression approximately equal to
that of 10 mg morphine .
- Its effectiveness in reversing fentanyl - induced respiratory
depression (5 g / kg followed by an infusion of 3 g/kg/hr) by
butorphanol 1 mg only.
162.
- Does not produce significant elevation in intrabiliary
pressure.
- Effective in the treatment of postoperative shivering.
- Antipruritic effect that is blocked by a selectiveantagonist
.
- Reduce morphine - induced pruritus without completely blocking
its analgesic effect .
- Lower incidence of opioid - induced ileus compared with -
selective opioids.
163. Extra Info.
- Use as a sedative as low as 0.5 mg.
- Treatment of moderate postoperative pain .
- Single analgesic doses range from0.5 to 2 mg.
- Administered as patient - controlled analgesia.
- Can be administered epidurally and transnasally .
164. Buprenorphine
- Highly lipophilic thebaine derivative.
- A partial opioid agonist .
- At small - to - moderate doses it is 25 to 50 times more potent
than morphine .
- Does not appear to have agonist activity at the - opioid
receptor.
- Its slow dissociation from receptors, which can lead to
prolonged effects not easily antagonized by naloxone .
165.
- Bell - shaped dose - response curve such that, at very high
doses, it produces progressively less analgesia .
- 10 or 20 g / kg buprenorphine during surgery were pain - free
postoperatively.
- 30 or 40 g / kg had significant postoperative pain .
166.
- Have a ceiling effect to its respiratory depressant dose -
response curve .
- Buprenorphine - induced respiratory depression can be prevented
by prior naloxone administration.
- Not easily reversed by naloxone once the effects have been
produced .Which require around 5 to 10 mg to antagonize it which
maximum occur after 3 hours.
167.
- A dose of 0.3 mg buprenorphine reduces CO 2responsiveness to
about 50% of control values.
- Did not antagonize fentanyl - induced respiratory depression,
and appears to increase respiratory rate without antagonizing
analgesic effects in slowly administered doses up to 0.5 mg .
168. Extra Info.
- Effective in treatment of moderate - to - severe pain.
- Analgesic duration can be >6 hours .
- A single dose of 0.3 to 0.4 mg appears to produce analgesia
equivalent to 10 mg morphine .
169. Opioid Antagonists
- They are competitive inhibitors of the opioid agonists.
- Effect profile depends on:
- The type of agonist administered
- Dose of agonist administered
- The degree to which physical dependence on the opioid
agonist
170. Naloxone
- The most widely used opioid antagonist.
- Structurally related to morphine and oxymorphone.
- It is a pure antagonist at - , - , and - opioid receptors
.
- Administered to antagonize opioid - induced respiratory
depression and sedation .
171. Naltrexone
- Long - acting oral agent.
- Relatively pure antagonist activity .
172.
- Mediated by endogenous opioids:
- reverse stress analgesia.
- antagonize analgesia produced by low-frequency stimulation with
acupuncture needles.
- reverse analgesia produced by placebo medications.
- Trials in prevention of treatment of opioid - mediated
gastrointestinal dysfunction.
173. Side Effects
- Producing sudden, severe pain in postoperative patients.
- Tachycardia and ventricular dysrhythmias.
- Precipitate opioid withdrawal symptoms in opioid-dependent
individuals.
- Acute, sometimes fatal, pulmonary edema even in healthy young
patients who have received relatively small doses( 80 to 500 g )
.
174. The Mechanism Pulm. Edema
- The mechanism for this phenomenon is thought to be centrally
mediated catecholamine release, which causes acute pulmonary
hypertension.
- It is also essential to monitor vital signs and oxygenation
closely after naloxone is administered to detect occurrence of any
of these potentially serious complications.
175.
- Very fast onset of action = easy to titrated.
- Peak effects occur within 1 to 2 minutes.
- Duration is dose - dependent.
- Total doses of0.4 to 0.8 mglast 1 to 4 hours.
- Suggested incremental doses for IV titration are20 to 40 ggiven
every few mins until the patient's ventilation improves, but
analgesia is not completely reversed.
176. Using As Infusion
- Because naloxone has a short duration of action, respiratory
depression may recur if large doses and / or long - acting opioid
agonists have been administered .
- When prolonged ventilatory depression is anticipated, an
initial loading dose followed by a naloxone infusion can be used
.
- Infusion rates between 3 and 10 g / hr have been effective in
antagonizing respiratory depression from systemic and epidural
opioids .
177. Use of Opioids in Clinical Anesthesia
- The goal of opioid premedication is to provide moderate
sedation, anxiolysis, and analgesia while maintaining hemodynamic
stability .
- Potential risks of opioid premedication include:
178. For induction of anesthesia
- Opioids are often used to blunt or prevent the hemodynamic
responses to tracheal intubation .
- Opioids with rapid onset of action, such as fentanyl and its
derivatives, are appropriate for this use .
179. During maintenance of general anesthesia
- Opioid dosage is titrated to the desired effect based on :
- individual patient characteristics, such as
- other systemic disease states .
180.
- Important pharmacokinetic differences among these opioids
include volumes of distribution and intercompartmental
(distributional) and central (elimination) clearances.
- A smaller distribution volume tends to shorten recovery
time.
- A reduction in clearance tends to increase recovery time .
181.
- The major pharmacodynamic differences among these opioids are
potency and the equilibration times between the plasma and the site
of drug effect .
- Equilibration half - times between plasma and effect site are 5
to 6 minutes for fentanyl and sufentanil.
- Equilibration half - times between plasma and effect site are
1.3 to 1.5 minutes for alfentanil and remifentanil .
182.
- The rate of recovery after a continuous infusion will depend on
the duration of the infusion as well as the magnitude of decline
that is required .
183. 184.
- If only a 20% drop in effect site concentration is required,
recovery from all three opioids will be rapid, although recovery
time increases for fentanyl after 3 hours of drug infusion .
- If a 50% decrease is required, recovery from sufentanil will be
fastest for infusions 8 hours .
185. Context - Sensitive Half - Time
- Defined as the time required for the drug concentration in the
central compartment to decrease by 50%, and demonstrated how this
half - time changes as drug infusion duration increases .
186. Explanation
- During an infusion, the peripheral( fast and slow )compartments
begin to fill up . After the infusion is stopped, drug will be
eliminated, but will also continue to be redistributed as long as
the concentration in a peripheral compartment is lower than that in
the central compartment .This leads to a rapid drop in central
compartment drug concentration .
187.
- When central compartment( plasma )concentration drops below
that of the peripheral compartment ( s ) , the direction of drug
redistribution will reverse and will slow the decline in plasma
concentration .
188.
- The degree to which redistribution will affect the rate of drug
elimination depends on the ratio of the distributional to
elimination time constants .Thus, a drug that can rapidly
redistribute will have a correspondingly larger contribution from
the peripheral compartment ( s ) , and plasma concentration will
drop progressively more slowly as infusion duration continues
.
189. Context - sensitive half - times 190. THANK YOU