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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
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
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
• 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
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)
Inhalation anaesthetics: solubility in blood
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
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
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
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 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
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 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
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 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 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