General anaesthetics

1. General anaesthetics Anton Kohút

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

3. General anaesthetics

4. History of general anaesthesia • Hwa Tuo in the second century performed operations under general anaesthesia with "foamy narcotic powder" • William Mortonon September 30, 1846, etherized Boston merchant Eben Frost before extracting his ulcerous tooth (110-208) (1819 - 1868)

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

6. Drugs given to induce or maintain general anaesthesia are either given as: • Gases or vapours (inhalational anaesthetics- volatileliquids or gases and are usually delivered using an anaesthesia machine. • Injections Most commonly these two forms are combined, with an injection given to induce anaesthesia and a gas used to maintain it,

7. I. Inhalation GA Halothane Nitrouse oxide Enflurane Isoflurane Desflurane II. Intravenous GA Thiopental Etomidate Ketamine Propofol Groups of GA most commonly these two forms are combined, with an injection given to induce anaesthesia & a gas used to maintain it III. Neurolept-analgesia Droperidol + Fentanyl

8. Inhalation anaesthetics

9. 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

10. Characteristics of inhalation GA 1. are nonspecific, they do not act by interacting with specific one receptor (there are not specific antagonists) 2. effects: hypnosis, analgesia sceletal muscle relaxation, reduction of certain autonomic reflexes (there are among GA quantitative defferences). 3. elimination is mainly by pulmonary rout (do not depends on the hepatic metabolism or renal excretion). 4. At supra-anaesthetics doses all GA can cause the death by the loss of cardiovascular function and respiratory paralyses.

11. Anaesthetics disolves in the phospholipids bilayer of neuronal mambrane, causing membrane expand, this impedes opening of ion channels necessary for generation and propagation of action potential Mechanism of action of GA Lipid -volume expansion theory

12. Mechanism of action Lipid theory GA exert their action by acting on the plasma membrane. The potency of the drug has a direct, positive correlation with the lipid solubility of the blood. - increased fluidity of the membrane.

14. Extent and rate of GA • To achieve their effects, must pass from the alveolar air into the blood and hence into the CNS. Extent and rate depend upon: • concentration (or partial pressure), • solubility - GA with low solubility produce rapid induction and recovery –nitrous oxide and vice versa –halothane), • pulmonary physiology(ventilation, blood flow).

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

18. Figure 15-4. Distribution of cardiac output and volume capacity for general anesthetics among the major tissue compartments. The tissues of the body can be divided into four groups based on their level of perfusion and their capacity to take up anesthetic. • These include the Vessel-Rich Group (VRG), • Muscle Group (MG), • Fat Group (FG), and • Vessel-Poor Group (VPG). • (The contribution of the VPG is generally ignored in most pharmacokinetic models of anesthesia.) The VRG, which contains the internal organs including the brain, constitutes a small percentage of the total body weight (9%), has the lowest capacity for anesthetic, and receives most of the cardiac output (75%). The high perfusion and low capacity allow PVRG to equilibrate rapidly with Part. Also, the VRG makes the largest contribution to the mixed venous return partial pressure PMVR, which is equal to (0.75 PVRG + 0.18 PMG + 0.055 PFG + 0.015 PVPG).

19. Stages of general anaesthesia Stage 1: analgesia - is partial until stage 2 Consciousnes and sense of touch are retained and sense of hearing is increased. Stage 2: delirium. Uncounsciuos - but automatic movements may occur. Laryngospasm may develop. Suden death, probably due to vagal inhibition of the heart or to sensitisation of the heart to adrenaline by the anaesthetic agent. Stage 3:surgical anaesthesia. This is divided into four planes. Depth is determined by changes in respiration, pupils, spontaneous eyeball position, reflexes and muscle tone. Stage 4: medullary paralysis.

21. Halothane • drugs now in common use, and it is the standard to which others are compared • has weak analgesic action • respiratory depresant – assistant ventilation • bronchial dilatation – suitable for asthmatic patients • relaxant effect on the uterus – limited using for obstetric purposes • hepatotoxic effect of metabolites

22. Halothane – cont. Heart and Circulation • A dose-dependent reduction of arterial blood pressure. • The myocardium is depressed directly and cardiac output is decreased. (cardiac output is reduced by 20% to 50%) - vagal predominance). • Increases sensitization of myocard to catecholamines • May increase the automaticity of the myocardium

23. Nitrous oxide • strong analgesic – weak anaesthetic • it does not produce surgical anaesthesia – is not used on its own anaesthesia • is used other with anaesthetics (halothane, enflurane) • nitrous oxide/oxygen mixture 50:50 – rapid analgesia – obstetric analgesia • generally is non-toxic

24. Isoflurane and enflurane are somewhat less potent than halothane (they have a smaller λ(oil/gas)), but they equilibrate faster because they have a smaller λ(blood/gas). Enflurane is metabolically defluorinated to a greater extent than isoflurane, and may thus have a greater risk of causing renal toxicity. It also induces seizure-like activity in the EEG of some patients. Isoflurane is probably the most widely used general anesthetic today. • Desflurane and sevoflurane are newer anesthetics that, by design, have low λ(blood/gas); times of equilibration between their alveolar and inspired partial pressures are nearly as short as that of nitrous oxide. Furthermore, they are much more potent than nitrous oxide because their oil/gas partition coefficients are higher.

25. Adverse effects of inhalation GA (rare, unpredictable) Idiosyncratic reactions to the volatile agents: • malignant hyperpyrexia (triggered most often by halothane with suxamethonium) • halothane hepatitis(direct toxicity from the products of reductive metabolism or immunologically mediated haptens formed by liver proteins & the products of oxidative metabolism) • prolonged nitrous oxide(N2O) exposure can cause: • bone marrow depression • life-threatening pressure effects by expansion of air-filled spaces within the body

26. Intravenous anaesthetics

27. Anesthetics potentiate the action of endogenous agonists at inhibitory receptors, such as GABAA and glycine receptors, anesthetics both decrease the EC50 of GABA (i.e., GABA becomes more potent) • Inhibit the action of endogenous agonists at excitatory receptors, such as nicotinic acetylcholine, 5-HT3, and NMDA glutamate receptors. and increase the maximum response At excitatory receptors, anesthetics decrease the maximum response while leaving the EC50 unchanged; these are the pharmacologic hallmarks of noncompetitive inhibition.

29. II. Intravenous GA • Thiopental • Etomidate • Ketamine • Propofol • Thiopental /Thiamylat/ • III. Neurolept-analgesia • Droperidol + Fentanyl

30. Intravenous anaesthetics 1. most of them have documented effect on membrane receptor thiopental (barbiturate)- GABA ketamin – NMDA receptor 2. are often used for rapid induction of anaesthesia – then combination with inhalation agent 3. advantages – rapid onset, controled dosage ease administration

31. Effects of GA on ligand-gated ion channels dark green = potentiation; dark pink = inhibition; light green = little potentiation; light pink = little inhibition; empty = no effect

33. Thiopental • most widely used ultra short-acting –onset less than 1 min. • no analgesic action • cardiac depression – decrease of cardiac output, no change in peripheral resistance • depresses respiratory center, induction often accompanied with coughing or laryngospazm • decreases cerebral blood flow and oxygen consumption in the brain

34. Propofol is an important intravenous anesthetic prepared in an intralipid formulation. This agent produces anesthesia at a rate similar to the ultrashort-acting barbiturates. • Etomidate is an imidazole that is used for induction of anesthesia because its kinetics are similar to those of propofol. This agent causes minimal cardiopulmonary depression, perhaps because of its unique lack of effect on the sympathetic nervous system. • ketamineproduces dissociative anesthesia, in which the patient seems to be awake but is actually in an analgesic and amnesic state. Ketamine has the unusual property that it increases cardiac output by increasing sympathetic outflow; for this reason, it is occasionally useful in emergency trauma situations. However, it can also produce unpleasant hallucinations. This agent is rarely used today.

35. 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

36. Preanesthetic medication Before surgery. Aims are to provide: 1. Anxiolysis and amnesia Benzodiazepines – temazepam, diazepam, midazolam. 2. Analgesia – morphine, fentanyl, 3. Anticholinegic drugs. To prevent gastric and bronchial secretion and vomiting (H2 blockers (ranitidine, cimetidine, atropine, scopolamine, chlorpromazine). 4. Muscle relaxation

37. During surgery a. Induction – thiopentone, etomidate or propofol, b. Maintanance usually with nitrous oxide and oxygen + vollatile agent (halotane or isoflurane) i.v. less often with nitrous oxide and oxygen + analgesic (fentanyl, morphine, pethidine) + competitive neuromuscular blocking agent if muscular relaxation is needed (for abdominal surgery), After surgery a. Relief of pain (morphine and its derivates are commonly used and other analgesics NSAIDs). b. Postoperative vomiting – antiemetics (metoclopramide, ondansetron, prochlorperazine). Medication during and aftersurgery