An introduction to general anaesthesia
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The document provides an overview of general anaesthesia, detailing the pharmacology and mechanisms of intravenous and inhalation anaesthetics. It covers the types of anaesthetics, their effects on the central nervous system, and the roles of adjunct medications during surgical procedures. Key factors influencing the induction and recovery of different anaesthetic agents are discussed, alongside their blood and lipid solubility properties.
An introduction to general anaesthesia
- 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
- 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
- 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
Editor's Notes
- #14: The use of nitrous oxide to relieve the pain of surgery was suggested by Humphrey Davy in 1800. He was the first person to make nitrous oxide, and he tested its effects on several people, including himself and the Prime Minister, noting that it caused euphoria, analgesia and loss of consciousness. The use of nitrous oxide, billed as 'laughing gas', became a popular fairground entertainment and came to the notice of an American dentist, Horace Wells, who had a tooth extracted under its influence, while he himself squeezed the inhalation bag. Ether also first gained publicity in a disreputable way, through the spread of 'ether frolics', at which it was used to produce euphoria among the guests.
- #17: The volume of a gas that can be dissolved by a unit volume of solvent alveolar ventilation rate (uptake from lungs) cardiac output Gradient – i.e. how fast it will move from the lungs to brain therefore how fast the onset is determined by the solubility of the anaesthetic in different tissues How fast also depends on cardiac output
- #18: The volume of a gas that can be dissolved by a unit volume of solvent alveolar ventilation rate (uptake from lungs) cardiac output At equilibrium