an introduction to general anaesthesia

Dr Clare Guildinge.mail: [email protected]

General anaesthesia

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

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

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

Adjunct medications

Medication Use

Benzodiazepines Anxiolysis and amnesia presurgery

H2 blockerse.g. ranitidine

Prevent gastric acid secretion

Antimuscarinic drugse.g. atropine

Prevents bradycardia and secretion of fluids into the respiratory tract

Neuromuscular blockerse.g. suxamethonium

Facilitates intubation and suppresses muscle tone to degree required for surgery

Analgesicse.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

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 (reduceexcitatory and increase inhibitory activity, especially in reticular activating system)

• Depress cardiovascular, respiratory and other systems

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

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

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

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

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

• 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

Examples of general anaesthetics

• Inhalation (volatile)• Isoflurane, Sevoflurane,

Desflurane, Halothane

• (Historically ether, chloroform)

• Nitrous oxide

• Intravenous• Thiopental sodium,

Propofol

• Ketamine

Stages of anaesthesia

Rapid induction with intravenousanaesthesia

Maintenance with inhalationanaesthesia

Recovery via withdrawal of anaesthesia

Side effects

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


• 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


• 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

• 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)


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

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)


LOW solubility in blood= fast induction and recovery

HIGH solubility in blood= slower induction and recovery

blood/gas partition

coefficient


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

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

Characteristics of example inhalation anaesthetics

Drug Partition coefficient

Blood:gas Oil:gas

Induction/recovery

Notes

Nitrous oxide

0.47 1.4 Fast Good analgesic effectLow 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

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 YB. Drug Y is more potent than drug XC. Recovery from Drug Y will be slower than from drug ZD. Drug Z is more potent than drug Y

Testing knowledge

Answers on next slides

Anaesthetic drug


Blood:gas Oil:gas

X 2.9 48

Y 7.5 120

Z 1.0 2.1


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

Anaesthetic drug


Blood:gas Oil:gas

X 2.9 48

Y 7.5 120

Z 1.0 2.1


B. Drug Y is more potent than drug XTrue 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

Anaesthetic drug


Blood:gas Oil:gas

X 2.9 48

Y 7.5 120

Z 1.0 2.1


C. Recovery from Drug Y will be slower than from drug ZTrue 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

Anaesthetic drug


Blood:gas Oil:gas

X 2.9 48

Y 7.5 120

Z 1.0 2.1


D. Drug Z is more potent than drug YFalse 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

Intravenous anaesthetics

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

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

• 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

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

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)

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 TherapeuticsRelevant 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

an introduction to general anaesthesia

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