Lecture 4 General Anaesthetics PDF

Lecture 4: General Anaesthetics Prof. David Finn Pharmacology and Therapeutics Pharmacological effects Learning objectives Types (based on route of administration) Mechanism of action (parenteral vs inhalation) Adverse side effects and toxicity Definition General anaesthesia: loss of response to and...

Lecture 4: General Anaesthetics Prof. David Finn Pharmacology and Therapeutics Pharmacological effects Learning objectives Types (based on route of administration) Mechanism of action (parenteral vs inhalation) Adverse side effects and toxicity Definition General anaesthesia: loss of response to and perception of all external stimuli A general anaesthetic (GA) drug should be readily controllable o Induction and recovery should be rapid o Adjust level of anaesthesia according to surgical requirement Great discovery: made modern surgery possible o Rare to go through life without being anaesthetised at least once Fun and frolics led to early anesthesia Components of general anaesthesia Unconsciousness (loss of perception of all senses) Analgesia Amnesia Immobility (neuromuscular relaxation) Loss of reflexes Reversible Phases of anaesthesia Induction: putting the patient to sleep o I.v. induction agent (e.g. propofol) Maintenance: keeping the patient asleep o Inhalation agent (e.g. nitrous oxide or halothane) o Supplement with i.v. analgesic (e.g. fentanyl) Recovery: waking the patient up Most anesthetic procedures today involve the combination of different anesthetic drugs which are being used in concentrations that are considerably smaller than those needed if the drug were to be used alone Chemistry of GA General anaesthesia can be caused by a remarkable number of structurally diverse molecules No recognizable chemical class Suggests common site of action or common mechanism (Unitary Hypothesis, 1870, C. Bernard) Classification Based on route of administration General anaesthetics Inhaled Parenteral (i.v., i.m., s.c.) Gas Nitrous oxide Volatile liquids* Halothane Isofluorane Desflurane Sevofluorane Barbiturates Opioids Thiopental Fentanyl Benzodiazepines Midazolam *In the beginning there was ether and chloroform, replaced with the ‘fluoranes’ which have fewer side effects and are non-flammable Dissociative Ketamine Miscellaneous Etomidate Propofol Molecular actions of GAs Meyer-Overton rule The correlation of anaesthetic potency with lipid solubility provides a means of predicting anaesthetic potency This correlation has traditionally been interpreted as meaning that primary anaesthetic action sites are lipid portions of nerve membranes. The “old theory” of general anaesthesia (the consensus circa 1980) Patient wakes up Induction The exact opposite of the non-specific “miracle” occurs…. Anaesthetic molecules partition into lipid bilayers Non-specific “miracle” occurs… Δ cell lipid bilayer physical properties? Stereospecific effects? Unconsciousness Remove anaesthetic Molecular actions of GAs Meyer-Overton-Lipid Theory Anaesthetic potency is correlated with lipid solubility Higher the solubility (in oil)  greater the anaesthetic potency Protein (Receptor) Theory Anaesthetic potency is correlated with the ability of anaesthetics to inhibit enzyme activity of a pure, soluble protein (Franks & Lieb, 1984) Proteins are molecular targets of general anaesthetics Mechanisms of action of GAs (1) Inhibit excitatory channels (glutamate, ACh, 5-HT) Facilitate inhibitory channels (GABA, glycine) Block synaptic transmission (not axonal conductance) Inhibit NT release and post-synaptic receptors Mechanisms of action of GAs (2) 1. Inhibit NMDA (glutamate) receptors (nitrous oxide, ketamine, xenon, high dose barbiturates) 2. Inhibit synaptic release ( NT release) 3. Block nicotinic receptor subtypes (moderate to high conc of inhaled anaesthetics) Mechanisms of action of GAs (3) 4. Enhanced GABA effect on GABAA Receptors (inhaled anaesthetics, barbiturates, benzodiazepines, etomidate, propofol) 5. Enhance glycine effect on glycine receptors (immobility) 6. Activate K+ channels (hyperpolarize membranes) (nitrous oxide, ketamine, xenon) Sites of action of GAs Neural substrates Hippocampus: Amnesia Short-term memory Sedation, loss of consciousness ( Midbrain reticular formation) Analgesia ( Thalamic firing- CNS nociceptive relay) Amnesia -short term memory ( Hippocampal neurotransmission) Thalamus: Analgesia Pain relay Midbrain: Consciousness Sedation Parenteral vs Sedative drug classes Induction- rapid onset Maintenance- combined with muscle relaxants and analgesics Unconsciousness ~20 sec 1) 2) 3) 4) High potency and rapid onset/ reversibility Adds flexibility and permits administration of lower doses of inhalational agents Ease of administration Elimination is slow vs inhalation GAs (prolonged after effects i.e. “hangover”) Inhalation Gases or volatile liquids Maintenance of anaesthesia Unconsciousness > 2 min Speed of induction and recovery determined by: 1) Blood : gas partition coefficient (PC): determines solubility in blood o Lower => faster induction and recovery 2) Oil : gas PC: determines solubility in fat o Potency of anaesthetic o High lipid solubility => Delays recovery 3) Alveolar ventilation rate 1. Parenteral anaesthetics (intravenous) Most commonly used drugs to induce anaesthesia Barbiturates (thiopental*) Benzodiazepines (midazolam, diazepam) Opioids (morphine, fentanyl) Miscellaneous (propofol**, etomidate*) *Most commonly used for induction *Can be used for maintenance but usually inhalation GAs used Barbiturates & Benzodiazepines Mechanism of action Both bind to GABAA receptors, at different sites o Both cause increase Cl- influx in presence of GABA o BDZ binding can be blocked by flumazenil Barbiturates at high doses: block Na+ channels and NMDA/glutamate receptors Flumanezil: antagonist used to speed recovery or antidote to overdose Benzos mainly used preoperatively (slower acting) Barbs: fast acting, slow leaching => “hangover” Some dependence o  Respiration & CV depression GABA Barbiturates Benzodiazepines ( and ) Flumazenil Barbiturates & Benzodiazepines Dose response relationships 2. Inhaled anaesthetics Liquid halogenated hydrocarbons Easily vaporized Administered as gases Lower blood:gas PC o Lower solubility o Faster induction  Because less drug has to be absorbed via lungs in order to achieve partial pressure in blood (gas) 2. Inhaled anaesthetics Partial pressure or “tension” in inspired air is a measure of their concentration The speed of induction of anaesthesia depends on: i. Inspired gas partial pressure (GA concentration) ii. GA solubility (less soluble GAs equilibrate more quickly with blood and into tissues such as the brain) iii. Ventilation rate (faster rate = faster equilibration/induction) Gas partial pressure Solubility effect on arterial anaesthetic tension Solubility in blood represented as compartment More soluble = larger compartment Partial pressure = degree of filling of compartment Why induction of anesthesia is slower with more soluble anesthetic gases? In this schematic diagram, solubility in blood is represented by the relative size of the blood compartment (the more soluble, the larger the compartment). Relative partial pressures of the agents in the compartments are indicated by the degree of filling of each compartment. For a given concentration or partial pressure of the two anesthetic gases in the inspired air, it will take much longer for the blood partial pressure of the more soluble gas (halothane) to rise to the same partial pressure as in the alveoli. Since the concentration of the anesthetic agent in the brain can rise no faster than the concentration in the blood, the onset of anesthesia will be slower with halothane than with nitrous oxide. Solubility effect on arterial anaesthetic levels Tensions of three anesthetic gases in arterial blood as a function of time after beginning inhalation. Nitrous oxide is relatively insoluble (blood:gas partition coefficient = 0.47); methoxyflurane is much more soluble (coefficient = 12); and halothane is intermediate (2.3). Effect of ventilation rate on arterial anaesthetic tension Hyperventilation increases the speed of induction for GAs with normally slow onset Ventilation rate and arterial anesthetic tensions. Increased ventilation (8 versus 2 L/min) has a much greater effect on equilibration of halothane than nitrous oxide. Minimum alveolar concentration (MAC) The alveolar anaesthetic concentration required to eliminate the motor response to a painful stimulus in 50% of patients A measure of GA potency MAC is gold standard for measuring anaesthesia It’s “a population average” When several GAs are mixed, their MAC values are additive (e.g. nitrous oxide is commonly mixed with other anesthetics) MAC % Nitrous Oxide Halothane Methoxyflurane >100 0.75 0.16 Minimum alveolar concentration (MAC) Importance Allow easy comparison of anaesthetics Easily measured Important clinical endpoints Consistent and reproducible Elimination Anaesthesia is most commonly terminated by redistribution of drug from brain to the blood and out through the lungs Rate of recovery from GAs with low blood:gas PCs is faster than for highly soluble GAs Blood:Gas PCs Halothane Sevoflurane Desflurane 2.30  slower recovery, more lipid soluble 0.69 0.42  faster induction and recovery Elimination If highly-fat soluble GA maintained for a long time, fat accumulates [GA] => “hangover” period pronounced and patient may remain drowsy for hours Search for improved inhalation GA = low blood and tissue solubility ~ similar to N2O but higher potency (e.g. desflurane) Effects on CVS and respiration  cardiac contractility & BP*  respiration  PCO2 At supra-anaesthetic doses, all GAs can cause death by loss of CV reflexes and respiratory paralysis *Exception is nitrous oxide:  HR & BP Neuromuscular junction blockers Succinylcholine, Pancuronium – NAchR Used to: o Relax skeletal muscle (surgery not disturbed by contractions) o Facilitate intubation* o Ensure immobility Reversed by neostigmine** and glycopyrrolate** during post-op period * Intubation is usually needed for airway maintenance and to prevent aspiration ** Quaternary drugs Key points  GAs constitute a number of structurally diverse molecules  M/A: enhance activity of GABAA receptors and many GAs inhibit excitatory channels (NMDA, NAChR)  Potency related to lipid solubility  Induction speed related to blood solubility  Main side effects are due to narrow therapeutic index => circulatory depression & respiratory failure  Most dangerous drugs in use => small margin of safety. However important and useful => made modern surgery possible Recommended reading + Rang and Dale’s Pharmacology 10th Ed. Chapter 41 + Kalant, Grant and Mitchell. Principles of Medical Pharmacology. Chapter 20