GENERAL ANAESTHETICS

Pharmacology & Toxicology Dept

Dr. Mariam Yousif
24/12/2006
 Objectives
1. What are the different stages of anaesthesia?
2. What are the pharmacological effects of anaesthetic
agents?
3. Identify the two main classes of general anaesthetics:
A. Inhalational
# Minimum alveolar concentration (MAC).
# Pharmacokinetic properties.
# Properties of some inhalational anaesthetics
B. Intravenous
#Properties of individual intravenous anaesthetics
4. To define: neurolept anaesthesia & balanced anaesthesia
General anaesthetics are used as an adjunct
to surgical procedures in order to render the
patient unaware of, and unresponsive to,
painful stimulation.

Classified on the basis of their route of

administration (i.e. inhaled or intravenous).
 History of Anaesthesia
First scientific demonstration of drug-
induced anaesthesia during surgery was in
1846. William Morton used diethyl ether in
Boston.

Inscription on Morton’s tombstone:

Inventor and Revealer of Inhalation Anesthesia:
Before Whom, in All Time, Surgery was Agony; By
Whom, Pain in Surgery was Averted and Annulled;
Since Whom, Science has Control of Pain.
October 16th 1846
First successful public demonstration of anaesthesia
Massachusetts General Hospital, Boston
Anaesthetist: William Thomas Green Morton A replica of Morton's inhaler
Agent: Diethyl Ether
Patient: Gilbert Abbott
Operation: Excision of tumor under jaw
Surgeon: Charles Warren
Comment: “Gentlemen, this is no humbug”
 The state of “general anaesthesia” usually
includes: loss of consciousness, analgesia and
muscle relaxation

An ideal anaesthetic drug would induce

anaesthesia smoothly and rapidly and permit rapid
recovery as soon as administration ceased.

The drug would also possess a wide margin of

safety and be devoid of adverse effects.
Single anaesthetic agents are rarely used
on their own.

The modern practice involves the use of

combinations of drugs, taking advantage
of their individual favorable properties,
while attempting to minimize their
potential for harmful actions.
 A common procedure would be to:
# Produce unconsciousness rapidly with an
intravenous induction agent (e.g. thiopental,
propofol),

# Maintain unconsciousness and produce

analgesia with one or more inhalation agents (e.g.
nitrous oxide and halothane), which might be
supplemented with an intravenous analgesic agent
(e.g. an opiate),

# Produce skeletal muscle relaxation with a

neuromuscular blocking drug.
 Stages of anaesthesia
Stage I – Analgesia: the subject is conscious but drowsy.
Responses to painful stimuli are reduced.

Stage II – Excitement: the subject loses consciousness

and no longer responds to non-painful stimuli but
responds in a reflex fashion to painful stimuli.

Stage III – Surgical anaesthesia: spontaneous movement

ceases and respiration becomes regular.

Stage IV – Medullary paralysis: respiration and vasomotor

control cease, and death occurs within a few minutes.
Pharmacological effects of anaesthetic agents

-At supra-anaesthetic doses, all anaesthetic

agents can cause death by loss of
cardiovascular reflexes and respiratory
paralysis.
 -At the cellular level, anaesthetic agents
affect synaptic transmission rather than
axonal conduction.
The release of excitatory transmitters and
the response of the postsynaptic
receptors are both inhibited.
GABA-mediated inhibitory transmission
is enhanced by most anaesthetics.
Types of general anaesthetics

3.Inhalational

2. Intravenous
 1. Inhalational Anaesthetics

Are inert vapours used during surgery to

achieve sedation, muscle relaxation and
analgesia.

The first anaesthetic, ether, was introduced

in 1846.
 Inhalational Anaesthetics

The depth of general anaesthesia is

directly proportional to the partial pressure
of the anaesthetic agent in the brain.

These agents enter the body through the

lungs, dissolve in alveolar blood and are
transported to the brain and other tissues.
 Inhalational Anaesthetics

Mechanism of action is not clear.

Theories suggest that they work by altering
the lipids in cell membranes since the
potency of anaesthetics correlates
extremely closely with the solubility of the
drug in oil.
 Theories of anaesthesia
Anesthesia potency is closely correlated
with lipid solubility (Overton-Meyer
correlation), not with chemical structure.

The relationship between anaesthetic

activity and lipid solubility has been
repeatedly confirmed.
 MAC (Minimum alveolar concentration)
The measure of potency is the minimum
alveolar concentration (MAC).

Definition?

MAC is the concentration of anaesthetic

that causes immobility in 50% of subjects
exposed to the agent at one atmosphere.
 MAC (Minimum alveolar
concentration)

The lower the MAC the more potent

the general anaesthetic agent

(MAC is inversely proportional to

potency)
 Inhalational Anaesthetics

The MACs of commonly used anaesthetics

are;
Halothane: 0.75
Enflurane: 1.68
Isoflurane: 1.15
Nitrous oxide: 105
nitrous oxide is a poor anaesthetic when used
alone.
 Pharmacokinetic properties

-Rapid induction and recovery are important

properties of an anaesthetic agent, allowing
flexible control over the depth of anaesthesia.

-Speed of induction and recovery are determined

by two properties of the anaesthetic: solubility in
blood (blood :gas partition coefficient) and
solubility in fat (lipid solubility).
 Pharmacokinetic properties

The main factors that determine the speed of

induction and recovery can be summarized as:
# Properties of the anaesthetic
-blood :gas partition coefficient (i.e. solubility in blood).
-Oil : gas partition coefficient (i.e. solubility in fat, lipid
solubility).

# Physiological factors
-Alveolar ventilation rate.
-Cardiac output.
 The solubility of anaesthetics
-Their solubility in different media is
expressed as partition coefficients,
defined as the ratio of the concentration
of the agent in two phases at equilibrium.

-Blood: gas partition coefficient is the

main factor that determines the rate of
induction and recovery of an inhalation
anaesthetic.
 Pharmacokinetic properties

-Agents with low blood :gas partition

coefficients produce rapid induction and
recovery (e.g. nitrous oxide, desflurane);
agents with high blood :gas partition
coefficients show slow induction and
recovery (e.g. halothane).
 Rate of induction and rate of recovery from
anaesthesia

3. The more soluble the agent is in blood, the

more drug it takes to saturate the blood and
the more time it takes to raise the partial
pressure and the depth of anaesthesia.

2. The less soluble the agent is in blood, the less

drug it takes to saturate the blood and the less
time it takes to raise the partial pressure and
depth of anaesthesia.
 100
Alveolar concentration N2O Induction
(percent of inspired
concentration) Isoflurane

50 Enflurane

Halothane

0
20 40
Minutes
100 Recovery
Alveolar concentration
Percent of initial

Halothane
50 Enflurane
Isoflurane
N2O
0
20 40
Minutes
 Pharmacokinetic Properties
Oil: gas partition coefficient, a measure of
fat solubility, the main effect being that high
lipid solubility tends to delay recovery from
the effects of anaesthesia.

Agents with high lipid solubility (e.g.

halothane) accumulate gradually in body fat
and may produce a prolonged hangover if
used for a long operation.
 50
Carbon tetrafluoride
10

1
Nitrous oxide
MAC
0.1
Cyclopropane

Ether 0.01
Halothane
Chloroform
Methoxyflurane
0.001
5000 1000 100 10 1 0.1
Oil/gas partition coefficient (37oC)
Correlation of anaesthetic potency with oil :gas partition coefficient.
Anaesthetic potency is expressed as MAC required to produce surgical
anaesthesia. There is close correlation with lipid solubility, expressed as the
oil : gas partition coefficient.
Factors affecting the rate of equilibrium of inhalation anaesthetics in the
body: The body is represented as two compartments. Lean tissues,
including the brain, have a large blood flow and low partition coefficient for
anaesthetics and, therefore, equilibrate rapidly with the blood. Fat tissues
have a small blood flow and large partition coefficient and, therefore,
.equilibrate slowly, acting as a reservoir of drug during the recovery phase
 Properties of individual inhalational anaesthetic agents

Halothane, nitrous oxide, enflurane and isoflurane.

Ether (largely obsolete)

Malignant hyperthermia, characterized by a sudden and

often lethal increase in body temperature, is a serious
reaction to inhalation anaesthetics.
Occurs in genetically susceptible patients only. Treated
with the skeletal muscle relaxant dantrolene.
 Halothane
Widely used.
Potent non-irritant.
Hangover likely because of high lipid solubility.
Risk of liver toxicity if used repeatedly.

Nitrous oxide
Low potency, therefore must be combined with other
agents.
Rapid induction and recovery.
Risk of bone marrow depression with prolonged
administration.
 Enflurane
Less metabolism than halothane, therefore less
risk of toxicity.
Faster induction and recovery than halothane
(less accumulation in fat).
Can cause epilepsy-like seizures.
Isoflurane
Similar to enflurane, but lacks epileptogenic
property.
Irritant to respiratory tract.
 2. Intravenous Anaesthetics
Thiopental, fentanyl, etomidate, propofol,
ketamine & midazolam.

Act much more rapidly, producing

unconsciousness in about 20-30 seconds, as
soon as the drug reaches the brain from its site
of injection.

Usually used for induction of anaesthesia,

followed by inhalation agent.
 Thiopental
A barbiturate that is generally used to
induce anaesthesia.

very high lipid solubility.

Rapid action because of rapid transfer

across blood-brain barrier; short duration
(about 5 minutes) because of
redistribution, mainly to muscle.
 Thiopental

Slowly metabolized and liable to

accumulate in body fat; therefore may
cause prolonged effect if given repeatedly.

Narrow margin between anaesthetic dose

and dose causing cardiovascular
depression.
 100

Blood
Lean tissues
80
Brain &
percent of dose

viscera
60

40

Fat
20

0
0.125 0.5 1 4 16 64 256
Time (min)
Redistribution of thiopental after an intravenous bolus administration.
 Etomidate
Similar to thiopental but more quickly metabolized.

Propofol
Very lipid-soluble, acts rapidly and recovery is very rapid.

Useful for day case surgery.

Most significant cardiovascular adverse effect is
hypotension.
 Ketamine
Produces 'dissociative' anaesthesia, characterized by
catatonia (abnormal mental state), amnesia & analgesia.

Patient may remain conscious, though amnesic and

insensitive to pain.

Midazolam
Used as preoperative sedative for procedures such as
endoscopy where full anaesthesia is not required.
 Drug interactions

-Administering ketamine with halothane increases the risk

of hypotension.

-Giving ketamine and nondepolarizing drugs together

increases neuromuscular effects, resulting in prolonged
respiratory depression.

-Ketamine plus theophylline may promote seizures.

-Barbiturates or narcotics with ketamine may prolong

recovery time after anaesthesia.
 Neurolept anaesthesia
(Droperidol + Fentanyl)
The combined use of droperidol, a dopamine antagonist,
and an opiate analgesic, such as fentanyl, can be used to
produce a state of deep sedation and analgesia
(neuroleptanalgesia)

The patient remains responsive to simple commands and

questions but does not respond to painful stimuli or retain
any memory of the procedure.

This is used for minor surgical procedures, such as

endoscopy.
 Balanced Anaesthesia

The co-administration of two or more

intravenous agents (including benzodiazepines
and opioids) along with an inhaled anaesthetic
provides the best hemodynamic control for
major surgery. These are known as
components of balanced anaesthesia.
 Components of balanced anaesthesia
Relieve anxiety (benzodiazepines)
Relax muscles (muscle relaxant)
Prevent secretion of fluids into the respiratory tract
(anti-cholinergic drug)
Rapid induction of anaesthesia (short-acting
barbiturate)
Prevent post-surgical nausea and vomiting
(antiemetic drug)

Some functions of adjuncts to

anaesthesia
DRUG LIST
Halothane
Nitrous oxide
Enflurane
Thiopental
Etomidate
Propofol
Ketamine
Droperidol
Fentanyl