INTRAVENOUS ANESTHESIA AND OPIOIDS ANESTHESIOLOGY | MIDTERMS (1st Sem)

„‟ Dr. Jayber L. Tagacay

OUTLINE PHARMACOKINETICS
I. INTRODUCTION IV. OPIOID AGONISTS  Primarily metabolized by the liver and subsequently its inactive
II. INTRAVENOUS A. Morphine and water- soluble metabolites are excreted by the kidneys
ANESTHETICS B. Meperidine  Clearance rate: 20-30mL/kg/min (approx.1.5L/min)
A. Propofol C. Fentanyl
B. Etomidate D. Sufentanil
 Initial distribution half- life: 1-8 min
C. Ketamine E. Alfentanil  Secondary slow distribution half- life: 30-70 min
D. Dexmedetomidine F. Remifentanil  Elimination half- life: 2-24 hrs
E. Benzodiazepines G. Codeine  Infusion duration of up to 8hrs maintains a reliable context-
F. Barbiturates H. Hydromorphone
G. New Intravenous I. Oxymorphone sensitive half- life of 40 min or less.
Anesthetics J. Oxycodone
III. OPIOID AGONISTS AND K. Hydrocodone PHARMACODYNAMICS
ANTAGONISTS L. Methadone  Primary mechanism: GABA- A receptor agonist
A. Introduction M. Tramadol
B. Terminologies N. Heroin (Diacetyl  Alteration of the central cholinergic transmission by propofol may
C. Classification morphine) also play a role in achieving a state of unconsciousness.
D. Mechanism of Action V. OPIID AGONISTS-  Initial low doses: sedation
E. Opioid Receptors ANTAGONISTS
F. Common Opioid Side A. Pentazocine
 Increased doses: state of paradoxical excitation may occur
Effect B. Butarphanol o Disinhibition
C. Nalbuphine o Unpredictable movement
VI. OPIOID ANTAGONISTS o Broken speech
A. Naloxone
o Not readily arousable
B. Naltrexone
 Further increase: loss of consciousness, apnea, relative
relaxation of muscles, necessitates airway support
I. INTRODUCTION
General Principles: SYSTEMIC EFFECTS
 Intravenous anesthetics are now a key component of modern  CNS
anesthesia practice. o Lower sedative doses may cause changes in EEG
pattern
Properties of the Ideal Intravenous Anesthetic o Induction dose:
Pharmacodynamic/ Pharmacokinetic Properties  Initial stages of genera; anesthesia are
 Hypnosis and amnesia reached
 Rapid onset (time of one arm – brain circulation)  β-wave activity decreases, with simultaneous
 Rapid metabolism to inactive metabolites increase in α and δ activity
 Minimal cardiovascular and respiratory depression  Burst suppression: commonly employed as
 No histamine release or hypersensitivity reactions neuroprotective measure prior to aneurysm
 Non- toxic, nonmutagenic, noncarcinogenic clipping, attained at concentrations of 8ug/mL
 No untoward neurologic effects, such as seizures, o Lower cerebral metabolic oxygen consumption rate
myoclonus, analgesia, neurtoxicity (CMRO2)
 Other beneficial effects: analgesia, antiemetic, o Decreased intracranial pressure primarily by lowering
neuroprotection, cardioprotection cerebral blood flow
 Pharmacokinetic- based models to guide accurate dosing o Cerebral perfusion pressure may also be lowered
 Ability to continuously monitor delivery o Generally considered an anticonvulsant
Physiochemical Properties o Loss of consciousness
 Water- soluble
 Stable formulation, nonpyrogenic  Cardiovascular
 Non-irritating: painless on intravenous injection o Characteristic drop in systolic and diastolic blood
 Small volume needed for induction pressure without the expected increase in heart rate.
 Inexpensive to prepare and formulate o Decrease in cardiac output, stroke volume, and
 Antimicrobial preparation systemic vascular resistance (SVR).
o Decreased sympathetic activity- indirect arterial
II. INTRAVENOUS ANESTHETICS vasodilation and venodilation.
A. PROPOFOL o Suppression of supraventricular tachycardia.
 One of the most frequently used IV anesthetics on the market  Respiratory
today. o Apnea is relatively common with a higher induction
 Desirable rapid onset dose
 Predictable context- sensitive half- time o typical maintenance dose of propofol results in
 Rapid emergence from anesthesia diminished tidal volumes and increased respiratory rate.
 Wide spectrum of uses: o Blunted response to hypoxia that may be a direct effect
o Induction and maintenance of general anesthesia on chemoreceptors.
o Intensive care unit sedation o Decreased respiratory response to hypercarbia
o Sedative- hypnotic in a variety of outpatient procedures o Potent bronchodilator  direct effects on intracellular
 The lipid emulsion comes in a familiar milky white consistency Calcium homeostasis.
and can be stored at room temperature without any significant
degradation.

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CLINICAL USES
 IV Sedative Hypnotic
o Rapid and smooth induction and emergence from
anesthesia
o Induction dose in a healthy adult (approx. 1-2.5mg/kg)
o Loss of consciousness (close to 3ug/kg)
o Elderly patients prolonged effects and increased
sensitivity to propofol
o Children larger than average volume of distribution
and quicker clearance
o Patients with chronic alcohol abuse increased
induction dose requirement.
 Maintenance of General Anesthesia
o Infusions between 100 and 200ug/kg/min
o TIVA with propofol alone, or together with opioids as
part of a balanced anesthetic, has been utilized
successfully for all types of surgery.
 Major Benefit
o Prevention of post-operative nausea and vomiting
 Sedation
o Sedation for minor procedures, outpatient surgery, and
off- site anesthetics, as well as ICU sedation of
mechanically ventilated patients
SIDE EFFECTS
 Pain on injection
o 60-70% of patients when administered peripherally
alone
 Propofol Infusion Syndrome (PrIS)
o Extremely rare but deadly side effect of propofol
o Unexplained metabolic acidosis
o Hyperkalemia
o Hyperlipidemia
o Rhabdomyolysis
o Hepatomegaly
o Renal failure
o ECG changes, Arrythmia, Progression to Cardiac
failure
B. ETOMIDATE
 Introduced into anesthetic practice as an induction agent
 Gained much popularity because of its safe hemodynamic
profile.
 Increased reports of adrenal suppression, pain on injection,
thrombophlebitis, PONV, myoclonus, and hiccups.
 The use of Etomidate is the result of a risk/benefit analysis.
PHARMACOKINETICS
 Imidazole derivative (the D(+) enantiomer) and is not stable in
neutral pH solutions
 Quick onset of action (“vein to brain”)
 Fast resolution of effect secondary to redistribution
 Metabolized in the liver and excreted predominantly by the
kidneys (approx. 80%) and in bile (approx. 20%)
 Largely protein bound (approx. 75%)
Initial distribution half- life 2.7 mins
Redistribution half- life 29 mins
Elimination half- life 2.9 – 5.3 hrs
Volume of Distribution 2.5 – 4.5L/kg
Induction Dose 0.2 – 0.3mg/kg
PHARMACODYNAMICS
 Binds as an agonist to the GABA-A receptors and thus has an
inhibitory influence on the brain
 Neurodepressant properties
 Potent vasoconstrictor that reduces CBF, ICP, and CMRO2.
ARAO
Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020
CLINICAL USES
 Hemodynamically stable induction medication with relatively large
safety margin.
 For induction of anesthesia in cardiac operating rooms
 Used for trauma patients who are hemodynamically unstable and
are often hypovolemic.
 Reasonable choice for MAC sedation
o Depresses airway reflexes less than Propofol (unless
co- administered with another sedative/ analgesic
agent)
o Relaxes the smooth musculature of the pulmonary
vasculature system to a similar degree as propofol.
Key Pharmacology
 GABA- A receptor agonist
 Hemodynamically stable
 Suppression
 Postoperative nausea and vomiting
Key Clinical Uses
 Hemodynamically stable induction
 Cardiac, trauma, and hypovolemic patients
SIDE EFFECTS
 Adrenocortical Supression
o Most significant adverse effect of Etomidate
o Inhibits the activity of the enzyme 11β- hydroxylase and
prevents the conversion of cholesterol to cortisol.
o Pretreatment with Dexamethasone to curtail this effect
o Most practitioners, in an effort to limit this possibility, will
not administer repeat doses or continuous infusions.
 Vasoconstrictor
o Potent vasoconstrictor that reduces CBF, ICP, and
CMRO2.
 Neurodepressant
o Despite ite neurodepressant properties at high doses,
Etomidate is often associated with epileptogenic
activity (excitatory spikes) on EEG.
o Undesirable induction agent for patients undergoing
neurosurgical procedures.
C. KETAMINE
 Emergence from Ketamine anesthesia was associated with:
o Emergence delirium
o Hallucinations
o Alterations in mood and affect
 NMDA receptor has been found to play a key role in nociception.
o Low dose Ketamine has an opiate sparing effect in the
management of acute pain.
 Effects of Ketamine related to pain can be best described as
antihyperalgesic, antiallodynic, or toleranceprotective.
 Has gained interest I the treatment of major depression, however
its clinical effects are of short duration.
PHARMACOKINETICS
 Analog of Phencyclidine that is a chiral compound and is a
racemic mixture of S and R enantiomers.
 Routes of administration (Bioavailability)
o Intramuscular (93%)
o Transnasal (25-50%)
o Rectal or Oral (16%)
 High lipid solubility and low protein binding (20%)
o Allow for a rapid uptake of Ketamine in the brain, as
well as a fairly rapid redistribution.
IV onset 30 – 60 sec
Duration 10 – 15 mins
IV induction dose 0.5 – 2 mg/kg
IM induction dose 4 – 6 mg/kg
Peak plasma levels 0.75 mg/mL
CSF levels 0.2 mg/mL 1hr after dosing
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 Metabolized primarily in the liver by cytochrome P450 enzymes
demethylation to its principal metabolite Norketamine.
 Norketamine is eliminated by renal excretion
 Due to its lipophilicity, Ketamine is only partially removed by
dialysis.
CLINICAL USES
 Anesthesia
o Less likely to cause a seizure and may in fact have
CNS protective properties.
o Associated with profound analgesia that occurs at
subanesthetic levels.
o Associated with increase in heart rate and blood
pressure.
 Good choice for anesthetic induction in th
hemodynamically unstable patient.
o Causes dissociative amnestic sate
 Unconscious with eyes open, maintain
spontaneous respiration, and do not react to
painful or noxious stimuli.
o Increase in PVR associated with Ketamine may make it
an unsuitable choice in patients with severe right heart
dysfunction.
o Management of acute postoperative pain
o Lower pain scores and decrease opiate requirements in
postoperative patients
o Analgesic effects are achieved at subanesthetic blood
concentrations.
o Reduces opiate requirements for postsurgical pain, but
it cannot replace opiates altogether.
 Sedation
o Burn patients during wound care
 Include analgesia as well as maintenance of
spontaneous respiration and airway reflexes.
o Sedation or anesthesia in uncooperative or hostile
patients
o Used in pediatric patients for painful procedures
such as reduction and casting of bone fractures in the
emergency department.
 Chronic Pain
o Chronic Regional Pain Syndrome (CRPS)
 Yields a decrease in pain scores and opiate
consumption
 These effects are only of limited duration
after Ketamine administration
o Cancer patients with severe pain
o CNS side effect and lack or oral administration limit the
application of Ketamine in patients with chronic pain.
 Depression
o Possible treatment for Major Depression
o Decreased depression symptoms and suicidal ideation
within 1hr of administration.
o Antidepressant effects of Ketamine may not be related
to its NMDA antagonism, but to its effect on other CNS
receptors (Dopamine, adrenergic).
o Duration of Ketamine’s antidepressant effect is short
after single administration.
SIDE EFFECTS
 CNS
o Psycogenic reactions (major side effect)
 Hallucinations and out-of-body experiences
that have been described as frightening
 These symptoms can be reduced with co-
administration of Benzodiazepines.
o Ketamine also causes patients to have a lateral gaze
nystagmus.
ARAO
Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020
 Cardiovascular
o Associated with increased heart rate and blood
pressure.
 Causes activation of the sympathetic
nervous system
o Increased SVR and therefore it is an attractive option
for the induction of anesthesia in patients who are
hemodynamically unstable.
 Respiratory
o Hypoxia can occur but can easily treated with
supplemental oxygen.
o Ketamine is also a Bronchodilator
 A secondary agent to consider for the
management of severe bronchospasm or
status asthmaticus.
o Caused increased salivation that may result in
laryngospasm.
D. DEXMEDETOMIDINE
 α2- adrenergic agonist
 introduced into clinical practice in 1999
o ICU sedation in mechanically ventilated patients
o Procedural sedation
o Component of general anesthesia
 Is unique as sedative
Key Pharmacology
 α2- adrenergic agonist
 Sedation with minimal respiratory depression
 Mimics normal sleep pattern on ecg
 Provides analgesia at the spinal cord level
 Administration: bolus 0.5-1ug/kg over 15mins, followed by
0.3-0.7ug/kg/hr infusion
Key Clinical Uses
 ICU sedation in mechanically ventilated patients
 Procedural sedation
 Pediatrics: preoperative anxiolysis and emergence
delirium
PHARMACOKINETICS
 Following intravenous administration:
o Distribution hal-life: 6mins
o Terminal elimination half- life: 2hrs
o Steady state volume of distributions: 118L
 Linear pharmacokinetics: dose range from 0.2 to 0.7ug/kg/hr
 Average protein binding: 94%
 Almost complete biotransformation  involves both direct
glucoronidation and cytochrome P450- mediated metabolism
PHARMACODYNAMICS
 Acts on the α2- adrenergic receptors in the spinal cord
 Effects are primarily at the locus coeruleus
 EEG pattern resembles that of non-REM sleep
 Cardiovascular effects: bradycardia and hypotension
o 7mmHg decrease in systolic blood pressure
o 1 to 8 bpm decrease in mean heart rate
CLINICAL USES
 Sedation for mechanically ventilated patients in the ICU
 Used for procedural sedation
 Pediatrics: pre-operative anxiolysis and emergence delirium
SIDE EFFECTS
 Main adverse reactions
o Hypotension, bradycardia, dry mouth, nausea, and
hypertension
 Bradycardia
o Typically occurs after a loading dose
o Management: atropine, ephedrine, or volume
administration
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 Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020

o Omitting the loading dose decreases the incidence o Manufactured as an acidic formulation that may
 Hypotension produce mild local tissue and vein irritation.
o After a 1ug/kg bolus, blood preassure decreases at  Benzodiazepines bind to specific receptor sites that are part of the
23%. GABA-A receptor complex

E. BENZODIAZEPINES MIDAZOLAM DOSING BY CLINICAL USE

MIDAZOLAM Premedication: anxiolysis, 0.02-0.04mg/kg IV/IM; 0.4-
 Anxiolysis, anterograde amnesia, sedation, and anterograde amnesia 0.8mg/kg PO
hypnosis Induction: hypnosis, amnesia 0.1-0.2mg/kg IV
 Muscle relaxants and anticonvulsants sedation
 Quick onset, short elimination half- life, anterograde Infusion (in conjuction with 0.25-1ug/kg/min
amnestic effect, and minimal side- effect profile. volatile anesthetics): hypnosis,
 Administered intravenously, intranasally, orally, amnesia
rectally, and intramuscularly  Anticonvulsants  first line therapy in the management of
 Also used as an infusion in the ICU setting seizures
Key Pharmacology
 Can also have a profound effect on the respiratory system
 GABA-A receptor agonist
 In induction doses, depress SVR and decrease BP
 Minimal respiratory depression
 Minimal cardiovascular depression
SIDE EFFECTS
 Large therapeutic window
 Reversible with Flumazenil  Anaphylaxis (extremely rare)
Key Clinical Uses  Pain or Thrombophlebitis
 Anxiolysis o More frequently described following IV injection
 Anterograde amnesia (especially Diazepam)
 Sedation o Midazolam may also cause burning with injection
 Induction of anesthesia, hemodynamically stable secondary to its acidic formulation.
 Anticonvulsant
F. BARBITURATES
PHARMACOKINETICS  2 major classes of Barbiturates:
 Highly protein bound and highly lipophilic 1. Thiobarbiturates
 Metabolism: hepatic cytochrome P450 system via oxidation and a. Thiopental
glucuronic conjugation b. Thiamylal
 Excretion: renal 2. Oxybarbiturates
a. Methohexital
 Midazolam
o Active metabolite (1- hydroxymidazolam) contributes
PHARMACOKINETICS
minimally to its clinical effects.
 Primary metabolism: hepatic; eliminated in urine and bile
Volume of distribution 1 to 3.1L/kg after a single bolus
dose  Most common form of metabolism: oxidation of Thiopental an
Elimination half- life 1.8 – 2.6 hrs Methohexital to their respective hydroxyl derivatives.
Total clearance 6.4 – 11mL/kg/min Elimination Half-life Clearance rate
Thiopental 12 hrs 3 ml/kg/min
BENZODIAZEPINE METABOLISM AND CLEARANCE Methohexital 4 hrs 11 ml/kg/min
DRUG DURATION METABOLITE HEPATIC
CLEARANCE PHARMACODYNAMICS
Midazolam Short 1-hydroxymidazolam High  Involves cortical and brainstem GABA inhibitory pathways,
(mild CNS leading to loss of consciousness, as well as respiratory and
depressant) cardiovascular depression.
Diazepam Intermediate Onazepam and Slow  Hypnotic effects are likely enhanced by the inhibition of central
Desmethyldiazepam excitatory pathways, specifically those mediated by glutamate via
Lorazepam Long Inactive Intermediate NMDA receptors and acetylcholine.
 Central Nervous System Effects
BENZODIAZEPINE PHARMACOKINETICS o Thiopental
DRUG INDUCTI DURATIO HALF PROETEI VOL. OF CLEARANCE ELIM  Generally considered an anticonvulsant
ON
DOSE
N
ACTION
OF LIFE N
BINDING
DIST HALF-
LIFE
 Used successfully for treatment of status
Midazolam 0.1- 15-20min 7- 94% 1- 6.4- 1.8- epilepticus
0.3mg/kg 15min 1.3L/kg 11mL/kg?min 2.6hr
Diazepam 0.3- 15-30min 10- 98% 0.7- 0.2- 20-
 Smaller concentrations noted to have
0.6mg/kg 15min 1.7L/kg 0.5mL/kg/min 50hr proconvulsant properties
Lorazepam 0.03- 60-120min 3- 98% 0.8- 0.8- 11-
0.1mg/kg 10min 1.3L/kg 1.8mL/kg/min 22hr o Methohexital
 Considered to have proconvulsant effects in
PHARMACODYNAMIC AND CLINICAL USES patients with epilepsy
 3 most commonly used parenteral Benzodiazepines:  Agent of choice for induction of anesthesia
o Lorazepam prior to electroconvulsive therapy.
o Diazepam o Decrease in CMRO2
o midazolam o Increase in cerebrovascular resistnce, leading to
 Lorazepam and Diazepam decreased CBF and ICP
o Not suitable in water and often cause vein irritation due o Neuroprotective properties
to the propylene glucol admixture  Anticonvulsant properties
 Improved blood flow to ischemic parts of the
 Midazolam
brain (reversal steal effect)
o Water-soluble and undergoes conformational change in
 Free- radical scavenging
the bloodsream, becoming more lipophilic.

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 Attenuation of excitatory neurotransmitter
release and pathways
 Membrane stabilization
 Cardiovascular Effects
o Thiopental
 Decrease in both MAP and cardiac output
 Negative inotropic effects
o Methohexital
 Smaller decrease in MAP and larger increase
in heart rate.
 Respiratory System Effects
o Apnea
 After a typical induction dose, apnea is
commonly noted after 1 to 1.5 mins, with
ventilator response to carbon dioxide
returning to baseline in approximately 6 mins
o Respiratory depression
 Can cause respiratory depression in a dose-
dependent manner, leading to central apnea
at deeper stages of anesthesia.
CLINICAL USES
 Thiopental
o Ideal induction agent
o Typical induction dose: 2.5-5mg/kg
o Light stages of anesthesia in 15-30sec and deeper
stages in 30-40sec that last for approximately 1min.
o Rapid onset and emergence
o Patient variability:
 Unpremedicated healthy children: 5-6mg/kg
induction dose
 Infants: higher dose requirement
 Elderly: lower induction dose requirement
 Obesity: lower induction requirement on a per
kilogram basis
 Comorbid states: decrease in induction dose
requirement
 Methohexital
o Used for induction anesthesia with typical IV induction
dose of 1-2mg/kg
o Used as Sedative and is administered rectally in
solution form in the pediatric population, with
recommended dose of 25mg/kg
o Maintenance of sedation and general anesthesia at
infusion doses of 50-150ug/kg/min.
SIDE EFFECTS
 Discomfort on injection sites
o Can cause discomfort if injected outside the vein into
subcutaneous tissue
 Tissue necrosis
o Inadvertent arterial administration can lead to
decreased blood flow due to vasospasm and thrombus
formation, pain at the arterial site, and possible tissue
necrosis.
o Management
 Arterial administration of Papaverine
 Heparinization
 Arteriolar dilation by appropriate regional
anesthetic technique
Key Pharmacology
 GABA-A receptor agonist
 Prolonged context- sensitive half time
 CNS depressant, neuroprotective, anticonvulsant,
decreases CMRO2, CBF, and ICP
 EEG burst suppression (thiopental)
 Cardiovascular: decreases mean arterial pressure,
venous vascular tone, and cardiac output
 Pulmonary: dose-dependent respiratory depression, does
not cause bronchodilation
ARAO
Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020
Key Clinical Uses
 Induction of general anesthesia
 Methohexital used for sedation, premedication, and
electroconvulsive therapy
 Barbiturate coma (thiopental)
 Thiopental intra-arterial injection can lead to tissue
necrois
G. NEW INTRAVENOUS ANESTHETICS
REMIMAZOLAM
 Benzodiazepine with a structure and onset time similar to
midazolam
 Takes advantage of hypnotic and amnestic effects of midazolam
with a speed and mode of metabolism similar to Remifentanil.
 Binds as an agonist to the GABA receptor
 Quick onset and offset
 Initially developed for procedural sedation during procedure such
as colonoscopy
 Considered for ICU sedation
 Alternative to Propofol by avoiding accumulation of drug leading
to prolonged sedation.
FOSPROPOFOL
 Prodrug of Propofol produced to reduce or eliminate the averse
effects of the current Propofol emulsion.
 Water- based solution that yields less pain on injection, less
hyperlipidemia, and less risk for bacteremia.
 Sedative- hypnotic approved for MAC sedation
 Associated with an increase in pruritus and paresthesia.
III. OPIODS AGONISTS AND ANTAGONISTS
A. INTRODUCTION
 Mainstay of modern perioperative care and pain management
 Modern word “opium” is derived from the Greek word opion
(poppy juice).
 The term narcotics is derived from the Greek word for stupor
and traditionally has been refer to morphine-like analgesics with
the potential to produce physical dependence.
 The German pharmacist Sertuener isolated what he called the
oporific principle in opium in 1806.
 1817 named it morphine, after the Greek god of dreams,
Morpheus.
 The development of synthetic drugs with morphine-like properties
has led to the use of the term opioid to refer to all exogenous
substances, natural and synthetic, that bind specifically to any of
several subpopulations of opioid receptors and produce at least
some agonist (morphine-like) effects.
B. TERMINOLOGIES
 Opiate
o Drugs derived from opium, including morphine, its
semisynthetic derivatives, and codeine.
 Opioid
o All drugs, both natural and synthetic, with morphine-like
properties, including endogenous peptides.
o Opioid can be:
 Agonist: produce the maximum possible
effect of binding with the receptor
 Antagonist: produces no direct effect when it
binds the receptor
 Partial Agonist: has a dose-effect ceiling
that is lower than the maximum possible
effect
 Mixed agonist- antagonist: acts as an
agonist (or partial agonist) at one receptor
and an antagonist at another
 Narcotic
o Morphine and morphine-like analgesics.
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 Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020

 Efficacy  k - Receptor
o Range in magnitude of an effect produced by a drug o k - Receptor–mediated analgesia may be less effective
receptor combination relative to the maximum possible for high-intensity painful stimulation than µ-opioid–
effect mediated
 Potency o Opioid agonist–antagonists often act principally on k-
o The relative dose required to achieve an effect, and is receptors
related to receptor affinity

C. CLASSIFICATION

AGONISTS AGONISTS- ANTAGONISTS

ANTAGONISTS
 Morphine  Pentazocine  Naloxone
 Morphine-6-  Butorphanol  Naltrexone
glucuronide  Nalbuphine  Nalmefene
 Meperidine  Buprenorphine
 Sufentanil  Nalorphine
 Fentanyl  Bremazocine
 Alfentanyl  Dezocine
 Remifentanil  Meptazinol
 Codeine
F. COMMON OPIOID SIDE EFFECT
 Hydromorphon
e  Cardiovascular System
 Oxymorphone o Morphine, even in large doses, given to supine and
 Oxycodone normovolemic patients is unlikely to cause direct
 Hydrocodone myocardial depression or hypotension.
 Propoxyphene o The same patients changing from a supine to a
 Methadone standing position, however, may manifest orthostatic
 Tramadol hypotension and syncope, presumably reflecting
 heroin morphine-induced impairment of compensatory
sympathetic nervous system responses
o Morphine can decreases in systemic blood pressure
D. MECHANISM OF ACTION due to drug-induced bradycardia (stimulation of the
 Act as agonists at specific opioid receptors at presynaptic and vagal nuclei in the medulla, direct depressant effect on
postsynaptic sites in the central nervous system (mainly the the sinoatrial node) or histamine release
brainstem and spinal cord) as well as in the periphery. o In contrast to morphine, the infusion of fentanyl does
 These opioid receptors normally are activated by three not cause release of histamine in any patient.
endogenous peptide opioid receptor ligands known as o During anesthesia, opioids are commonly administered
enkephalins, endorphins, and dynorphins. (Opioids mimic the with inhaled or intravenous anesthetics to ensure
actions of these endogenous ligands by binding to opioid amnesia.
receptors, resulting in activation of pain-modulating  The combination of an opioid agonist such
[antinociceptive] systems.) as morphine or fentanyl with nitrous oxide
o The principal effect of opioid receptor activation is a results in cardiovascular depression which
decrease in neurotransmission that occurs largely by does not occur when either drug is
presynaptic inhibition of neurotransmitter release administered alone.
(acetylcholine,dopamine, norepinephrine, substance P).  Decreases in systemic vascular resistance
o The intracellular biochemical events initiated by and systemic blood pressure may
occupation of opioid receptors with an opioid agonist accompany the combination of an opioid and
are characterized by increased potassium conductance a benzodiazepine, whereas these effects do
(leading to hyperpolarization), calcium channel not accompany the administration of either
inactivation, or both, which produce an immediate drug alone.
decrease in neurotransmitter release. o Opioids recognized as playing a role in protecting the
 Opioid receptors are coupled with inhibitory G-proteins and their myocardium from ischemia.
activation has a number of actions:  Ventilation
o Closing of voltage sensitive calcium channels o All opioid agonists produce dose-dependent and
o Stimulation of potassium efflux leading to gender-specific depression of ventilation, primarily
hyperpolarization and reduced cyclic adenosine through an agonist effect at mu2 receptors, leading to a
monophosphate (cAMP) production direct depressant effect on brainstem ventilation
 Overall, the effect is a reduction in neuronal cell excitability centers
leading to reduced transmission of nociceptive impulses. o Opioid-induced depression of ventilation is
characterized by decreased responsiveness of these
E. OPIOID RECEPTORS ventilation centers to carbon dioxide as reflected by an
 µ - Receptors increase in the resting Paco2 and displacement of the
o Principally responsible for supraspinal and spinal carbon dioxide response curve to the right
analgesia. o Death from an opioid overdose is almost invariably due
o Respiratory depression characteristic of µ - receptor to depression of ventilation.
activation is less prominent with k-receptor activation, o Clinically, depression of ventilation produced by opioids
although dysphoria and diuresis may accompany manifests as a decreased frequency of breathing that
activation of these receptors is often accompanied by a compensatory increase in
tidal volume

ARAO 6 of 10

 Central Nervous System
o In the absence of hypoventilation, opioids decrease
cerebral blood flow and possibly intracranial pressure
(ICP)
o Rigidity
 Rapid intravenous (IV) administration of large
doses of an opioid (particularly fentanyl and
its derivatives as used in cardiac surgery) can
lead to generalized skeletal muscle rigidity
o Sedation
 Postoperative titration of morphine frequently
induces sedation that precedes the onset of
analgesia
 The usual recommendation for morphine
titration includes a short interval between
boluses (5 to 7 minutes) to allow evaluation
of its clinical effect
o Nausea and Vomiting
 Opioid-induced nausea and vomiting are
caused by direct stimulation of the
chemoreceptor trigger zone in the floor of
the fourth ventricle
 Morphine cause nausea and vomiting by
increasing gastrointestinal secretions and
delaying passage of intestinal contents
toward the colon.
o Placental Transfer
 Opioids are readily transported across the
placenta (depression of the neonate can
occur)
o Overdose
 The principal manifestation of opioid
overdose is depression of ventilation,
manifesting as a slow breathing frequency,
which may progress to apnea (triad of
miosis, hypoventilation, and coma should
suggest overdose with an opioid)
 Treatment of opioid overdose is mechanical
ventilation of the patient’s lungs with oxygen
and administration of an opioid antagonist
such as naloxone (may precipitate acute
withdrawal in dependent patients)
IV. OPIOID AGONISTS
A. MORPHINE
 Is the prototype opioid agonist to which all other opioids are
compared, producing analgesia, euphoria, sedation, nausea, and
pruritus (especially in the cutaneous areas around the nose)
 The cause of pain persists, but even low doses of morphine
increase the threshold to pain and modify the perception of
noxious stimulation such that it is no longer experienced as pain
(continuous, dull pain is relieved by morphine more effectively
than is sharp, intermittent pain)
 In contrast to non-opioid analgesics, morphine is effective against
pain arising from the viscera
 Analgesia is most prominent when morphine is administered
before the painful stimulus occurs
PHARMACOKINETICS:
 Absorbed after intramuscular (IM) administration, with onset of
effect in 15 to 30 minutes, a peak effect in 45 to 90 minutes and a
clinical duration about 4 hours
 Usually administered IV in the perioperative period, thus
eliminating the unpredictable influence of drug absorption
 The peak effect after IV administration of morphine is delayed
compared with opioids such as fentanyl and alfentanil, requiring
about 15 to 30 minutes
ARAO
Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020
METABOLISM:
 Primarily through conjugation with glucuronic acid in hepatic and
extrahepatic sites, especially the kidneys
 about 75% to 85% of a dose of morphine appears as morphine-
3-glucuronide pharmacologically inactive, major metabolite
 5% to 10% as morphine- 6-glucuronide pharmacologically
active, causes respiratory depression and sedation
ELIMINATION:
 Small amount of unchanged opioid is excreted in the urine
 Concentrations of morphine in the colostrum of parturients
receiving patient-controlled analgesia with morphine are low and it
is unlikely transferred to the breast-fed neonate.
B. MEPERIDINE
 Is a synthetic opioid agonist at µ and k - opioid receptors
 Shares several structural features that are present in local
anesthetics and structurally similar to atropine (possesses a mild
atropine-like antispasmodic effect on smooth muscle)
PHARMACOKINETICS
 About one-tenth as potent as morphine producing equivalent
sedation, euphoria, nausea, vomiting, and depression of
ventilation with a duration of action of 2 to 4 hours.
METABOLISM
 Is extensive, with about 90% of the drug initially undergoing
demethylation to normeperidine and hydrolysis to meperidinic
acid
 Normeperidine (one-half as active as an analgesic) undergoes
hydrolysis to normeperidinic acid
CLINICAL USES
 Declined greatly in recent years because of possible
normeperidine toxicity
 Effective in suppressing postoperative shivering (anti shivering
effects may reflect stimulation of k - receptors)
SIDE EFFECTS
 Resemble those described for morphine
 In contrast to morphine, rarely causes bradycardia but instead
may increase heart rate, reflecting its modest atropine-like
qualities
 Large doses of meperidine result in decreases in myocardial
contractility, which, among opioids, is unique for this drug.
C. FENTANYL
 Is a phenylpiperidine-derivative synthetic opioid agonist that is
structurally related to meperidine
 As an analgesic, fentanyl is 75 to 125 times more potent than
morphine
PHARMACOKINETICS
 Single dose of fentanyl administered IV has a more rapid onset
and shorter duration of action than morphine
 Produces a rapid onset
 Greater potency and more rapid onset of action reflect the across
the blood–brain barrier
 The lungs serve as a large inactive storage site, with an estimated
75% of the initial fentanyl dose undergoing first-pass pulmonary
uptake
METABOLISM
 Metabolized by N-demethylation
 Pharmacologic activity of fentanyl metabolites is believed to be
minimal.
7 of 10

ELIMINATION HALF TIME
 Has a short duration of action, but its elimination half-time is
longer than that for morphine
 Longer elimination half-time reflects a larger volume of distribution
(Vd) of fentanyl due to its greater lipid solubility and thus more
rapid passage into highly vascular tissues compared with the less
lipid-soluble morphine
 The plasma concentrations of fentanyl are maintained by slow
reuptake from inactive tissue sites, which accounts for persistent
drug effects that parallel the prolonged elimination half-time
 Prolonged elimination half-time for fentanyl in elderly patients is
due to decreased clearance of the opioid because Vd is not
changed in comparison with younger adults
CLINICAL USES
 Analgesia (1-2ug/kg IV)
 Adjuvant to inhaled anesthetics to blunt the response to direct
laryngoscopy or sudden changes in the level of surgical
stimulation (2-20ug/kg IV); consider effect- site equilibration time
 Decrease doses of inhaled anesthetics needed to blunt
sympathetic nervous system responses to surgical stimulation
(1.5-3ug/kg IV 5min before induction of anesthesia)
 Produce surgical anesthesia (50-150ug/kg IV)
 Analgesia for early labor (25ug intrathecal)
 Preoperative medication (transmucosal)
 Postoperative analgesia (transdermal patch)
SIDE EFFECTS
 Cardiovascular Effects
o Even in large doses (50 g/kg IV), does not evoke the
release of histamine
o Bradycardia is more prominent with fentanyl than
morphine and may lead to occasional decreases in
blood pressure and cardiac output.
 Seizure Activity
o It is difficult to distinguish opioid-induced skeletal
muscle rigidity or myoclonus from seizure activity
 Intracranial Pressure
o Associated with increase (6 to 9 mm Hg) in ICP despite
maintenance of an unchanged Paco2 together with
alfentanil
DRUG INTERACTIONS
 Fentanyl greatly potentiate the effects of benzodiazepines
(synergism with respect to hypnosis and depression of ventilation)
 The advantage of synergy between opioids and benzodiazepines
for the maintenance of patient comfort is carefully weighed
against the disadvantages of the potentially adverse depressant
effects of this combination.
D. SUFENTANIL
 Is a thienyl analogue of fentanyl with an analgesic potency of
sufentanil that is 5 to 10 times that of fentanyl.
PHARMACOKINETICS
 Elimination half-time of sufentanil is intermediate between that of
fentanyl and alfentanil
 Permits rapid penetration of the blood–brain barrier and onset of
CNS effects
 Redistribution to inactive tissue sites terminates the effect of small
doses, but a cumulative drug effect can accompany large or
repeated doses of sufentanil
METABOLISM
 Rapidly metabolized by N-dealkylation and the products are
pharmacologically inactive, whereas desmethyl sufentanil has
about 10% of the activity of sufentanil
ARAO
Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020
CLINICAL USES
 A single dose of sufentanil, 0.1 to 0.4 g/kg IV, produces a longer
period of analgesia and less depression of ventilation than does a
comparable dose of fentanyl (1 to 4 g/kg IV)
 Dose of 18.9 g/kg IV results in more rapid induction of anesthesia,
earlier emergence from anesthesia, and earlier tracheal
extubation
 Produces bradycardia that may be sufficient to decrease cardiac
output
E. 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
 Unique advantage compared with fentanyl and sufentanil is the
more rapid onset of action (rapid effect-site equilibration) after the
IV administration of alfentanil.
PHARMACOKINETICS
 Has a short elimination half-time compared with fentanyl and
sufentanil
 Despite its lesser lipid solubility, penetration of the blood–brain
barrier by alfentanil is rapid because of its large nonionized
fraction at physiologic Ph
METABOLISM
 Hepatic clearance of about 96% from the plasma within 60
minutes of its administration
 Alfentanil clearance is markedly influenced by CYP3A activity
CLINICAL USES
 Has a rapid onset and off set of intense analgesia, reflecting its
very prompt effect-site equilibration.
 Used to provide acute but transient analgesia
 Associated with a lower incidence of postoperative nausea and
vomiting in outpatients compared with fentanyl and sufentanil
F. REMIFENTANIL
 Is a selective opioid agonist with an analgesic potency similar to
that of fentanyl (15 to 20 times as potent as alfentanil) and a
blood–brain equilibration time similar to that of alfentanil
 Short-acting phenylpiperidine derivatives, structurally unique
because of its ester linkage structure that is susceptible to
hydrolysis by nonspecific plasma and tissue esterases to inactive
metabolites
 The unique pathway of metabolism leads to (a) brief action, (b)
precise and rapidly titratable effect due to its rapid onset and off
set, (c) lack of accumulation, and (d) rapid recovery after
discontinuation of its administration.
PHARMACOKINETICS
 Characterized by small Vd, rapid clearance, and low
interindividual variability compared to other IV anesthetic drugs
 Because of its rapid systemic clearance, remifentanil provides
pharmacokinetic advantages in clinical situations requiring
predictable termination of drug effect
 Combination of rapid clearance and small Vd produces a drug
with a uniquely transient effect
METABOLISM
 Unique among the opioids in undergoing metabolism by
nonspecific plasma and tissue esterases to inactive metabolites
 Clearance not affected by cholinesterase deficiency or
anticholinergic
 Pharmacokinetics will be unchanged by renal or hepatic failure
because esterase metabolism is usually preserved
CLINICAL USES
 Unique pharmacokinetics which allows rapid onset of drug effect,
precise titration to the desired effect, the ability to maintain a
sufficient effect-site concentration to suppress the stress
response, and rapid recovery from the drug’s effect
 Remifentanil, 0.05 to 0.10 g/kg/min in combination with
midazolam, 2 mg IV, provides effective sedation and analgesia
8 of 10

during monitored anesthesia care in otherwise healthy adult
patients
SIDE EFFECTS
 The short recovery period may be considered a disadvantage if
the infusion is stopped suddenly
 Nausea and vomiting, depression of ventilation, and mild
decreases in systemic blood pressure and heart rate
 Hyperalgesia
o Patients receiving large doses of remifentanil
intraoperatively are often surprisingly high, suggesting
remifentanil may be associated with acute opioid
tolerance
G. CODEINE
 Ss the result of the substitution of a methyl group for the hydroxyl
group on the number 3 carbon of morphine
 The presence of this methyl group limits first-pass hepatic
metabolism and accounts for the efficacy of codeine when
administered orally
 About 10% of administered codeine is demethylated in the liver
to morphine, which may be responsible for the analgesic effect
of codeine, although codeine-6-glucuronide may also exert an
analgesic effect.
 Effective at suppressing cough at oral doses
 Maximal analgesia, equivalent to that produced by 650 mg of
aspirin, occurs with 60 mg of codeine
 When administered IM, 120 mg of codeine is equivalent in
analgesic effect to 10 mg of morphine
 Included in medications as an antitussive or is combined with
nonopioid analgesics for the treatment of mild to moderate pain.
H. HYDROMORPHONE
 Derivative of morphine that is about five times as potent as
morphine but has a slightly shorter duration of action
 Hydromorphone is an effective alternative to morphine in the
treatment of opioid-responsive moderate to severe pain
I. OXYMORPHONE
 About 10 times as potent as morphine and seems to cause more
nausea and vomiting
 Has a great potential for physical dependence
J. OXYCODONE
 Commonly used orally for treating acute pain (about twice as
potent as oral morphine and has a similar duration of analgesic
action)
 Abuse potential is but new, abuse-resistant formulations that are
not easily solubilized for IV injection are now widely marketed
K. HYDROCODONE
 A commonly used oral opioid for treating acute pain and is similar
in potency to oral morphine and has a similar duration of
analgesic action (high abuse potential)
L. METHADONE
 Synthetic opioid agonist that produces analgesia in the setting of
chronic pain syndromes and is highly effective by the oral route
 The efficient oral absorption, prompt onset of action, and
prolonged duration of action render this an attractive drug for
suppression of withdrawal symptoms in physically dependent
persons such as heroin addicts
M. TRAMADOL
 A centrally acting analgesic that is 5 to 10 times less potent than
morphine in volunteers
 Naloxone antagonized only an estimated 30% of the effect of
tramadol.
N. HEROIN (DIACETYLMORPHINE)
 A synthetic opioid produced by acetylation of morphine
 There is rapid penetration of heroin into the brain,where it is
hydrolyzed to the active metabolites monoacetylmorphine and
morphine
ARAO
Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020
 Compared with morphine, parenteral heroin has a
a. more rapid onset
b. less opioid-induced nausea
c. greater potential for physical dependency
V. OPIOID AGONIST- ANTAGONISTS
 These drugs bind to receptors, where they produce limited
responses (partial agonists) or no effect (competitive antagonists)
 The side effects are similar to those of opioid agonists, and, in
addition, these drugs may cause dysphoric reactions
 The advantages of opioid agonist–antagonists are the ability to
produce analgesia with limited depression of ventilation and
a low potential to produce physical dependence
 In general, agonist–antagonist drugs should be reserved for
patients who are unable to tolerate a pure agonist.
A. PENTAZOCINE
 Possesses opioid agonist actions (antagonized by naloxone) as
well as weak antagonist actions (sufficient to precipitate
withdrawal symptoms when administered to patients who have
been receiving opioids on a regular basis).
PHARMACOKINETICS
 Well absorbed after oral or parenteral administration
 First-pass hepatic metabolism is extensive, with only about 20%
of an oral dose entering the circulation.
CLINICAL USES
 10 to 30 mg IV or 50 mg orally, is used for the relief of moderate
pain.
 An oral dose of 50 mg is equivalent in analgesic potency to 60 mg
of codeine
 Useful for treatment of chronic pain when there is a high risk of
physical dependence
SIDE EFFECTS
 The most common side effect of pentazocine is sedation
 Nausea and vomiting are less common than with morphine
 Dysphoria, including fear of impending death, is associated with
high doses.
 Pentazocine, 20 to 30 mg IM, produces analgesia, sedation, and
depression of ventilation similar to 10 mg of morphine.
B. BUTARPHANOL
 Compared with pentazocine, butorphanol’s agonist effects are
about 20 times greater, whereas its antagonist actions are 10 to
30 times greater
 Rapidly and almost completely absorbed after IM injection
 In postoperative patients, 2 to 3 mg IM produces analgesia and
depression of ventilation similar to 10 mg of morphine.
SIDE EFFECTS
 Common side effects include sedation, nausea, and diaphoresis
 Dysphoria is infrequent
C. NALBUPHINE
 Phenanthrene opioid derivative
 The most common side effect was drowsiness
 Used to antagonize the ventilatory depressant effects of µ opiod
receptor agonist while still providing analgesia by K receptor
stimulation.
VI. OPIOID ANTAGONISTS
 Minor changes in the structure of an opioid agonist can convert
the drug into an opioid antagonist at one or more of the opioid
receptor sites
 Naloxone, naltrexone, and nalmefene are pure opioid receptor
antagonists with no agonist activity
A. NALOXONE
 Nonselective antagonist at all three opioid
 1 to 4 g/kg IV reverses opioid-induced analgesia and depression
of ventilation
9 of 10
 Midterms (1st Sem) Intravenous Anesthesia and Opioids
Dr. Jayber L. Tagacay
ANESTHESIOLOGY· December 5, 2020

 Duration of action (30 to 45 minutes) is presumed to be due to its B. NALTREXONE

rapid removal from the brain  In contrast to naloxone, is highly effective orally, producing
sustained antagonism of the effects of opioid agonists for as long
SIDE EFFECTS as 24 hours.
 Depression of ventilation accompanied by an inevitable reversal
of analgesia
 Titrate the dose of naloxone such that depression of ventilation is References
partially but acceptably antagonized to also maintain partial  Dr. Tagacay‟s ppt
analgesia
 Nausea and vomiting related to the dose and speed of injection
 Cardiovascular stimulation increased sympathetic nervous system
activity manifest as tachycardia, hypertension, pulmonary
edema, and cardiac dysrhythmia.

ARAO 10 of 10