Frederick J.

Goldstein, PhD, FCP

GENERAL ANESTHETICS
1800 (Approx.):
First suggestion that N20 could produce general anesthesia.
1845:
First recorded administration of N20 to pt for general anesthesia.
Performed at Massachusetts General Hospital (MGH) by Dr. H. Wells,
a dentist.
Failed.
1846:
First recorded administration of ether for general anesthesia.
Also performed at MGH but by another dentist, Dr. W. Morton.
Successful.
CLASSIFICATION
I. Inhalation Anesthetics
A. Gas
Nitrous oxide (N20)
B. Volatile Liquids
Desflurane (SUPRANE)
Enflurane (ETHRANE)
Halothane (FLUOTHANE)
Isoflurane (FORANE)
Methoxyflurane (PENTHRANE)
Sevoflurane (ULTANE)
II. Intravenous Anesthetics
A. Ultrashort-acting Barbiturates
Methohexital (BREVITAL)
Thiamylal (SURITAL)
Thiopental (PENTOTHAL)
B. Nonbarbiturates
Etomidate (AMIDATE)
Propofol (DIPRIVAN)
C. Dissociative Agent
Ketamine (KETALAR)

Frederick J. Goldstein, PhD, FCP

D. Neuroleptanalgesia
Droperidol/Fentanyl combination

(INNOVAR)

THERAPEUTIC INDEX
GA's are very dangerous drugs; have very low therapeutic index:
Circulatory Arrest Dose / General Anesthetic Dose 3/1
STAGES OF ANESTHESIA
Induction period = Stage I + Stage II
Stage I: ANALGESIA
Begins with administration of anesthetic
Depression of transmission of signals in:
- RAS (general sensory)
- dorsal horn cells (pain)
Stage II: DELIRIUM
Begins with loss of consciousness.
Depression of cortex which results in less inhibition of
subcortical areas
'disinhibition'.
Disinhibition can produce several dangerous events:
Hyperreflexia:
- violent muscular contractions
Irregular respiration:
- apnea alternating with hyperpnea
- creates problem in achieving stable level of
inhalational anesthesia
Vomiting:
- aspiration into respiratory tract
- can cause asphyxiation & postop pneumonia
Stage III: SURGICAL ANESTHESIA
2

Frederick J. Goldstein, PhD, FCP

Begins with muscular relaxation and a return to a regular but
lower respiratory rate and blood pressure.
Greater depression of RAS and spinal cord.
Stage IV: MEDULLARY PARALYSIS
Begins with cessation of spontaneous respiration.
Depression of pons and medulla.
Ends with circulatory failure.

UPTAKE AND DISTRIBUTION

Objective: transfer pt from conscious to unconscious state as
rapidly and safely as possible.
Highest
Lowest
__________________________________________________________________
Perfusion Rate
Brain
Muscle
Adipose
__________________________________________________________________
Lipid Content
Adipose
Brain
Muscle
__________________________________________________________________
BRAIN
GEN. INSPIRED
AN.
AIR

LUNGS

BLOOD

MUSCLE

ADIPOSE
Parenteral
Maximum blood level achieved almost instantaneously with IV.
Slower with IM.
Both bypass lung transfer.
Inhalation
3

Frederick J. Goldstein, PhD, FCP

Factors influencing transfer of inhalational GA's include:
A.

Solubility of General Anesthetic

Blood/Gas Partition Coefficient (B/G PC) is relative
index of 'solubility' of GA in blood.
High B/G PC means GA is more 'soluble' in blood; it
will less readily (i.e., more slowly) move out of blood
into tissues. Induction is long (e.g., 20-30 min.)
Low B/G PC indicates that GA has limited 'solubility'
in blood; it will rapidly leave the blood and enter the
tissues. Induction is short (e.g., few minutes).

UPTAKE AND DISTRIBUTION

(continued)

Factors influencing transfer of inhalational GA's:

B.

Anesthetic Concentration in Inspired Air

Higher concentration = rate of transfer =
shorter induction period.
STAGE

|
|
IV
|
|---------------------------------------------------BLOOD | III
|
LEVEL |---------------------------------------------------|
II
of |
|
GA |
I
|____________________________________________________
TIME (minutes)
4

Frederick J. Goldstein, PhD, FCP

C.

Pulmonary Ventilation
Faster rate = faster transfer.
Deeper breath = faster transfer.

ELIMINATION
Recovery slower than induction because GA gradually released from
tissue storage. Factors are:
Expired Air
Major route of elimination for inhalational GA's.
Higher B/G PC = longer recovery time.
Biotransformation
Contributory to elimination but not a primary factor.
As duration of administration of the GA increases, tissue stores
increase and recovery takes longer.
ANESTHETIC POTENCY
Determined by two methods:
1.

Blood levels
Employed for any type of GA

2.

Minimum Alveolar Concentration (MAC)

Used only for inhalational GA's
Assumption: partial pressure of anesthetic in lung
air is related to GA concentrations in the brain.
Definition:
1 MAC = conc. of GA in alveolar (lung) space
at which 50% of pts do not feel initial
surgical incision
Very steep dose-response curve; 95% of all pts do not
5

Frederick J. Goldstein, PhD, FCP

feel initial surgical incision at 1.1 MAC.
MECHANISM OF ACTION
Probably not related to a specific receptor since molecules of
very different structures produce general anesthesia:
Mg+ / N20 / Cyclopropane / Ether / Halothane / Thiopental /Ketamine
Theories
1.

Myer-Overton (Lipid Solubility): 1901

Attempted to relate general anesthetic action of lipid
solubility of GA's.
Explains of access of GA to brain tissue but not related to
mechanism of action. Reason for rejection of this theory is
related to the following:
- alkanes were synthesized in increasing chain length
- both general anesthetic potency and lipid solubility
increased as alkanes increased in chain length up
to decane
- decane had the highest lipid solubility of the series
but was inactive as a GA

MECHANISM OF ACTION

(continued)

Theories (continued)
2. Interaction with Lipid Component of Membrane of Brain Cell
Normally, membranes shift between states:
GEL
(ordered)

----->
<-----

LIQUID
(disordered)

GA's interact with lipid molecules of cell membrane.

GA's shift membrane -------> disordered state.
Volume of membrane increases.
6

Frederick J. Goldstein, PhD, FCP

Compression of Na+ channel occurs.
Influx of Na+

in depolarization and cell activity.

Also influx of Ca2+

release of excitatory NTs

Problem with theory:

- at blood level of GA which produces general anesthesia,
there is one GA molecule/5000 A2 of brain cell membrane
- in same area of brain cell membrane: 100 lipid molecules
- one GA molecule interacting with one (or even two) lipid
molecules is not sufficient to cause the shift
3. Interaction with Protein Component of Membrane of Brain Cell
In same 5000 A2 area of brain cell membrane is 1 protein
molecule.
Therefore, one GA molecule could bind to this protein
molecule & inactivate it; could interfere with operation of
an ion channel.
Most likely one to be inactivated is the K+ channel.
The result is an increase in K+ efflux and hyperpolarization.
4. Activation of GABA-A Receptor
GAs may enhance activity of the GABA-A receptor.
influx of Cl-

hyperpolarization.

Of current interest since GABA-A receptor complex may have

multiple sites to which GAs having very different molecular
structures can bind.
PRE-ANESTHETIC MEDICATION
Many reasons for the administration of drugs prior to general
surgery including:
1. Relief of Anxiety
Sedative/hypnotics given HS.
7

Frederick J. Goldstein, PhD, FCP

Antianxiety agents (e.g., benzodiazepines) given immediately
prior to surgery.
Any CNS depressant will enhance effect of GA.
2. Decrease Secretions
Salivary and bronchial mucous.
Scopolamine > atropine.
3. Counteract Bradycardia
Atropine > scopolamine
4. Elevate Gastric pH
To decrease scarring
contents if pt vomits.

of

lung

tissue

by

acidic

gastric

Cimetidine (Tagamet) has been employed for this purpose.

OBJECTIVES OF GENERAL ANESTHESIA
1. Rapid elimination of consciousness
2. Skeletal muscle relaxation
3. Analgesia
Since no single currently available GA can accomplish all of these
objectives, general surgery is usually performed using two or more
GA's and one or more adjunctive agents ('balanced anesthesia').
Induction agent (usually a rapidly-acting GA)
GA
Anesthetic adjuncts
Skeletal muscle relaxants (neuromusc. blocking agents)
Opioids
SPECIAL PROBLEMS WITH BIOTRANSFORMED GA's
1.
Pre-existing enzyme induction
8

Frederick J. Goldstein, PhD, FCP

2.

Obesity

I. INHALATION ANESTHETICS
A.GAS
NITROUS OXIDE
Not flammable or explosive.
Effects at various concentrations are:
20% N20 / 80% O2:

provides analgesia = morphine;

in beta-endorphin levels

50% N20 / 50% O2:

used in dental procedures;

no significant respir depression

65% N20 / 35% O2:

highest concentration that provides

adequate oxygenation (no hypoxia)

80% N20 / 20% O2:

most pts unconscious: Stage II

could ppt sickle cell crisis
in pts with this condition

100% N2O:

will not take pts into Stage III

Uses
Analgesic (e.g., dentistry, acute MI, first stage of labor)
Induction of general anesthesia
Advantages
Rapid
Pleasant
Disadvantages
Not potent
Inadequate skeletal muscle relaxation
Dreams of sexual assaults (conc. at or > 50%)
Acute Toxicity
Pt falls and sustains bone fractures
Death due to positional asphyxia
Chronic Toxicity
Loss of balance / ataxia
9

Frederick J. Goldstein, PhD, FCP

Leg weakness
Peripheral neuropathy
Impotence
I. INHALATION ANESTHETICS

(continued)

B. VOLATILE LIQUIDS
HALOTHANE
F3-C-CHBrCl
Developed as result of planned investigation
Potent GA; 1 MAC at 0.75% (conc. for surgery approx. 1.2 - 1.8%)
B/G PC = 2.4
Approximate 15-20% biotransformation.
Advantages
Nonexplosive; nonflammable
Smooth, relatively rapid induction
Bronchodilation
Relatively low incidence of toxicity
Disadvantages
Poor analgesia
Poor muscle relaxation
Sensitization of myocardium
- any halogenated hydrocarbon can produce card. arrhythmias
Hepatitis
- not dose-related
- possibly an allergic reaction
- rare but fatal rxn can occur on repeated exposure
Hypotension
- can be severe
- mechanisms include:
1) decreased myocardial contractility
a) decreased entrance of Ca2+ into contractile
protein of cardiac muscle
10

Frederick J. Goldstein, PhD, FCP

b) decreased interaction of Ca2+ with
contractile protein of cardiac muscle
2) decrease in compensatory tachycardia

I. INHALATION ANESTHETICS
B. VOLATILE LIQUIDS
HALOTHANE

(continued)

(continued)

(continued)

BP
Normal

Hypotension

|
CONTROL
HALOTHANE
|
|
|
|
|- - - - - - - - - - - - - - - - - - - |
|
|
|
|_________________________________________
TIME (minutes)

METHOXYFLURANE
Most potent GA; 1 MAC = 0.16% (maintenance at 0.2 - 0.8%)
B/G PC = 12; slow induction (20-30 minutes if used alone)
Compared to halothane, methoxyflurane provides:
11

Frederick J. Goldstein, PhD, FCP

- more skeletal muscle relaxation
- more analgesia
- less myocardial sensitization
Significant biotransformation; 50-70%.
- can result in toxic levels of F- (>50 umol/L serum)
- plasma F- levels remain elevated for 2 4 days
- damages renal system
- produce fluoride diabetes insipidus
Fluoride toxicity increased with long operations (> 2 hours).
Use limited
only).

to

providing

I. INHALATION ANESTHETICS
B. VOLATILE LIQUIDS

analgesia

during

labor

(small

doses

(continued)

(continued)

ENFLURANE
1 MAC = 1.68% (maintenance at 1.5% - 3.0%).
B/G PC = 1.9; moderately fast induction.
Same advantages as methoxyflurane over halothane.
Fluoride toxicity possible; less likely than with methoxyflurane
Seizures may occur; more likely in pt with pre-existing seizure
disorder.
ISOFLURANE
1 MAC = 1.4%
B/G PC = 1.4
More respiratory irritation on induction than halothane.
Very limited biotransformation; about 0.17%.
DESFLURANE
1 MAC = 7.3%
B/G PC = 0.42
Biotransformation only about 0.02%.
Induction of general anesthesia within 2 - 4 minutes but NOT
12

Frederick J. Goldstein, PhD, FCP

recommended for this purpose due to high incidence of respiratory
tract irritation (e.g., laryngospasm, coughing, secretions,
breathholding, apnea)
SEVOFLURANE
Low blood/gas solubility
No significant odor (special advantage in pediatric surgery)
Biotransformed into two metabolites:
F- rapidly eliminated because parent molecule rapidly cleared
- compared to methoxyflurane:
less production of F- in kidney / less nephrotoxicity
HFIP (hexafluoroisopropanol)
- rapidly glucuronidated / low toxic potential
II. INTRAVENOUS ANESTHETICS
A. ULTRASHORT-ACTING BARBITURATES
THIOPENTAL
IV injection or infusion
Anesthesia occurs within seconds
Primary site of action: RAS
Emergence:
- rapid due to redistribution from brain to other tissues
- not due to biotransformation (only about 15% per hr)
- can be slow if IV infusion performed for prolonged period
- thiopental stored in adipose tissue and slow released
Uses
13

Frederick J. Goldstein, PhD, FCP

Induction of general anesthesia
As sole GA for short procedures without significant pain
Advantages
Easy to administer
Rapid induction
Pleasant induction
Disadvantages
Lack of moment-to-moment control
Poor analgesia (may cause hyperalgesia)
Powerful respiratory depressant
Poor skeletal muscle relaxation
Contraindications
Pt with porphyria; may cause N, V, paralysis, death

II. INTRAVENOUS ANESTHETICS

(continued)

B. NONBARBITURATES
ETOMIDATE
Rapid-acting hypnotic; high lipid solubility; wide distribution
Not an analgesic.
Major use: IV for induction of general anesthesia
Minimal effects on HR, cardiac output and peripheral circulation
Uses
Induction of general anesthesia
14

Frederick J. Goldstein, PhD, FCP

- onset usually within 1 minute
- effects persist for 3 to 5 minutes
Supplemental anesthesia during short operative procedures
Prolonged sedation of critically ill patients
Dosage
Induction:
Maintenance:

0.2 mg/kg to 0.6 mg/kg IV over 30 to 60 seconds

0.1 mg/kg to 0.3 mg/kg as needed in comb. N2O & O2

Biotransformation
Rapid metabolism in the liver; primarily excreted by kidneys
ADRs
Transient venous pain on injection
Myoclonic skeletal muscle movements after injection
Hypotension, tachycardia, arrhythmias
Hyperventilation, transient apnea, laryngospasm, hiccups
Postop N & V

II. INTRAVENOUS ANESTHETICS

B. NONBARBITURATES

(continued)

(continued)

PROPOFOL
Pharmaceutical formulation: emulsion
Rapid and wide distribution into highly perfused tissues (e.g.,
brain; heart; lungs, liver)
Hypnosis within 40 sec. of IV admin.
Induction of anesthesia within 1 to 3 minutes after injection.
15

Frederick J. Goldstein, PhD, FCP

Some degree of analgetic actvity
Uses
Continuous sedation in patients who are intubated or who are on
mechanical ventilation in the ICU
Induction of general anesthesia
Maintenance of general anesthesia in 'balanced anesthesia'
Dosage
As with any drug to be administered via parenteral administration,
especially IV, doses are always approximate:
Sedation:
Induction: adults (<55 years old), 100-150 g/kg/min
Maintenance: 25 to 75 g/kg/min
Anesthesia:
Induction:

adults (<55 years old), 2 to 2.5 mg/kg

Maintenance: 100 to 200 g/kg/min

Biotransformation
Extensive biotransformation to inactive metabolites (primarily
glucuronide).
Rapid recovery from sedation or anesthesia; patients oriented and
respond to verbal commands approx. 8 min. after infusion
terminated
Patients awake at plasma levels of approximately 0.5 mcg/mL
Elimination T ranges from 300 to 700 minutes.

II. INTRAVENOUS ANESTHETICS

B. NONBARBITURATES
PROPOFOL

(continued)

(continued)

(continued)
16

Frederick J. Goldstein, PhD, FCP

ADRs
Pain at injection site, rash, pruritis
Clonic/myoclonic movements, seizures, rigidity, thrashing
Confusion, delirium, hallucinations
Hypersalivation
Bronchospasm, cough, hyperventilation
Green urine, urinary retention
Caution:
In patients with increased intracranial pressure.
Not recomended for delivery since neonatal depression may occur.
Fatalities have occurred when used to provide ICU sedation in
pediatric patients presenting with infections of the respiratory
tract (most deaths correlated with doses > adult doses)

C. DISSOCIATIVE AGENTS
PHENCYCLIDINE
Also known as 'PCP' and 'Angel Dust'
Developed initially for use as clinical (not animal) GA.
___________________________________________________
Analgesia
BP
RR
__________________________________________________________________
Morphine
__________________________________________________________________
PCP
__________________________________________________________________
PCP withdrawn for human use due to occurrence of adverse
psychological reactions (e.g., hallucinations) during emergence.

17

Frederick J. Goldstein, PhD, FCP

II. INTRAVENOUS ANESTHETICS
C. DISSOCIATIVE AGENTS

(continued)

(continued)

KETAMINE
Related on chemical basis to PCP;
profile.
Production of 'Dissociative
anesthesia.
Pt exhibits:
- catatonia
- analgesia
- amnesia

very similar pharmacological

Anesthesia';

not

true

general

Eyes are open but pt appears to be in a trance.

Unresponsive to pain; other stimuli (e.g., visual; auditory).
Primary sites of action: cerebral cortex and limbic system.
Onset of action after IV is approximately 15 seconds.
Duration of:
- unconsciousness: about 10-15 minutes.
- analgesia:
about 40 minutes.
- amnesia:
about 60-120 minutes.
Advantages
Strong analgesia
No significant respiratory depression
Support of the CV system
- increased HR
- increased BP
Compared to PCP, reduced occurrence of adverse psychological
reactions

18

Frederick J. Goldstein, PhD, FCP

II. INTRAVENOUS ANESTHETICS

C. DISSOCIATIVE AGENTS
KETAMINE

(continued)

(continued)

(continued)

Disadvantages
Prolonged retention in body
- stored in adipose tissue
- traces appear in urine for weeks after administration
Adverse psychological reactions upon emergence:
- nightmares
- hallucinations
- delirium
- schizoid reactions
- occur more frequently in pts > 30 years old.
- to reduce these reactions:
- confer with pt before injection to reduce pt fears
- premedicate with diazepam
- avoid tactile or verbal stimulation during emergence
Flashbacks can occur up to one year after administration:
- memory phenomenon
- ketamine not stored in body for one year
Uses
Emergency surgery.
Outpt procedure which requires general anesthesia.
Changes in burn dressings.
Diagnostic procedures in children.
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Frederick J. Goldstein, PhD, FCP

DRUG INTERACTIONS
Interactions of drugs with GA's include:
Tetracyclines
Increased risk of nephrotoxicity with methoxyflurane
Other Antibiotics
Additive
skeletal
muscle
paralysis
blocking agents (non-depolarizing).
include:

with
neuromuscular
These antibiotics

bacitracin
aminoglycosides (kanamycin, neomycin, streptomycin)
polymixins (colistin, polymixin)
CNS Depressants
Acute:
Increased effect
Chronic:

Possible effect if used at time of surgery

Posssible of GA effect if tolerance & physical
dependence are present:
- may need to increase dose of GA

Cigarette Smokers
May require increased dose of GA due to enzyme induction.
20

Frederick J. Goldstein, PhD, FCP

NEUROLEPTANALGESIA
Combination of a neuroleptic (antipsychotic) + opioid.
Neuroleptic will:
- reduce initiative
- reduce emotions (flat affect)
- produce some slowness in responding to stimuli
- have no significant effect on intelligence
- have no significant effect on coordination
INNOVAR
Combination of:
- neuroleptic / droperidol (Inapsine)
+
- potent opioid / fentanyl (Sublimaze)
Given by slow (5 to 10 minutes) IV infusion.
May cause significant respiratory depression.
Duration of action:
- droperidol / 3 to 6 hours
- fentanyl / 0.5 hr.
21

Frederick J. Goldstein, PhD, FCP

Uses include:
- minor surgery
- diagnostic procedures (e.g., endoscopy)
- changing of burn dressings

NEUROLEPTANESTHESIA
Add 65% N20 to neuroleptanalgesia combination (above).

22