A teaching slide set describing the mechanisms of general anaesthetic agents. Provided by Dr Clare Guilding, Newcastle University, UK

1. Dr Clare Guilding
e.mail: clare.guilding@ncl.ac.uk
General anaesthesia

2. Learning Outcome
– Describe the basic pharmacology of intravenous and
inhalation anaesthetics
Lecture Outline
1. Adjunct medications
2. Theories of the mechanism of action of general anaesthetics
3. Stages of anaesthesia
4. Inhalation anaesthetics
5. Intravenous anaesthetics
General anaesthesia

3. General anaesthesia
• General anaesthetics are used to render patients unaware of,
and unresponsive to, painful stimulation during surgical
procedures
• The discovery of general anaesthetics revolutionised modern
medicine and marked the birth of modern surgery
• Until that time surgeons could use drugs such as opiates or
alcohol to render the patient insensible but surgery was still
quick and brutal
Images from the Wellcome archive

4. General anaesthesia
• General anaesthetics are given systemically and exert their
main effects on the central nervous system (CNS), in contrast to
local anaesthetics
• The aim of anaesthesia during surgery is to induce:
1. Unconsciousness
2. Analgesia
3. Muscle relaxation
• No single agent provides all these properties so several
categories of drugs are used in combination during surgery
The triad of anaesthesia

5. Adjunct medications
Medication Use
Benzodiazepines Anxiolysis and amnesia presurgery
H2 blockers
e.g. ranitidine
Prevent gastric acid secretion
Antimuscarinic drugs
e.g. atropine
Prevents bradycardia and secretion of fluids
into the respiratory tract
Neuromuscular blockers
e.g. suxamethonium
Facilitates intubation and suppresses muscle
tone to degree required for surgery
Analgesics
e.g. fentanyl
Relieve pain
Antiemetics Prevents postoperative vomiting and nausea
• Adjunct medications are given before (premedication), during
(perioperative) and after (postoperative) surgery to calm the
patient, protect against undesirable effects of anaesthesia and
relieve pain

6. General anaesthetics
• Many are small lipid soluble molecules
• They are administered systemically (by inhalation or
intravenous injection)
• They have rapid induction and termination
What anaesthetics do to the body:
• Decrease CNS activity
— Reduce neuronal activity in the brain and spinal cord (reduce
excitatory and increase inhibitory activity, especially in reticular
activating system)
• Depress cardiovascular, respiratory and other systems

7. How do general anaesthetics work?
• A wide variety of agents (ranging from single atoms such as
xenon to complex hydrocarbons) can produce insensibility to
pain and loss of awareness
• The molecular targets for these different agents do not
appear to be the same
Thus there is probably no single molecular mechanism of
action for all anaesthetic agents
Xe
Xenon

8. How do general anaesthetics work?
• Are a number of theories, which can be classified as
physicochemical or structural:
1. Physicochemical theories
Anaesthetic effect is exerted through physical/chemical
perturbation of structures in the body
- Lipid solubility theory (anaesthetic effect is exerted through
some perturbation of the lipid bilayer)
2. Structural theories
Anaesthetic effect is exerted through interactions with proteins
- Effects on ion channels

9. Physicochemical: Lipid solubility theory
• Anaesthesia results when a sufficient amount of the anaesthetic
dissolves in the lipid bi-layer
This perturbs the physical properties of the lipid bi-layer, bulking
it up such that the component parts don’t fit together properly
This alters the excitability of the cell membrane
Increasing lipid solubility
Meyer-Overton rule
• Anaesthetics that are more
soluble in lipid are more
potent
Suggests a hydrophobic site
of action

10. Physicochemical: Lipid solubility theory
This theory has now been largely disregarded due to a number of
observations:
1. Not all small lipid soluble molecules act as anaesthetics
2. Not all anaesthetics are lipid soluble
3. Anaesthetics can exist as stereoisomers (exist as mirror
images) so while they can have identical physicochemical
properties the stereoisomers have differing anaesthetic
efficacies

11. Structural: Effects on ion channels
• Anaesthetics are thought to act on ligand gated ion channels
Excitatory receptors
(NMDA, 5-TH3, nicotinic
acetylcholine) are
inhibited by anaesthetics
Inhibitory receptors
(GABAA and glycine) are
potentiated by
anaesthetics

12. • Almost all anaesthetics (except ketamine, xenon, cyclopropane and
nitrous oxide) potentiate the action of GABA at the GABAAreceptor
Structural: Effects on ion channels
No anaesthetic With anaesthetic

13. Examples of general anaesthetics
• Inhalation (volatile)
• Isoflurane, Sevoflurane,
Desflurane, Halothane
• (Historically ether,
chloroform)
• Nitrous oxide
• Intravenous
• Thiopental sodium,
Propofol
• Ketamine

14. Stages of anaesthesia
Rapid
induction
with
intravenous
anaesthesia
Maintenance
with
inhalation
anaesthesia
Recovery via
withdrawal
of
anaesthesia
Side effects

15. Inhalation anaesthetics

16. Inhalation anaesthetics
• Level of anaesthesia is correlated with the partial pressure of
anaesthetic in brain tissue
• The forward movement of an inhalational agent is driven by a
series of partial pressure gradients (agent moves from an area
of high pressure to an area of low pressure)
Alveoli Blood Brain and other tissues
• Gradients are dependant on the solubility of the volatile
anaesthetic in blood and body tissue
Anaesthetic
breathed in

17. Inhalation anaesthetics
• The solubility of volatiles in different media can be
expressed as partition coefficients
• The partition coefficient is a simple ratio of amounts:
e.g. the blood/gas
coefficient is the ratio of
the amount of
anaesthetic dissolved in
blood to the amount in
the same volume of gas in
contact with that blood

18. Inhalation anaesthetics
• Nitrous oxide is not very soluble in the blood. On inhalation, it moves
from the air (alveoli) into to the blood down its pressure gradient until
the pressures are equalised.
• When we have an equal volume of air in contact with
an equal volume of blood, and nitrous oxide is
allowed to move freely between these
compartments until the pressure is equal in each
compartment, we have the equivalent of 1 molecule
of nitrous oxide in the air to every 0.47 molecules
dissolved in the blood
• Halothane is quite soluble in the blood.
• When we have an equal volume of air in contact with an equal volume of
blood, and halothane is allowed to move freely between these
compartments until the pressure is equal in each compartment, we have
the equivalent of 1 molecule of halothane in the air to every 2.3 molecules
dissolved in the blood

19. • The main factors that determine the pharmacokinetic
properties of a GA are:
– blood/gas partition coefficients (i.e. solubility in
blood)
– oil/gas partition coefficients (i.e. solubility in fat)
Inhalation anaesthetics

20. High solubility in blood
High blood/gas partition
coefficient
- Slow induction and recovery
- Slow adjustment of depth of
anaesthesia
(Blood acts as a reservoir
(store) for the drug so it
doesn’t enter or leave the brain
readily until the blood reservoir
is filled)
Inhalation anaesthetics: solubility in blood

21. High solubility in blood Low solubility in blood
High blood/gas partition
coefficient
Low blood/gas partition
coefficient
- Slow induction and recovery
- Slow adjustment of depth of
anaesthesia
(Blood acts as a reservoir
(store) for the drug so it
doesn’t enter or leave the brain
readily until the blood reservoir
is filled)
- Rapid induction and recovery
- Rapid adjustment of depth of
anaesthesia
(Because the blood reservoir is
small the anaesthetic is available
to pass into/out of the brain
quicker)
Inhalation anaesthetics: solubility in blood

22. LOW solubility in blood=
fast induction and recovery
HIGH solubility in blood=
slower induction and recovery
blood/gas
partition
coefficient
Inhalation anaesthetics: solubility in blood

23. Inhalation anaesthetics: lipid solubility
High solubility in lipid Low solubility in lipid
High oil/gas partition coefficient Low oil/gas partition
coefficient
- More potent GA
(GA is held at the site of action -
lipid membrane/proteins within
the membrane)
- Less potent GA

24. Inhalation anaesthetics: lipid solubility
• Clinically, potency/anaesthetic strength is measured in MAC –
minimum alveolar concentration
 Percentage of anaesthetic in lungs that abolishes a
movement response, in 50% of patients, to a surgical
incision

25. Characteristics of example inhalation anaesthetics
Drug Partition coefficient
Blood:gas Oil:gas
Induction
/recovery
Notes
Nitrous
oxide
0.47 1.4 Fast Good analgesic effect
Low potency, therefore must be
combined with other agents
Sevoflurane 0.6 53 Fast Used for day-case surgery because
of fast onset and recovery
Isoflurane 1.4 91 Medium Pungent odour, not used for
induction
Halothane 2.3 220 Medium Little used nowadays due to the
potential for accumulation of toxic
metabolites
Ether 12.0 65 Slow Now obsolete, except where
modern facilities are lacking

26. Anaesthetic
drug
Partition coefficient
Blood:gas Oil:gas
X 2.9 48
Y 7.5 120
Z 1.0 2.1
From the information provided in the table do you think the
following statements could be true or false?
A. Drug X has faster induction than drug Y
B. Drug Y is more potent than drug X
C. Recovery from Drug Y will be slower than from drug Z
D. Drug Z is more potent than drug Y
Testing knowledge
Answers on
next slides

27. Anaesthetic
drug
Partition coefficient
Blood:gas Oil:gas
X 2.9 48
Y 7.5 120
Z 1.0 2.1
From the information provided in the table do you think the
following statements could be true or false?
A. Drug X has faster induction than drug Y
True based on the fact that drug X has a lower blood gas
partition coefficient so is less soluble in blood, thus fills up the
blood reservoir quicker and is pushed on down the pressure
gradient into the brain
Testing knowledge

28. Anaesthetic
drug
Partition coefficient
Blood:gas Oil:gas
X 2.9 48
Y 7.5 120
Z 1.0 2.1
From the information provided in the table do you think the
following statements could be true or false?
B. Drug Y is more potent than drug X
True based on the fact that drug Y has a higher oil gas partition
coefficient so is more soluble in fat (brain) and held for longer at
the lipophilic site of action (receptors in the lipid bi-layer)
Testing knowledge

29. Anaesthetic
drug
Partition coefficient
Blood:gas Oil:gas
X 2.9 48
Y 7.5 120
Z 1.0 2.1
From the information provided in the table do you think the
following statements could be true or false?
C. Recovery from Drug Y will be slower than from drug Z
True based on the fact that Drug Y has a higher blood gas
partition coefficient so is more soluble in the blood so takes
longer to move from the brain to the blood to the lungs hence
has a longer recovery
Testing knowledge

30. Anaesthetic
drug
Partition coefficient
Blood:gas Oil:gas
X 2.9 48
Y 7.5 120
Z 1.0 2.1
From the information provided in the table do you think the
following statements could be true or false?
D. Drug Z is more potent than drug Y
False based on the fact drug Z has a lower oil gas partition
coefficient so is less soluble in fat and therefore less potent
Testing knowledge

31. Intravenous anaesthetics

32. Intravenous anaesthetics
• Intravenous anaesthetics enable rapid induction because the
blood concentration can be raised quickly
• As non-volatile compounds, intravenous agents cannot be
removed from the body by ventilation
• Recovery occurs rapidly as the drug is redistributed around the
body
• Metabolism and/or excretion then slowly decreases overall
body levels

33. Intravenous anaesthetics - redistribution
• The drug firstly moves into compartments of the body that are
highly perfused and lipid soluble e.g. the brain, bringing on
anaesthesia
• The drug then starts to
distribute to other less well
perfused tissues such as the
muscle
• As it moves from the blood
into the muscle the blood
concentration will fall, so
the anaesthetic will start to
move back down its
concentration gradient from
the brain into the blood
resulting in recovery from
anaesthesia
Highly
perfused and
lipophilic
Less
perfused
Poorly
perfused
but very
lipophilic

34. • Thiopental sodium
– Very high lipid solubility - rapid transfer across blood-brain
barrier but accumulation in body (‘hangover’)
– Short duration (due to redistribution)
• Propofol
– Rapid metabolism - rapid recovery – no ‘hangover’
– Can be used alone for induction and maintenance
(total intravenous anaesthesia)
• Ketamine
– Dissociative anaesthesia
– Slower onset, longer duration of action
– Significantly different cardiovascular system and
respiratory system effects
Example intravenous anaesthetic agents

35. Summary
• Intravenous anaesthetics are the most used drugs
for anaesthetic induction in adults
→Their lipophilicity and the high perfusion of the
brain and spinal cord results in rapid onset and
offset of anaesthesia after a single bolus dose
→They accumulate in fatty tissue – prolonging
recovery if multiple doses are given

36. Summary
• Inhalation anaesthetics are primarily used for the
maintenance of anaesthesia
• An advantage is that the depth of anaesthesia can be rapidly
altered by changing the inhaled concentration of the drug
• Speed of induction/recovery and potency are determined by
two properties of the anaesthetic: solubility in blood
(blood:gas partition coefficient) and solubility in fat (lipid
solubility)
• 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)

37. Recommended reading
Rang, Dale, Ritter and Flower. Pharmacology.
Relevant sections within the chapter ‘General anaesthetics’
Brunton et. al. Goodman and Gilman’s The Pharmacological
Basis of Therapeutics
Relevant sections of chapter ‘General anaesthetics and
therapeutic gases’
Golan et al. Principles of Pharmacology.
Relevant sections within the chapter ‘General anaesthetic
pharmacology’
Additional images from Lippincott's Illustrated Review
Pharmacology