General Anesthesia

1. General Anesthesia By: Asst. Prof. Yogendra Mavai M.Pharm (Pharmacology) ShriRam College of Pharmacy Banmore

2. Contents 1-Introduction and History of General anesthesia2- Properties of ideal General anesthetic3- Classification of General anesthetic agents4- Mechanism of Anesthesia5- Stages of Anesthesia6- Inhalation anesthetic agents7- Intravenous anesthetic agent8- Complications of General anesthesia9- Preanesthetic medication

3. General Anesthetics • General anaesthetics (GAs) are drugs which produce reversible loss of all senations and consciousness. • Or, • General anaesthetics (GAs) are a class of drugs used to depress the CNS to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures.

4. History of Anesthesia • Ether synthesized in 1540 by Cordus • Ether used as anesthetic in 1842 by Dr. Crawford W. Long • Ether publicized as anesthetic in 1846 by Dr. William Morton • Chloroform used as anesthetic in 1853 by Dr. John Snow

5. History of Anesthesia

6. History of Anesthesia • Endotracheal tube discovered in 1878 • Local anesthesia with cocaine in 1885 • Thiopental first used in 1934 • Curare first used in 1942 - opened the “Age of Anesthesia”

7. Basic Principles of Anesthesia • Anesthesia defined as the abolition of sensation • Analgesia defined as the abolition of pain • “Triad of General Anesthesia” • need for unconsciousness • need for analgesia • need for muscle relaxation

8. Purpose • General anaesthesia has many purposes including: • Analgesia — loss of response to pain, • Amnesia — loss of memory, • Immobility — loss of motor reflexes, • Hypnosis — loss of consciousness, • Skeletal muscle relaxation.

9. Properties of an ideal anaesthetic • For the patient- • It should be pleasant, nonirritating, should not cause • nausea or vomiting. • Induction and recovery should be fast with no after effects. • B. For the surgeon – • It should provide adequate analgesia, immobility and • muscle relaxation. • It should be noninflammable and non explosive so • that cautery may be used.

10. C. For the anesthetist- • Its administration should be easy, controllable and versatile. • Margin of safety should be wide - no fall in BP. Heart, liver • and other organs should not be affected. • It should be potent so that low concentrations are needed and • oxygenation of the patient does not suffer. • It should be cheap, stable and easily stored. • It should not react with rubber tubing or soda lime

11. CLASSIFICATION

12. Mechanism action of anaesthetia The mechanism of action of GAs is not precisely known. A wide variety of chemical agents produce general anaesthesia. Therefore, GA action had been related to some common physicochemical property of the drugs. Minimal alveolar concentration (MAC) is the lowest concentration of the anaesthetic in pulmonary alveoli needed to produce immobility in response to a painful stimulus (surgical incision). MAC reflects capacity of the anaesthetic to enter into CNS and attain sufficient concentration in neuronal membrane.

13. Mayer and Overton (1901) proposed that the anaesthetic by dissolving in the membrane lipids increases the degree of disorder in their structure favouring a gel-liquid transition (fluidization) which secondarily affects the state of membrane bound functional proteins, or expands the membrane disproportionately (about 10 times their molecular volume) closing the ion channels.

14. The biochemical mechanism of action of general anaesthetics is not yet well understood. To induce unconsciousness, anaesthetics affect the GABA and NMDA systems. For example, halothane is a GABA agonist and ketamine is an NMDA receptor antagonist Certain fluorinated anaesthetics and barbiturates in addition inhibit the neuronal cation channel gated by nicotinic cholinergic receptor. As such, the receptor operated ion channels appear to be a major site of GA action. Unlike local anaesthetics which act primarily by blocking axonal conduction, the GAs appear to act by depressing synaptic transmission

15. Mode of administration Drugs given to induce or maintain general anaesthesia are either given as:Gases or vapours (inhalational anaesthetics), Injections (intravenous anaesthetics) Inhalation Inhalational anaesthetic substances are either volatile liquids or gases, and are usually delivered using an anaesthesia machine. Desflurane, isoflurane and sevoflurane are the most widely used volatile anaesthetics today. They are often combined with nitrous oxide. Older, less popular, volatile anaesthetic, include halothane, enflurane, and methoxyflurane. Researchers are also actively exploring the use of xenon as an anaesthetic.

16. Injection Injection anaesthetic are used for induction and maintenance of a state of unconsciousness. Anaesthetist prefer to use intravenous injections, as they are faster, generally less painful and more reliable than intramuscular or subcutaneous injections. Among the most widely used drugs are: Propofol, Etomidate, Barbiturates such as methohexital and thiopentone/thiopental, Benzodiazepine such as midazolam Ketamine is used in the UK as "field anaesthesia", for instance at a road traffic incident, and is more frequently used in the operative setting in the US.

17. Stages of anaesthesia The four stages of anaesthesia were described in 1937 GAs cause an irregularly descending depression of CNS, i.e. the higher functions are lost first and progressively lower areas of the brain are involved, but in the spinal cord lower segments are affected somewhat earlier than the higher segments. The vital centres located in the medulla are paralysed the last as the depth of anaesthesia increases. Guedel (1920) described four stages withether anaesthesia, dividing the III stage into 4 planes.

18. I. Stage- Analgesia Starts from beginning of anaesthetic inhalation and lasts upto the loss of consciousness. Pain is progressively abolished during this stage. Patient remains conscious, can hear and see, and feels a dream like state. Reflexes and respiration remain normal. Though some minor and even major operations can be carried out during this stage, it is rather difficult to maintain - use is limited to short procedures.

19. II. Stage-Delirium From loss of consciousness to beginning of regular respiration. Apparent excitement is seen - patient may shout, struggle and hold his breath; muscle tone increases, jaws are tightly closed, breathing is jerky; vomiting, defecation may occur. Heart rate and BP may rise and pupils dilate due to sympathetic stimulation. No stimulus should be applied or operative procedure carried out during this stage. This stage can be cut short by rapid induction, premedication etc. and is inconspicuous in modern anaesthesia.

20. III. Stage- Surgical anaesthesia Extends from onset of regular respiration to cessation of spontaneous breathing. This has been divided into 4 planes which may be distinguished as: •Plane 1 Roving eye balls. This plane ends when eyes become fixed. •Plane 2 Loss of corneal and laryngeal reflexes.•Plane 3 Pupil starts dilating and light reflex is lost.•Plane 4 Intercostal paralysis, shallow abdominalrespiration, dilated pupil.

21. IV. Stage- Medullary paralysis Cessation of breathing to failure of circulation and death. Pupil is widely dilated muscles are totally flabby, pulse is thready or imperceptible and BP is very low.

22. Inhalational Anesthetic Agents • Inhalational anesthesia refers to the delivery of gases or vapors from the respiratory system to produce anesthesia • Pharmacokinetics--uptake, distribution, and elimination from the body • Pharmacodyamics-- MAC value

23. Nitrous Oxide • Prepared by Priestly in 1776 • Anesthetic properties described by Davy in 1799 • Characterized by inert nature with minimal metabolism • Colorless, odorless, tasteless, and does not burn

24. Nitrous Oxide • Simple linear compound • Not metabolized • Only anesthetic agent that is inorganic

25. Nitrous Oxide • Major difference is low potency • MAC value is 105% • Weak anesthetic, powerful analgesic • Needs other agents for surgical anesthesia • Low blood solubility (quick recovery)

26. Nitrous Oxide Systemic Effects • Minimal effects on heart rate and blood pressure • May cause myocardial depression in sick patients • Little effect on respiration • Safe, efficacious agent

27. Nitrous Oxide Side Effects • Manufacturing impurities toxic • Hypoxic mixtures can be used • Large volumes of gases can be used • Beginning of case: second gas effect • End of case: diffusion hypoxia

28. Nitrous Oxide Side Effects • Inhibits methionine synthetase (precursor to DNA synthesis) • Inhibits vitamin B-12 metabolism • Dentists, OR personnel, abusers at risk

29. Halothane • Synthesized in 1956 by Suckling • Halogen substituted ethane • Volatile liquid easily vaporized, stable, and nonflammable

30. Halothane • Most potent inhalational anesthetic • MAC of 0.75% • Efficacious in depressing consciousness • Very soluble in blood and adipose

31. Halothane Systemic Effects • Inhibits sympathetic response to painful stimuli • Inhibits sympathetic driven baroreflex response (hypovolemia) • Sensitizes myocardium to effects of exogenous catecholamines-- ventricular arrhythmias • Johnson found median effective dose 2.1 ug/kg • Limit of 100 ug or 10 mL over 10 minutes • Limit dose to 300 ug over one hour • Other medications

32. Halothane Systemic Effects • Decreases respiratory drive-- central response to CO2 and peripheral to O2 • Respirations shallow-- atelectasis • Depresses protective airway reflexes • Depresses myocardium-- lowers BP and slows conduction • Mild peripheral vasodilation

33. Halothane Side Effects • “Halothane Hepatitis” -- 1/10,000 cases • fever, jaundice, hepatic necrosis, death • metabolic breakdown products are hapten-protein conjugates • immunologically mediated assault • exposure dependent

34. Halothane Side Effects • Malignant Hyperthermia-- 1/60,000 with succinylcholine to 1/260,000 without • halothane in 60%, succinylcholine in 77% • Classic-- rapid rise in body temperature, muscle rigidity, tachycardia, acidosis, hyperkalemia • family history

35. Halothane Side Effects • Malignant Hyperthermia (continued) • high association with muscle disorders • autosomal dominant inheritance • diagnosis--previous symptoms, increase CO2, rise in CPK levels, myoglobinuria, muscle biopsy • physiology--hypermetabolic state by inhibition of calcium reuptake in sarcoplasmic reticulum

36. Halothane Side Effects • Malignant Hyperthermia (continued) • treatment--early detection, d/c agents, hyperventilate, bicarb, IV dantrolene (2.5 mg/kg), ice packs/cooling blankets, lasix/mannitol/fluids. ICU monitoring • Susceptible patients-- preop with IV dantrolene, keep away inhalational agents and succinylcholine

37. Enflurane • Developed in 1963 by Terrell, released for use in 1972 • Stable, nonflammable liquid • Pungent odor • MAC 1.68%

38. Enflurane Systemic Effects • Potent inotropic and chronotropic depressant and decreases systemic vascular resistance-- lowers blood pressure and conduction dramatically • Inhibits sympathetic baroreflex response • Sensitizes myocardium to effects of exogenous catecholamines-- arrhythmias

39. Enflurane Systemic Effects • Respiratory drive is greatly depressed-- central and peripheral responses • increases dead space • widens A-a gradient • produces hypercarbia in spontaneously breathing patient

40. Enflurane Side Effects • Metabolism one-tenth that of halothane-- does not release quantity of hepatotoxic metabolites • Metabolism releases fluoride ion-- renal toxicity • Epileptiform EEG patterns

41. Isoflurane • Synthesized in 1965 by Terrell, introduced into practice in 1984 • Not carcinogenic • Nonflammable,pungent • Less soluble than halothane or enflurane • MAC of 1.30 %

42. Isoflurane Systemic Effects • Depresses respiratory drive and ventilatory responses-- less than enflurane • Myocardial depressant-- less than enflurane • Inhibits sympathetic baroreflex response-- less than enflurane • Sensitizes myocardium to catecholamines -- less than halothane or enflurane

43. Isoflurane Systemic Effects • Produces most significant reduction in systemic vascular resistance-- coronary steal syndrome, increased ICP • Excellent muscle relaxant-- potentiates effects of neuromuscular blockers

44. Isoflurane Side Effects • Little metabolism (0.2%) -- low potential of organotoxic metabolites • No EEG activity like enflurane • Bronchoirritating, laryngospasm

45. Sevoflurane and Desflurane • Low solubility in blood-- produces rapid induction and emergence • Minimal systemic effects-- mild respiratory and cardiac suppression • Few side effects • Expensive • Differences

46. Intravenous Anesthetic Agents • First attempt at intravenous anesthesia by Wren in 1656-- opium into his dog • Use in anesthesia in 1934 with thiopental • Many ways to meet requirements-- muscle relaxants, opoids, nonopoids • Appealing, pleasant experience

47. Thiopental • Barbiturate • Water soluble • Alkaline • Dose-dependent suppression of CNS activity--decreased cerebral metabolic rate (EEG flat)

48. Thiopental • Redistribution

49. Thiopental Systemic Effects • Varied effects on cardiovascular system in people-- mild direct cardiac depression-- lowers blood pressure-- compensatory tachycardia (baroreflex) • Dose-dependent depression of respiration through medullary and pontine respiratory centers

50. Thiopental Side Effects • Noncompatibility • Tissue necrosis--gangrene • Tissue stores • Post-anesthetic course