INDUCTION AGENTS BOTH IV AND INHALATIONAL IN ANAESTHESIA

A lecture presentation on Induction agents used Anaesthetia. These agents are either inhalational or intravenous.
The topic also covers side effects and pharmacology of these agents.

1. INDUCTION AGENTS IN ANAESTHESIA AND WHAT IS NEW? DR UWANDU CHIGOZIE CONSULTANT ANAESTHESIOLOGIST UNIVERSITY OF PORT HARCOURT TEACHING HOSPITAL PORT HARCOURT RIVERS STATE

2. Anaesthesia that is too light has its hazards-mainly for the Surgeons!!

3. OUTLINE Introduction Historical background Routes of induction Indications for inhalational induction Challenges The ideal inhalational agent Intravenous induction The ideal IV induction drug Novel IV anaesthetic agents Key points Conclusion References

4. INTRODUCTION I nduction agents in anesthesia are drugs used to induce unconsciousness during general anaesthesia before surgery or other painful procedures. General anesthesia is an altered physiological state characterized by reversible loss of consciousness, analgesia, amnesia, and some degree of muscle relaxation. A pharmacologically induced reversible loss of unconsciousness with the inability to respond to a surgical stimulus. T he discovery of GA drugs has revolutionized modern medicine and marked the birth and growth of modern surgery.

5. Historical background Davy’s ‘ researches chiefly concerning nitrous oxide was published in 1799 On 16 October 1846, at Massachusetts general hospital in Boston, the first public demonstration of ether anaesthesia by William Morton A professor of obstetrics in Edinburgh, James Simpson, in November 1847 introduced chloroform A more potent agent, worked well and was easier to use than ether and so, despite its drawbacks, became very popular. John snow, a London physician , in 1853 administered chloroform to Queen Victoria for the birth of Prince Leopold, and  Princess Beatrice in 1857 .

6. Anaesthetic agents in the decade 1835-1845

7. Then came the introduction of intravenous induction agents; barbiturates which enabled the patient to go off to sleep quickly, smoothly and pleasantly and therefore avoided any unpleasant inhalational agents 1932:Hexobarbital , became the 1 st widely used IV barbiturate. 1934:  Thiopentone first used 1941: High mortality in casualties of Pearl   Harbour: “an ideal method for euthanasia ” 1950s: Understanding of pharmacokinetics improved safety In the mid-1950s came halothane, a revolutionary inhalational agent, which was much easier to use. 1965:Ketamine was introduced into clinical practise 1973:Etomidate 1986:Propofol

8. Most of these drugs have since been refined so there are now much more potent and less toxic induction agents Anaesthesia is now very safe, with mortality of less than 1 in 250,000 directly related to anaesthesia in most high income countries The introduction of anaesthesia changed surgery; it could now be more precise and more accurate and could move into ‘forbidden areas’ of abdomen, chest and brain

9. The course of general anaesthesia can be divided into 3 phases Induction Maintenance Emergence Induction; putting to sleep Selecting the induction agent to use depends on the patients health, the type of procedure, the expected onset and duration of anaesthesia

10. Routes of Induction Inhalational Ether Gaseous- N2O Volatile liquids(Halothane and Sevoflurane ) Intravenous route Propofo l Thiopentone Etomidate Ketamine Midazolam Opioids(fentanyl) I ntramuscular R ectal

11. Mechanism of Action the Meyer –Overton reported that the potency of anaesthetic agents correlated with their lipid solubility, They surmised the Unitary Hypothesis that anaesthetics acted nonspecifically on the lipid component of the neuronal cell wall Most present-day anaesthetics exert significant effects on ligand gated ion channels, in particular GABA ( gamma aminobutyric acid)A receptors and also at other proteins responsible for neuronal activities No single unifying target can explain the action of all modern general anaesthetics . Some anaesthetics like Ketamine, Nitrous oxide and xenon deliver their effects through inhibition of N-methyl- Daspartate (NMDA) receptors on excitatory glutaminergic neurones

12. GABAA complexes form chloride anion channels and are molecular targets for benzodiazepines, barbiturates, i.v. anaesthetics ( propofol and etomidate), and volatile inhalation anaesthetics . Through its actions on GABAA receptors in the hippocampus and prefrontal cortex, propofol inhibits acetylcholine release → the sedative effects of Propofol , also induces inhibition of NMDA receptors that may contribute to its central effects Ketamine inhibits the excitatory neurotransmitter glutamate at NMDA receptors. It functions at the thalamus (which relays sensory impulses from reticular activating system to the cerebral cortex) and the limbic cortex (which is involved with the awareness of sensation).

13. Indications for inhalational induction Young children Upper airway obstruction e.g epiglottitis Lower airway obstruction with foreign body Bronchopleural fistula or empyema No venous access

14. Challenges of Inhalational Induction Slower induction of anesthesia Problems of stage 2 of anaesthesia Airway obstruction, bronchospasm Laryngospasm, hiccups Environmental pollution

15. The Ideal Inhalational agent Pleasant odour , non-irritant to the respiratory tract to allow pleasant and smooth induction of anaesthesia Possess a low blood/gas solubility, which promotes rapid induction and recovery Neither flammable or explosive Chemically stable in storage and not interact with breathing circuits or sodalime Unconciousness with analgesia and muscle relaxation Potent to allow the use of high inspired oxygen concentrations when necessary

16. Non toxic and not provoke allergic reactions Minimal depression of the CVS and RS Not interact with other drugs e.g pressor agents or catecholamines Not metabolized in the body, Completely inert, eliminated completely and unchanged from the lungs Easy to administer with standard vaporizers Not epileptogenic or raise ICP MAC = Minimum Alveolar Concentration (of inhaled anesthetic) required to prevent 50% of subjects from moving in response to noxious stimulus ( eg , skin incision). Potency = 1/MAC.

17. Diethyl Ether First used by William T.G Morton in the USA in 1846 Provides surgical anaesthesia without respiratory depression Slow rate of induction and recovery Dropped because of its flammability

18. CHLOROFORM James Simpson in 1847 brought attention to it Pleasant odour Nonflammable Severe CVS depression……death Dose dependent hepatotoxcity

19. Nitrous Oxide Sweet smelling, non-irritant and colourless gas Good analgesic via activation of opoid receptors in periaqueductal area of midbrain Weak anaesthetic - cant produce an adequate depth of anaesthesia , used with volatile MAC is 105% Inhibitory effect on N-methyl D-aspartate (NMDA) glutamate receptors Relatively nontoxic SG 1.5, Boiling point- -87o C, non-flammable, supports combustion

20. Stored in blue cylinder at 50 ATM Filling ratio = weight of nitrous oxide in the cylinder/ Weight of water the cylinder could hold (0.67 in the tropics and 0.75 in the temperate climate) No significant effect on respiration and CVS . Marrow depression and agranulocytosis with very prolonged use. Premix with oxygen for pain relief ratio, 1:1 D iffusion hypoxia; switch off nitrous oxide first and continue administration of oxygen for a few minutes. This is because nitrous oxide diffuses 30 times faster than nitrogen from the blood to fill gas filled cavities (i.e. alveolar space), thus resulting in hypoxia.

21. H alothane Most used inhalational anaesthetic drug in Nigeria. 2 bromo 2 chloro 1,1,1 trifluroethane Colourless with pleasant odour …..Smooth induction Stored in amber bottles cos its decomposed by light Corrodes metals in vaporizers and breathing circuits Highest blood gas solubility coefficient Good anaesthetic but poor analgesic Minimal stimulation of salivary and bronchial secretions Bronchodilation Potent depressant of myocardial contractility and myocardial metabolic activity due to inhibition of glucose uptake by myocardial cells CBF and ICP increase

22. Boiling point 50 C, blood: gas solubility 2.4, MAC 0.75 Non- flammaable Bradycardia may occur and is reversible with atropine. Increased myocardial irritability may predispose to dysrhythmias in the presence of adrenaline ventilation is reduced in dose related manner. relaxes the uterus and may contribute to postpartum hemorrhage halothane induce hepatitis is very rare Postoperative shivering – halothane shakes may occur so patient should be kept warm

23. Sevoflurane Currently the best An excellent choice for induction of anaesthesia and for paediatric anaesthesia Pleasant odour Low blood gas solubility(0.65)……smooth induction Halogenated with fluorine , MAC 2.0 CVS- mild depression of myocardial contractility

24. Respiratory system- depresses respiration. Cerebral- slight increase in cerebral blood flow and intracranial pressure. Cerebral metabolic oxygen requirement decreases . No seizure activity has been reported . Neuromuscular- adequate muscle relaxation for intubation of children after sevoflurane induction Renal – no evidence of nephrotoxicity even though inorganic fluorine is a by product. Liver – decrease portal vein blood flow but increases hepatic artery blood flow, thus maintain total hepatic blood flow and oxygen delivery.

25. Intravenous induction Drugs are given intravenously in an appropriate dose to cause a rapid loss of consciousness. within “one arm-brain circulation time” that is the time taken for the drug to travel from the site of injection (usually the arm) to the brain, where they have their effect. To induce anaesthesia prior to other drugs being given to maintain anaesthesia . As the sole drug for short procedures. To maintain anaesthesia for longer procedures by intravenous infusion. To provide sedation.

26. Classification C lassified according to their chemical structure Barbiturates Phenols Imidazoles Phencyclidines Benzodiazepines

27. Fate of IV Induction agents On entering the blood stream, a percentage of the drug binds to the plasma proteins, with the rest remaining unbound or “free”. The degree of protein binding will depend upon the lipid solubility and degree of ionization . The drug is carried in the venous blood to the right side of the heart, through the pulmonary circulation, and via the left side of the heart into the systemic circulation. 70% of the cardiac output passes to the brain, liver and kidney ( “vessel rich organs ”) The drug then passes along a concentration gradient from the blood into the brain . The rate of this transfer is dependent on a number of factors : the arterial concentration of the unbound free drug the lipid solubility of the drug the degree of ionization.

28. Unbound, lipid soluble, unionized molecules cross the blood brain barrier the quickest. the exact mode of action of the intravenous drugs is unknown. E ach drug acts at a specific receptor – GABA-A, NMDA and acetylcholine receptors . Following the initial flooding of the CNS and other vessel rich tissues with non-ionized molecules, the drug starts to diffuse in to other tissues that do not have such a rich blood supply. This secondary tissue uptake by skeletal muscle, causes the plasma concentration to fall, allowing drug to diffuse out of the CNS down the resulting reverse concentration gradient and leads to the rapid wake up seen after a single dose of an induction drug. Metabolism and plasma clearance are more important following infusions and repeat doses of a drug.

29. when cardiac output is reduced (shocked patients, the elderly), the body compensates by diverting an increased proportion of the cardiac output to the cerebral circulation. a greater proportion of any given drug will enter the cerebral circulation, therefore the dose of induction drug must always be reduced. Furthermore , as global cardiac output is reduced, the time taken for an induction drug to reach the brain and exert its effect is prolonged . The slow titration of a reduced dose of drug is the key to a safe induction in these patients.

30. The ideal IV induction drug Water soluble & stable in solution Stable on exposure to light Long shelf life No pain on intravenous injection Painful when injected into an artery Non-irritant when injected subcutaneously Low incidence of thrombophlebitis Cheap . Rapid onset in one arm-brain circulation time Rapid redistribution to vessel rich tissue

31. Rapid clearance and metabolism No active metabolites High therapeutic ratio ( ratio of toxic dose : minimally effective dose ) Minimal cardiovascular and respiratory effects No histamine release/hypersensitivity reactions No emetic effects No involuntary movements No emergence nightmares No hang over effect No adrenocortical suppression Safe to use in porphyria

32. Sodium Thiopental (STP) also referred to as thiopentone and Pentothal) is a barbiturate, a hygroscopic (attracts moisture from the atmosphere) pale yellow powder. Ampoules have 500mg of sodium thiopental with 6% sodium carbonate in an inert atmosphere of nitrogen. Reconstituted with 20ml of water this yields a 2.5% solution (25mg/ml) with a pH of 10.8. The alkaline solution is bacteriostatic and safe to keep for 48 hours . A dose of 4-5mg/kg of thiopental produces a smooth onset of hypnosis with good definitive endpoints within 30 seconds of intravenous injection. Recovery after a single dose is rapid due to redistribution and there is a low incidence of restlessness and nausea and vomiting . Thiopental is 65-85% protein bound in plasma. Enhances GABA activity Metabolism is slow and occurs in the liver.

33. Excretion of metabolites occurs mainly in the urine. Following repeated doses or infusions of thiopental, metabolism follows zero order kinetics; this means that a constant amount of drug is being eliminated per unit time, irrespective of the plasma concentration. first order kinetics; a constant fraction of drug is eliminated per unit time, i.e. dependant on plasma concentration . Zero order kinetics occur when the metabolic pathways become saturated leading to an accumulation of the active drug and delayed recovery.

34. STP directly depresses the contractile force of the heart, reducing cardiac output and BP.and a compensatory increase heart rate . decreases venous tone, causing pooling of blood in the peripheral veins; increasing the degree of hypotension, particularly in patients who are hypovolaemic (e.g. following haemorrhage ). Respiratory depression is common and a period of apnoea is usually seen following a bolus dose . Airway reflexes are well preserved in comparison with propofol Histamine release can occur which may precipitate bronchospasm. R educes cerebral blood flow, cerebral metabolic rate and oxygen demand

35. It has potent anticonvulsant properties. Following traumatic brain injury, infusion of thiopental to produce a “barbiturate coma” lowers intracranial pressure and may improve neurological outcome. The porphyrias are a group of disease characterised by overproduction and excretion of porphyrins (intermediate compounds produced during haemoprotein synthesis ). Acute attacks may be precipitated by drugs, stress, infection, alcohol, pregnancy and starvation . Thiopental may precipitate porphyria due to hepatic enzyme induction in susceptible patients, and hence it should be avoided

36. Management of intra-arterial injection Leave the needle in the artery Flush with normal saline to dilute the drug Inject a local anaesthetic – procaine 50 – 100mg (10ml of 10%) to reduce pain Inject a vasodilator – papaverine 20 – 40mg, tolazoline 40mg or phentolamine 2 – 5mg to reduce arterial spasm. Keep the arm / hand warm and elevated. Anticoagulate with heparin if indicated

37. Propofol (2,6 di- isopropylphenol ) Propofol is presented as a 1 or 2% aqueous emulsion containing soya oil, egg phosphatide and glycerol. isotonic to plasma and has a pH of 7.0 - 8.5. pain on injection into small veins. a short-acting general anaesthetic drug, with an onset of action of approximately 30 seconds. Its mechanism of action is enhacing GABA(gamma aminobutyric acid) activity leading to CNS depression. A smooth induction of anaesthesia usually follows a dose of 2-2.5mg/kg . Propofol should be titrated against the response of the patient until the clinical signs show the onset of anaesthesia ; loss of verbal contact with the patient. Following an IV bolus, there is rapid equilibration between the plasma and the highly perfused tissue of the brain Plasma levels decline rapidly as a result of redistribution, followed by a more prolonged period of hepatic metabolism and renal clearance . Moderate hepatic or renal impairment does not alter the pharmacokinetics of propofol

38. Propofol causes the most marked fall in blood pressure of all the induction drugs (due to systemic vasodilatation). an accompanying slight increase in heart rate. The fall in blood pressure is dose dependent and is most marked in the elderly and in shocked patients. This can be minimized by slow injection – avoiding inadvertent overdose. cause respiratory depression ; a period of apnoea is usually seen. Propofol also markedly reduces airway and pharyngeal reflexes, making it the ideal drug to use with the LMA. Propofol has been associated with epileptiform movements, but it is anticonvulsant in normal doses. It reduces cerebral blood flow, metabolic rate and intra-cranial pressure.

39. P rovides sedation for adult patients undergoing minor procedures and on the intensive care unit . T he most commonly used drug to provide total intravenous anaesthesia , TIVA . Propofol infusion is contraindicated for sedation in children due to concerns regarding its safety . A “ propofol infusion syndrome ”; effected children developing metabolic acidosis, lipidaemia , cardiac arrhythmias and an increased mortality. P ropofol is safe to use in patients susceptible to porphyria.

40. Etomidate an imidazole ester. as a lipid emulsion or as a clear solution containing propylene glycol at a concentration of 2mg/ml . Pain on injection is common and there is a high rate of thrombophlebitis in the post operative period . The standard induction dose is 0.3mg/kg, and recovery is rapid due to redistribution to muscle and fat . Induction of anaesthesia can be accompanied by involuntary movements which may be mistaken for generalized seizure activity. rapidly metabolized by hepatic and plasma esterases to yield inactive metabolites. Excretion is predominantly urinary and the elimination half life varies from 1 – 5 hours the least cardiovascular depression of the IV anaesthetic drugs, with only a small reduction in the cardiac output and blood pressure

41. induce anaesthesia in the shocked, elderly or cardiovascularly compromised patient . causes transient apnoea , though less so than other drugs, and can cause cough or hiccups. Recovery is frequently unpleasant and accompanied by nausea and vomiting Etomidate inhibits 11-B-hydroxylase, an enzyme important in adrenal steroid production. A single induction dose blocks the normal stress-induced increase in adrenal cortisol production for 4-8 hours, and up to 24 hours in elderly and debilitated patients . Continuous infusion of etomidate for sedation in critically ill patients has been shown to increase mortality. the use of etomidate has declined in recent years due to a perceived potential morbidity.

42. Ketamine a derivative of phencyclidine, a dissociative drug formerly used as an anaesthetic agent. R educes signals to the conscious mind from other parts of the brain, typically the senses . Ketamine is prepared in a slightly acidic solution (pH 3.5–5.5) containing 10, 50 or 100mg of Ketamine per ml. Standard ampoules also contain a preservative which prevents intrathecal or epidural use. Ketamine has hypnotic, analgesic and local anaesthetic properties. Noncompetitive antagonism at the N-methyl-D-aspartate (NMDA) receptor in the brain and spinal cord.

43. Other mechanisms of action of ketamine may include an interaction with opioid receptors; ‘ dissociative’ anaesthesia ; catalepsy in which the eyes may remain open with a slow nystagmic gaze & the corneal and light reflexes remain intact . Varying degrees of hypertonus and occasional purposeful movements unrelated to painful stimuli can be seen, even during adequate surgical anaesthesia . Psychic sensations including alterations in mood state, floating sensations, vivid dreams and hallucinations are common during emergence. Benzodiazepine premedication reduces this. the ketamine molecule exists in two stereo-isomers - R and S ketamine and they exhibit pharmacological and clinical differences.

44. S-ketamine is three times as potent as R-ketamine and the recovery time and psychomimetic sequelae are reduced. Ketamine is unique as it can be administered i.v , i.m , orally, nasally, rectally, and the preservative-free solution epidurally . For induction of anaesthesia a dose of 0.5–1.5 mg/kg can be given i.v , or 4 –10 mg/kg i.m . The onset of action is slower than other induction drugs (unconsciousness in 1-2min for IV use), and the end point may be difficult to judge with patients staring into the distance for a short period of time. The duration of action of a single dose is approximately 5-10 minutes

45. metabolised in the liver, and conjugated metabolites are excreted in the urine. The elimination half life is 2.5 hours. Associated with tachycardia, increased blood pressure, and increased cardiac output. This makes ketamine useful in the shocked, unwell patient. a minimal effect on central respiratory drive, although a transient decrease in ventilation can occur after bolus administration. T he protective airway reflexes remain relatively preserved, makes ketamine the ideal anaesthetic drug to be used in the prehospital environment. increase salivation which can lead to upper airway obstruction ; reduced by premedication with antimuscarinic drug such as glycopyrrolate .

46. Ketamine is a bronchial smooth muscle relaxant, and therefore has a special role in the management of severe asthma. ketamine was thought to increase cerebral blood flow and intracranial pressure, thereby limiting its use in patients with a head injury. However , providing hypoventilation and hypercapnia are avoided, this does not occur some evidence that ketamine may have some cerebral protective effects via its action on NMDA receptors. Ketamine is thought to be safe to use in porphyria.

47. Midazolam can be used to induce anaesthesia . Midazolam is a water soluble benzodiazepine. It comes as a clear solution, usually at a concentration of 2mg/ml . Midazolam exhibits a form of isomerism known as tautomerism ; In the ampoule, as an acidic solution, the molecule exists in an ionized form. At physiological pH the molecule changes to becomes a highly lipid soluble unionized ring, accounting for its rapid onset of action. It does not cause pain on injection . acts at specific receptors closely allied to the GABA-A receptor. Activation of the benzodiazepine receptor increases chloride influx to neuronal cells via the GABA-A receptor, causing neuronal hyperpolarisation and the clinical effects seen.

48. Its short duration of action and amnesic properties . In children it is useful as premedication - 30 minutes preoperatively at an oral dose of 0.5mg/kg. used for sedation at a dose range of 0.05-0.1mg/kg (IV ) and as a sole iv induction drug, at a dose of 0.3mg/kg, but its onset is slow, limiting its use. It undergoes hepatic metabolism and renal elimination. In the elderly, the lower hepatic blood flow and metabolic activity result in a significantly prolonged half life. mild cardiovascular and respiratory depressant effects, so monitoring is important duration sedation. The effects of midazolam can be reversed with flumazenil, a competitive benzodiazepine antagonist; given by intravenous injection in 100 mcg increments and should act with in 2 minutes.

49. Intramuscular Induction Mostly for children especially if cognitively impaired and extremely uncoperative Painful Slow onset Risk of sterile abscess formation ketamine

50. Rectal induction Previously esp for children less than 5 years Methohexital 15 to 25mg/kg, midazolam 1g/kg, ketamine 5m/kg or thiopentone 30 to 40mg/kg Poor bioavailability Laryngospasm Delayed recovery Sepsis may occur in immune compromised patients

51. Novel IV anaesthetic agents 1.Propofol derivatives PFO713 similar to propofol but contains larger side chains at the 2, 6 positions on the phenol ring . It contains two defined chiral centres also a potent GABAA receptor modulator producing reliable anaesthesia after bolus injection without pain and An improved cardiovascular side-effect profile compared with propofol . This molecule has a reduced aqueous phase concentration compared with propofol , which may explain its lack of pain on injection. However, its performance after continuous infusion remains to be evaluated in clinical trials.

52. Fospropofol Water soluble prodrug that is metabolized in vivo to propofol , phosphate and formaldehyde. It produces more complete amnesia and better conscious sedation for endoscopy than midazolam plus fentanyl. A slower onset and slower recovery than propofol It does not cause pain on injection. However, it may cause perineal pain or paraesthesia . It has been released in the USA but its performance in comparative clinical trials will determine whether it will stay.

53. 2.Etomidate derivatives Methoxy -carbonyl-etomidate (MOC etomidate) This rapidly metabolized analogue of etomidate causes only transient (min) adrenocortical suppression. H ighly cardiovascularly stable after single-bolus injection in experimental animal models . Like the newer propofol derivatives, however, its safety in continuous infusion remains to be evaluated. MOC etomidate is less potent than the etomidate and propofol and given its brief duration of action, maintaining anaesthesia by infusion will require relatively large doses However , adrenocortical suppression is likely for the duration of any infusion, potentially limiting its clinical applicability. It is rapidly metabolized to carboxylic acid and methanol .

54. Carboetomidate An etomidate analogue, with an alternative mechanism of minimizing adrenocortical suppression; Etomidate suppresses steroidogenesis by inhibiting the cytochrome P450 enzyme, 11 b-hydroxylase . Carboetomidate is modified in that it lacks a nitrogen atom within the imidazole ring of etomidate, which greatly reduces its ability to inhibit steroidogenesis, thereby minimizing adreno -cortical suppression It may prove suitable for maintenance of anaesthesia or sedation where cardiovascular stability is particularly indicated, but again requires investigation in comparative clinical trials .

55. 3. Midazolam derivative; Remimazolam is a ultra short acting benzodiazepine with GABA enhancing actions. As the name implies, remimazolam combines the properties of midazolam and remifentanil. It acts on GABA receptors, as does midazolam, and exhibits pharmacokinetic properties common to the ester-based opioid remifentanil. The addition of a benzodiazepine to remifentanil targets a hopeful synergy between the two, with improved sedation and anxiolysis . Outpatient settings where rapid recovery is desirable . While remimazolam was initially developed for use as a drug for procedural sedation, more studies are currently focused on utilizing this agent for the induction and maintenance of general anesthesia .

56. ADV6209: new formulation of oral midazolam A novel formulation of oral midazolam is currently under investigation, with phase I and II trials now started in both adults and children . This innovative 0.2% aqueous midazolam solution has been formulated by combining a sweetener (sucralose), an aroma (orange aroma), and y- cyclodextrin with a citric acid solution of midazolam. .

57. Neurosteroids( eg Ganaxolone ); MOA through GABA A receptor modulation which are still under investigation for their anaesthetic properties Promises to have a good safety profile, rapid onset and minimal adverse effects

58. S-ketamine=While ketamine is well-known, the S-enantiomer offers potent analgesia and anesthesia with fewer psychomimetic effects compared to the racemic mixture of ketamine. Increasingly used in both anesthesia and for treating depression, showcasing its versatility Dexmedetomidine : Although not a traditional induction agent, it is being investigated for its use in combination with other drugs to provide a smoother induction and improved perioperative hemodynamic stability. Provides sedation and analgesia with minimal respiratory depression, making it an attractive option.

59. Xenon was first administered to humans in 1951. It offers the advantages of having the lowest blood gas partition coefficient of any anesthetic, being non-flammable, being a non-teratogen with a minimal effect on the cardiovascular system, and having no deleterious effects on neurocognition in non-human models . A pproved for adult use in the EU in 2007, and the minimum alveolar concentration of xenon in adults is 63 %. A recent meta-analysis indicates that, in adults, xenon offers advantages of greater hemodynamic stability and a faster emergence from both inhalational and propofol anesthesia. A study is currently underway to examine the role of xenon as an adjuvant to inhalational anesthesia in the pediatric population undergoing interventional procedures of cardiac catheterization. The future implications for the application of xenon as a neuroprotective agent and for sedation have yet to be explored.

60. Key points The precise mechanism of action of IV induction remains elusive, but most agents exert their action through potentiation of GABA A receptor activity Potentiation of GABAA receptors increases chloride ion conductance, resulting in inhibitory post-synaptic currents and ultimately inhibition of neuronal activity. A naesthetic agents have wide-ranging effects not only in the central nervous system, but also in the cardiovascular, respiratory, and other major organ systems. Newer drugs are being developed, which are structurally related to propofol and etomidate. These novel agents may overcome some of the undesirable side-effects associated with their original counterparts.

61. CONCLUSION Induction agents are anaesthetists’ handy tools to produce hypnosis. An ideal agent is yet to be produced. Also their exact mechanism of actions are yet to be elucidated!! Most of the agents available now can be used safely in anaesthetic practice.

62. REFERENCES Hirsh I, Gary B S .Anaesthesia & Intensive care A-Z Encyclopedia of principles and practice 3 rd Edition,(2005), Pg 281-282, 317-318, 444, 529-530 . Campagna J, Miller K, Forman S. Mechanisms of action of inhaled anesthetics. N Engl J Med 2003; 348: 2110– 24 Peck T, Hill S, Williams M. Pharmacology for anaesthesia and intensive care. Greenwich medical media, 2003. Fryer M. Intravenous induction agents. Anaesthesia and intensive care medicine; 5(9): 317-32. • Pinnock C, Lin T, Smith T. Fundamentals of anaesthesia . Greenwich medical media, 2003 Morgan G. E. Clinical anaesthesiology 4 th Edition Chapter 8 Sneyd JR, Rigby-Jones AE. New drugs and technologies, intravenous anaesthesia is on the move again. Br J Anaesth 2010; 105: 246– 54 Continuing Education in Anaesthesia , Critical Care & Pain j Volume 14 Number 3 2014 103

63. THANK YOU FOR LISTENING ......