General anaestheticsGeneral anaesthetics

Anton KohútAnton Kohút

General anaesthetics (GA)General anaesthetics (GA)GA is a state of drug-induced loss GA is a state of drug-induced loss of consciousnes whereby surgical of consciousnes whereby surgical procedure can be caried out procedure can be caried out painlesslypainlessly

General General anaestheticsanaesthetics

History of general anaesthesiaHistory of general anaesthesia

Hwa TuoHwa Tuo in the second in the second century performed operations century performed operations under general anunder general anaaesthesiaesthesia with with "foamy narcotic powder""foamy narcotic powder"

William MortonWilliam Morton oon September n September 3030,, 1846, 1846, etherized etherized Boston Boston merchant Eben Frost before merchant Eben Frost before extracting his ulcerous tooth extracting his ulcerous tooth

(110 - 208)

(1819 - 1868)

Robert C. Hinckley’s painting “First Operation Under Ether”(1883)

Drugs given to induce or maintain general Drugs given to induce or maintain general anaesthesiaanaesthesia are either given as: are either given as:

Gases or vapoursGases or vapours ( (inhalationalinhalational anaestheticsanaesthetics- - volatilevolatile liquidsliquids or or gasesgases and and are usually delivered using an are usually delivered using an anaesthesiaanaesthesia machinemachine. .

Injections Injections Most commonly these two forms are Most commonly these two forms are

combined, with an injection given to combined, with an injection given to induce anaesthesia and a gas used to induce anaesthesia and a gas used to maintain it, maintain it,

Groups of GAGroups of GA

I. Inhalation GAI. Inhalation GA HalothaneHalothane Nitrouse oxideNitrouse oxide EnfluraneEnflurane IsofluraneIsoflurane DesfluraneDesflurane

II. Intravenous II. Intravenous GAGA

ThiopentalThiopental EtomidateEtomidate KetamineKetamine PropofolPropofol

III. Neurolept-analgesia Droperidol + Fentanyl

most commonly these two forms are combined, withan injection given to induce anaesthesia & a gas used to maintain it

Inhalation anaestheticsInhalation anaesthetics

GENERAL ANAESTHESIA

a state of total unconsciousness resulting from general anaesthetic drugs

stages of anaesthesia: stage 1 - "induction" - the period between the initial administration of the induction medications & loss of consciousness

stage 2 - "excitement stage" - the period following loss of consciousness & marked by excited & delirious activity

stage 3 - “surgical anaesthesia” - during this stage, the skeletal muscles relax & the patient's breathing becomes regular - surgery can begin

stage 4 - "overdose" - too much medication has been given & the patient has severe brain stem or medullary depression - cessation of respiration & potential cardiovascular collapse - lethal without cardiovascular & respiratory support

Characteristics of inhalation GACharacteristics of inhalation GA

1. 1. are nonspecificare nonspecific, they do not act by , they do not act by interacting with specific one receptor interacting with specific one receptor (there (there are not specific antagonists)are not specific antagonists)

2. 2. effects:effects: hypnosis, analgesia sceletal muscle hypnosis, analgesia sceletal muscle relaxation, reduction of certain autonomic relaxation, reduction of certain autonomic reflexes reflexes (there are among GA quantitative (there are among GA quantitative defferences).defferences).

3. 3. eliminationelimination is mainly by pulmonary rout is mainly by pulmonary rout (do (do not depends on the hepatic metabolism or not depends on the hepatic metabolism or renal excretion).renal excretion).

4. At supra-anaesthetics doses all GA can cause 4. At supra-anaesthetics doses all GA can cause the the death by the loss of cardiovascular death by the loss of cardiovascular function and respiratory paralysesfunction and respiratory paralyses..

Mechanism of action of GAMechanism of action of GA Lipid - Lipid -vvolume expansion olume expansion theorytheory

Anaesthetics Anaesthetics disolves in the disolves in the phospholipids phospholipids bilayer of neuronal bilayer of neuronal mambranemambrane, causing , causing membrane expand, membrane expand, this impedes opening this impedes opening of ion channels of ion channels necessary for necessary for generation and generation and propagation of action propagation of action potentialpotential

Mechanism of actionMechanism of action

Lipid theoryLipid theory

GA exert their action by acting on GA exert their action by acting on the the plasma plasma membranemembrane. The potency . The potency of the drug has a direct, positive of the drug has a direct, positive correlation with the lipid solubility correlation with the lipid solubility of the blood. of the blood.

- increased fluidity of the - increased fluidity of the membrane. membrane.

Extent and rate of GAExtent and rate of GA

To achieve their effects, must pass from To achieve their effects, must pass from the alveolar air into the blood and hence the alveolar air into the blood and hence into the CNS. Extent and rate depend into the CNS. Extent and rate depend upon:upon:

concentrationconcentration (or partial pressure), (or partial pressure), solubilitysolubility - - GA with low solubility produce GA with low solubility produce

rapid induction and recovery –nitrous rapid induction and recovery –nitrous oxide and vice versa –halothane),oxide and vice versa –halothane),

pulmonary physiologypulmonary physiology (ventilation, blood (ventilation, blood flow).flow).

agents with smaller λ(blood/gas) such as nitrous agents with smaller λ(blood/gas) such as nitrous oxide, the alveolar partial pressure approaches oxide, the alveolar partial pressure approaches the inspired partial pressure quickly, the inspired partial pressure quickly,

Figure 15-4. Distribution of cardiac output and volume Figure 15-4. Distribution of cardiac output and volume

capacity for general anesthetics among the major tissue capacity for general anesthetics among the major tissue compartments.compartments. The tissues of the body can be divided into four The tissues of the body can be divided into four groups based on their level of perfusion and their capacity to take groups based on their level of perfusion and their capacity to take up anesthetic. up anesthetic.

These include the Vessel-Rich Group (VRG),These include the Vessel-Rich Group (VRG), Muscle Group (MG), Muscle Group (MG), Fat Group (FG), and Fat Group (FG), and Vessel-Poor Group (VPG).Vessel-Poor Group (VPG). (The contribution of the VPG is generally ignored in most (The contribution of the VPG is generally ignored in most

pharmacokinetic models of anesthesia.) The VRG, which contains pharmacokinetic models of anesthesia.) The VRG, which contains the internal organs including the brain, constitutes a small the internal organs including the brain, constitutes a small percentage of the total body weight (9%), has the lowest capacity percentage of the total body weight (9%), has the lowest capacity for anesthetic, and receives most of the cardiac output (75%). The for anesthetic, and receives most of the cardiac output (75%). The high perfusion and low capacity allow high perfusion and low capacity allow PPVRG to equilibrate rapidly VRG to equilibrate rapidly with with PPart. Also, the VRG makes the largest contribution to the mixed art. Also, the VRG makes the largest contribution to the mixed venous return partial pressure venous return partial pressure PPMVR, which is equal to (0.75 MVR, which is equal to (0.75 PPVRG + VRG + 0.18 0.18 PPMG + 0.055 MG + 0.055 PPFG + 0.015 FG + 0.015 PPVPG).VPG).

Stages of general Stages of general anaesthesiaanaesthesia

Stage 1Stage 1: analgesia: analgesia - - is partial until stage 2 is partial until stage 2 Consciousnes and sense of touch are retained and Consciousnes and sense of touch are retained and

sense of hearing is increased.sense of hearing is increased.

Stage 2Stage 2: delirium.: delirium. Uncounsciuos - but automatic Uncounsciuos - but automatic movements may occur. Laryngospasm may develop. movements may occur. Laryngospasm may develop. Suden death, probably due to vagal inhibition of the Suden death, probably due to vagal inhibition of the heart or to sensitisation of the heart to adrenaline by the heart or to sensitisation of the heart to adrenaline by the anaesthetic agent.anaesthetic agent.

Stage 3:Stage 3: surgical anaesthesia.surgical anaesthesia. This is divided into four This is divided into four planes. Depth is determined by changes in respiration, planes. Depth is determined by changes in respiration, pupils, spontaneous eyeball position, reflexes and pupils, spontaneous eyeball position, reflexes and muscle tone.muscle tone.

Stage 4:Stage 4: medullary paralysis medullary paralysis. .

HalothaneHalothane

1.1. drugs now in drugs now in common usecommon use, and it is the , and it is the standard to which others are comparedstandard to which others are compared

2.2. has has weak analgesicweak analgesic action action

3.3. respiratory depresantrespiratory depresant – assistant ventilation – assistant ventilation

4.4. bronchial dilatationbronchial dilatation – suitable for asthmatic – suitable for asthmatic patientspatients

5.5. relaxant effect on the uterusrelaxant effect on the uterus – limited using – limited using for obstetric purposesfor obstetric purposes

6.6. hepatotoxic effect of metaboliteshepatotoxic effect of metabolites

Halothane – cont.Halothane – cont.

Heart and CirculationHeart and Circulation A dose-dependent reduction of arterial blood A dose-dependent reduction of arterial blood

pressure.pressure. The myocardium is depressed directly and The myocardium is depressed directly and

cardiac output is decreased. (cardiac output cardiac output is decreased. (cardiac output is reduced by 20% to 50%) - is reduced by 20% to 50%) - vagal vagal predominance).predominance).

Increases sensitization of myocard to Increases sensitization of myocard to catecholaminescatecholamines

May increase the automaticity of the May increase the automaticity of the myocardiummyocardium

Nitrous oxideNitrous oxide

strong analgesic – weak anaestheticstrong analgesic – weak anaesthetic it does not produce surgical anaesthesia – is it does not produce surgical anaesthesia – is

not used on its own anaesthesianot used on its own anaesthesia is used other with anaesthetics (halothane, is used other with anaesthetics (halothane,

enflurane)enflurane) nitrous oxide/oxygen mixture 50:50 – rapid nitrous oxide/oxygen mixture 50:50 – rapid

analgesia – obstetric analgesiaanalgesia – obstetric analgesia generally is non-toxic generally is non-toxic

IsofluraneIsoflurane and and enfluraneenflurane are somewhat less potent are somewhat less potent than halothane (they have a smaller λ(oil/gas)), but than halothane (they have a smaller λ(oil/gas)), but they equilibrate faster because they have a smaller they equilibrate faster because they have a smaller λ(blood/gas). Enflurane is metabolically defluorinated λ(blood/gas). Enflurane is metabolically defluorinated to a greater extent than isoflurane, and may thus to a greater extent than isoflurane, and may thus have a greater risk of causing renal toxicity. It also have a greater risk of causing renal toxicity. It also induces seizure-like activity in the EEG of some induces seizure-like activity in the EEG of some patients. patients. Isoflurane is probably the most widely used Isoflurane is probably the most widely used general anesthetic today.general anesthetic today.

DesfluraneDesflurane and and sevofluranesevoflurane are newer anesthetics are newer anesthetics that, by design, have low λ(blood/gas); times of that, by design, have low λ(blood/gas); times of equilibration between their alveolar and inspired equilibration between their alveolar and inspired partial pressures are nearly as short as that of nitrous partial pressures are nearly as short as that of nitrous oxide. Furthermore, they are much more potent than oxide. Furthermore, they are much more potent than nitrous oxide because their oil/gas partition nitrous oxide because their oil/gas partition coefficients are highercoefficients are higher. .

Adverse effects of inhalation Adverse effects of inhalation GA (rare, unpredictable)GA (rare, unpredictable)

Idiosyncratic reactions to the volatile agentsIdiosyncratic reactions to the volatile agents:: malignant hyperpyrexiamalignant hyperpyrexia ( (triggered most often triggered most often

by by halothanehalothane with with suxamethoniumsuxamethonium)) halothanehalothane hepatitis hepatitis (direct toxicity from the (direct toxicity from the

products of reductive metabolismproducts of reductive metabolism or or immunologically mediated haptens formed by liver immunologically mediated haptens formed by liver proteins proteins && the products of oxidative metabolism) the products of oxidative metabolism)

pprolonged rolonged nitrous oxidenitrous oxide (N(N22O)O) exposure can cause exposure can cause::bone marrow depression bone marrow depression

life-threatening pressure effects by expansion of air-filled life-threatening pressure effects by expansion of air-filled spaces within the body spaces within the body

Intravenous anaestheticsIntravenous anaesthetics

Anesthetics potentiate the action of Anesthetics potentiate the action of endogenous agonists at inhibitory receptors, endogenous agonists at inhibitory receptors, such as GABAA and glycine receptors, such as GABAA and glycine receptors, anesthetics both anesthetics both decrease the EC50decrease the EC50 of GABA of GABA (i.e., GABA becomes more potent)(i.e., GABA becomes more potent)

Inhibit the action of endogenous agonists at Inhibit the action of endogenous agonists at

excitatory receptors, such as nicotinic excitatory receptors, such as nicotinic acetylcholine, 5-HT3, and NMDA glutamate acetylcholine, 5-HT3, and NMDA glutamate receptors. and increase the maximum receptors. and increase the maximum response At excitatory receptors, anesthetics response At excitatory receptors, anesthetics decrease the maximum response while decrease the maximum response while leaving the EC50 unchanged; these are the leaving the EC50 unchanged; these are the pharmacologic hallmarks of pharmacologic hallmarks of noncompetitive inhibition.noncompetitive inhibition.

II. Intravenous GAII. Intravenous GA ThiopentalThiopental EtomidateEtomidate KetamineKetamine PropofolPropofol Thiopental /Thiamylat/Thiopental /Thiamylat/ III. Neurolept-analgesia Droperidol + Fentanyl

Intravenous anaestheticsIntravenous anaesthetics

1. most of them have documented effect 1. most of them have documented effect on membrane receptoron membrane receptor

thiopentalthiopental (barbiturate)- GABA (barbiturate)- GABA ketamin ketamin – NMDA receptor– NMDA receptor2. are often used for rapid induction of 2. are often used for rapid induction of

anaesthesia – then combination with anaesthesia – then combination with inhalation agentinhalation agent

3. 3. advantagesadvantages – rapid onset, controled – rapid onset, controled dosage ease administrationdosage ease administration

Effects of Effects of GAGA on on ligand-gated ion ligand-gated ion

channelschannels

dark green dark green = = potentiationpotentiation; dark ; dark pinkpink = = inhibition inhibition; ; light greenlight green = = little potentiation little potentiation; ; light pink light pink = = little little inhibitioninhibition; ; empty empty = = no effectno effect

ThiopentalThiopental

most widely used ultra short-acting –onset most widely used ultra short-acting –onset less than 1 min.less than 1 min.

no analgesic actionno analgesic action cardiac depression – decrease of cardiac cardiac depression – decrease of cardiac

output, no change in peripheral resistanceoutput, no change in peripheral resistance depresses respiratory center, induction often depresses respiratory center, induction often

accompanied with coughing or laryngospazmaccompanied with coughing or laryngospazm decreases cerebral blood flow and oxygen decreases cerebral blood flow and oxygen

consumption in the brain consumption in the brain

PropofolPropofol is an important intravenous anesthetic is an important intravenous anesthetic prepared in an intralipid formulation. This agent prepared in an intralipid formulation. This agent produces anesthesia at a rate similar to the produces anesthesia at a rate similar to the ultrashort-acting barbiturates.ultrashort-acting barbiturates.

EtomidateEtomidate is an imidazole that is used for is an imidazole that is used for induction of anesthesia because its kinetics are induction of anesthesia because its kinetics are similar to those of propofol. This agent causes similar to those of propofol. This agent causes minimal cardiopulmonary depression, perhaps minimal cardiopulmonary depression, perhaps because of its unique lack of effect on the because of its unique lack of effect on the sympathetic nervous system. sympathetic nervous system.

ketamineketamine produces dissociative anesthesia, in produces dissociative anesthesia, in which the patient seems to be awake but is which the patient seems to be awake but is actually in an analgesic and amnesic state. actually in an analgesic and amnesic state. Ketamine has the unusual property that it Ketamine has the unusual property that it increases cardiac output by increasing increases cardiac output by increasing sympathetic outflow; for this reason, it is sympathetic outflow; for this reason, it is occasionally useful in emergency trauma occasionally useful in emergency trauma situations. However, it can also produce situations. However, it can also produce unpleasant hallucinations. This agent is rarely unpleasant hallucinations. This agent is rarely used today. used today.

Adverse effects of injection GA (rare, unpredictable)

Idiosyncratic reactions to the i.v. agents:

• anaphylactoid reactions (rare)

• triggering of acute porphyria - thiopenthal

• etomidate is immunologically 'clean', but it inhibits cortisol synthesis

Preanesthetic medicationPreanesthetic medication

Before surgery. Aims are to provide:Before surgery. Aims are to provide:

1. Anxiolysis and amnesia1. Anxiolysis and amnesiaBenzodiazepines – temazepam, diazepam, midazolam.Benzodiazepines – temazepam, diazepam, midazolam.2. Analgesia2. Analgesia – morphine, fentanyl, – morphine, fentanyl,

3. Anticholinegic drugs.3. Anticholinegic drugs. To prevent gastric and To prevent gastric and bronchial secretion and vomiting (H2 blockers bronchial secretion and vomiting (H2 blockers (ranitidine, cimetidine, atropine, scopolamine, (ranitidine, cimetidine, atropine, scopolamine, chlorpromazinechlorpromazine).).

4. Muscle relaxation 4. Muscle relaxation

Medication during and afterMedication during and after surgerysurgery

During surgeryDuring surgery a. Induction – a. Induction – thiopentone, thiopentone,

etomidate or propofol,etomidate or propofol,b. Maintanance b. Maintanance usuallyusually with nitrous oxide and with nitrous oxide and

oxygen + vollatile agent oxygen + vollatile agent (halotane or isoflurane) i.v. (halotane or isoflurane) i.v.

less oftenless often with nitrous oxide with nitrous oxide and oxygen + analgesic and oxygen + analgesic (fentanyl, morphine, (fentanyl, morphine, pethidine) + competitive pethidine) + competitive neuromuscular blocking neuromuscular blocking agent if muscular relaxation agent if muscular relaxation is needed (for abdominal is needed (for abdominal surgery),surgery),

After surgeryAfter surgerya. Relief of pain a. Relief of pain

(morphine and its (morphine and its derivates are derivates are commonly used and commonly used and other analgesics other analgesics NSAIDs).NSAIDs).

b. Postoperative b. Postoperative vomiting – vomiting – antiemetics antiemetics (metoclopramide, (metoclopramide, ondansetron, ondansetron, prochlorperazine).prochlorperazine).