PCTH 325

Pharmacology of
General Anesthetics

Heidi N Boyda, Ph.D. October 23, 2014

Post-Doctoral Fellow
Department of Pharmacology
University of British Columbia
Vancouver, BC, Canada
 Learning Objectives

o  Understand the idea of balanced anesthesia and

how it is achieved

o  Define the levels of anesthesia and the

measurement of anesthetic dose

o  Understand the mechanism of action of volatile

and intravenous general anesthetics

o  Be aware of the undesirable effects of general

anesthetics
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 Overview

I.  Introduction & History

II.  Types of General Anesthetic Agents
III.  Signs and Stages of Anesthesia
IV.  Mechanism of Action of Inhaled Anesthetics
V.  Organ Systems Affected By Volatile (Inhaled)
Anesthetics
VI.  Toxicity
VII. Intravenous Anesthetics
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Surgical Procedures Prior to Anesthesia

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Extracted from M.H Ossipov
 History of Anesthesia
Joseph Priestly – discovers N2O in 1773
Sir Humphrey Davy – experimented with N2O, reported loss of pain,
euphoria
1842, Crawford Long – First used ether. Did not publicize. Tried to
claim credit after Morton’s demonstration but…
Important lesson learned – if you don’t publish it, it didn’t
happen.
1846, William Morton, dentist – Diethyl Ether – First demonstration of
successful surgical anesthesia
1847, James Simpson – Chloroform
1930s, Intravenous Barbiturates
1940s, d-Tubocurarine to induce skeletal muscle relaxation
1956, Halothane (halogenated hydrocarbon)
1981, Isoflurane (currently most popular) Extracted from M.H Ossipov
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 Anesthesia

Anesthesia = loss of sensation

General Anesthesia = analgesia, amnesia, loss of
consciousness, inhibition of sensory and autonomic
reflexes and often skeletal muscle relaxation
(mixture)

Ideal General Anesthetic: Induce anesthesia

smoothly and rapidly and permit rapid recovery as
soon as administration ceases (balanced anesthesia)
Wide margin of safety (high therapeutic index)
Devoid of adverse effects Modified slide of Dr. Peter Smith
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 General Anesthesia
•  Sensory:
-Absence of intraoperative pain

•  Cognitive:
-Absence of intraoperative awareness
-Absence of recall of intraoperative events

•  Motor:
-Absence of movement & adequate muscular relaxation
•  Autonomic:
-Absence of hemodynamic response
-Absence of tearing, flushing, sweating 7  
Modified slide of Dr. Peter Smith
 General Anesthetics

o  Adverse Effects Include:

o  Vomiting (Post-operative nausea)

o  Cardiovascular depression
o  Respiratory depression
o  Toxicity (liver/kidney)
o  Respiratory irritant effect of volatile anesthetics

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 General Anesthetic Protocols

o  No single agent alone meets all criteria

o  Combinations to maximize favorable effects and
minimize untoward effects
o  Anesthetics have low therapeutic index

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Modified slide of Dr. Peter Smith
 General Anesthetic Protocols

o  No single agent alone meets all criteria

o  Combinations to maximize favorable effects and
minimize untoward effects
o  Anesthetics have low therapeutic index

Minor Procedures: oral sedatives and regional local

anesthesia
Conscious Sedation: IV benzodiazepines and opioid
analgesics (can respond to verbal commands, patent
airway)
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Modified slide of Dr. Peter Smith
 General Anesthetic Protocols

Major Surgical Procedures:

o  Preoperative sedatives (anxiolytic, amnesia),

muscle relaxants, atropine (to limit mucous
secretions)

o  Induction of anesthesia: IV thiopental, propofol,

etomidate or benzodiazepine (esp. midazolam)

o  Deep anesthesia: Inhaled anesthetics and IV

anesthetics
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Modified slide of Dr. Peter Smith
 Stages of General Anesthesia

o  Induction- initial entry to surgical anesthesia

o  Maintenance- continuous monitoring and

medication
–  Maintain depth of anesthesia, ventilation, fluid balance,
hemodynamic control, homeostasis

o  Emergence- resumption of normal CNS

function
–  Extubation, resumption of normal respiration

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Extracted from M.H Ossipov
 Stages of General Anesthesia
Stage I: Disorientation, altered consciousness
Stage II: Excitatory stage, delirium, uncontrolled movement, irregular breathing. Goal
is to move through this stage as rapidly as possible.
Stage III: Surgical anesthesia; return of regular respiration.
Plane 1: “light” anesthesia, reflexes, swallowing reflexes.

Plane 2: Loss of blink reflex, regular respiration (diaphragmatic and chest).

Surgical procedures can be performed at this stage.

Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation needed.

Level of anesthesia for painful surgeries (e.g.; abdominal exploratory
procedures).

Plane 4: Diaphragmatic respiration only, assisted ventilation is required.

Cardiovascular impairment.
Stage IV: Too deep; essentially an overdose and represents anesthetic crisis. This
Is the stage between respiratory arrest and death due to circulatory collapse.
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 Routes of Induction

• Intravenous
– Safe, pleasant and rapid
• Mask
– Common for children under 10
– Most inhalational agents are pungent, evoke coughing
and gagging
– Avoids the need to start an intravenous catheter before
induction of anesthesia
– Patients may receive oral sedation for separation from
parents/caregivers
• Intramuscular
– Used in uncooperative patients 14  
Extracted from M.H Ossipov
 Types of General Anesthetics

Inhalation:
Gas: Nitrous Oxide
Volatile Liquids: Ether, Halothane, Enflurane, Isoflurane,
Desflurane, Sevoflurane

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 Types of General Anesthetics

Inhalation:
Gas: Nitrous Oxide
Volatile Liquids: Ether, Halothane, Enflurane, Isoflurane,
Desflurane, Sevoflurane
Intravenous:
Barbiturates (thiopental)
Benzodiazepines (midazolam, diazepam)
Opioid Agonists (morphine, fentanyl, sufentanil, remifentanol)
Others: Propofol, etomidate
Ketamine = ‘Dissociative Anesthesia’
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Droperidol = ‘Neurolept anesthesia’
 Minimum Alveolar Concentration
(MAC)
o  Concentration (i.e the % of an alveolar gas mixture) that
results in immobility in 50% of patients when exposed to
a noxious stimulus such as a surgical incision
o  Analogous to ED50

o  A measure of relative potency and standard for

experimental studies

o  Anesthetic dosage is expressed in multiples of MAC

o  MAC values for different agents are ~ additive (0.7
MAC N2) + 0.6 MAC halothane = 1.3 MAC total)

o  MAC can exceed 100% for weak anesthetics like N2O 17  

Modified slide of Dr. Peter Smith
 Mechanism of action of inhaled
anesthetics

• Whereas local anesthetics impair nerve conduction,

general anesthetics have primary effects on synaptic
processes to decrease neuronal activity
• Volatile anesthetics may block the central (α7) nicotinic
cholinergic receptor and the 5-HT3 receptor

• Also activate (open) the 2 pore K+ channels to cause

hyperpolarization

• Cells of the substantia gelatinosa of the spinal cord are

especially sensitive to the actions of general anesthetics
= Stage 1 analgesia
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Modified slide of Dr. Peter Smith
Transverse Section of Spinal Cord

Substan(a  gela(nosa  

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 Spinal Cord and Pain
o  Substantia gelatinosa = termination of pain fibers in dorsal
horn of spinal cord

o  Disinhibitory effects (stage 2 effects) occur with higher

concentrations

o  Stage 3 anesthesia involves progressive depression of

reticular activating system and suppression of spinal reflex
activity and muscle relaxation

o  Dose response relationship is difficult to determine (minimal

response, no relief of pain; maximal response = death)

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 Organ Systems Affected By Volatile
Anesthetics
o  Cardiovascular System
o  Can lower blood pressure, some act on cardiac output
others lower peripheral resistance
o  Sensitization of myocardium to action of catecholamines
(CAT are potentially dysrhythmogenic and can cause
ventricular dysrhythmias)

o  Respiratory System
o  Decrease tidal volume and increase respiratory rate
o  Decrease overall minute respiration
o  Decrease ventilatory response to hypoxia
o  Depress mucocilliary function: pooling of mucous in lungs
(mucous secretion is attenuated by atropine and used for
premed) 21  
Modified slide of Dr. Peter Smith
 Toxicity

o  Nephrotoxicity
o  F- from hepatic metabolism

o  Hepatotoxicity (not much of a problem with modern drugs)

o  Malignant Hyperthermia
o  Rare, potentially fatal: a pharmacogenetic hypermetabolic state of
skeletal muscle induced in susceptible individuals by inhalational
anesthetics and/or succinylcholine (and maybe stress or exercise)

o  Genetic susceptibility-Ca2+ channel defect (CACNA1S) or ryanodine

receptor

o  Excess Ca2+ leads to excessive ATP breakdown/depletion, lactate

production, increased CO2 production, myonecrosis and
rhabdomyolysis, arrhythmias and renal failure [can be treated with
dantrolene: increases reuptake of Ca2+ in SR Modified Slide M.H Ossipov
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 Intravenous Anesthetics

o  Mechanism of Action
o  Barbiturates, benzodiazepines, propofol and (ethanol)
potentiate movement of Cl- ions through the GABAA
receptor channel

o  Barbiturates and
benzodiazepines bind
at different sites on the
GABAA channel

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h-p://thebrain.mcgill.ca/flash/i/i_04/i_04_m/i_04_m_peu/i_04_m_peu.html  
 Intravenous Anesthetics – GABAA
Receptor modulation
o  Benzodiazepines increase the frequency of channel opening

o  Barbiturates increase the duration of channel opening

o  Since GABA is an inhibitory NT, potentiation of effects, leads

to decreased neural activity 24  
 Ultra-short acting Barbiturates

o  Thiopental

o  Rapid onset of action, potent

enough for use alone for short procedures

o  Used with or without

inhalational agent

o  Large doses = hypotension/respiratory depression

o  Crosses BBB = brain, redistributed to other tissues 25  

Modified slide of Dr. Peter Smith
 Benzodiazepines

o  Midazolam and diazepam

o  Too slow in onset to be of use in induction of anesthesia

o  Used as premedication and as part of anesthetic mixtures

o  Alone cannot produce surgical anesthesia (level 3) but

can produce useful anterograde amnesia (patient will not
remember they are about to have surgery)

o  Slow recovery from anesthesia but a benzodiazepine

antagonist, flumazenil, can be used to speed recovery

Modified slide of Dr. Peter Smith

 Opioids

o  Fentanyl, sufentanil, alfentanil, remifentanil

o  Work through µ-, κ-, δ-opioid receptors

o  Advantages: cardiovascular stability, sedative, analgesic

o  Disadvantages: respiratory depression, Post-operative

recall

o  Naloxone or naltrexone can be used during recovery

o  Common combination: fentanyl + thiopental

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Modified slide of Dr. Peter Smith
 Neuroleptanesthesia

o  Fentanyl + droperidol + N2O

o  Droperidol = neuroleptic/dopaminergic D2 receptor

antagonist

o  Anti-emetic – less post-operative vomiting

o  Reduces motor activity

o  Reduces anxiety

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Modified slide of Dr. Peter Smith
 Others

o  Propofol

o  Important, rapid onset and offset

o  Post-operative vomiting uncommon,

patients ‘feel better’ in post operative period

o  Rapidly metabolized in liver

o  Large doses = hypotension/respiratory depression

o  Causes acidosis in children

o  Expensive 29  
Modified slide of Dr. Peter Smith
 Others

o  Etomidate

o  Rapid onset, used for induction, loss of consciousness

within seconds

o  Minimal cardiovascular and respiratory depression

o  No analgesic effects

o  Nausea and vomiting

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Modified slide of Dr. Peter Smith
 Others

o  Ketamine

o  Dissociative anesthesia: a state characterized by

immobility, amnesia, analgesia with light sleep and
feelings of dissociation from ones own body/mind

o  Catatonia, no loss of consciousness

o  Cardiovascular stimulation

o  Useful for geriatrics, children and burn dressings

o  Glutamate/NMDA receptor antagonist

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o  Untoward effects: hallucinations and nightmares
 Key Points to Remember

o  Definitions of general and balanced anesthesia

o  Examples of the absence of sensory, cognitive,

motor and autonomic components

o  Stages of anesthesia

o  Main adverse events for both inhalational and IV

agents

o  Mechanism of action of inhaled and IV agents

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 Thanks!

Heidi.boyda@ubc.ca
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