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Lecture notes of International Edcation General anaesthetics 1. Definition General anaesthetics (GAs) are drugs which producereversible loss of all sensations and consciousness. General anaesthetics (GAs) are drugs used to depress the CNS to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures. Triad of General Anesthesia: –need for unconsciousness –need for analgesia –need for muscle relaxation 2. history Joseph Priestly – discovers N 2 O in 1773 Crawford W. Long – 1842. Country Dr. in Georgia first used ether for neck surgery. Did not publicize, in part because of concerns about negative fallout from “frolics”. Tried to claim credit after Morton’s demonstration but…Important lesson learned – if you don’t publish it, it didn’t happen. Sir Humphrey Davy – experimented with N 2 O, reported loss of pain, euphoria Traveling shows with N 2 O (1830’s – 1840’s) Horace Wells 1844. Demonstrated N 2 O for tooth extraction – deemed a failure because patient “reacted”. William Morton, dentist – first demonstration of successful surgical anesthesia with ether 1846 John C. Warren, surgeon at MGH says “Gentlemen, this is no humbug!” – birth of modern anesthesia Dr. John Snow administers chloroform to Queen Victoria (1853) – popularizes anesthesia for childbirth in UK He becomes the first anesthesia specialist. Note that ether became anesthesia of choice in US, chloroform in UK 3. Phases of General Anesthesia (1)Induction- initial entry to surgical anesthesia (2)Maintenance- continuous monitoring and medication. Maintain depth of anesthesia, ventilation, fluid balance, hemodynamic control, hoemostasis (3)Emergence- resumption of normal CNS function Stage I: Analgesia─Starts from beginning of anaesthetic inhalation and lasts upto the loss of consciousness.Patient remains conscious and feels a dream like state. Reflexes and respiration remain normal. Use is limited to short procedures. Stage II: Delirium (Excitement) ─From loss of consciousness to beginning of regular respiration. Apparent excitement is seen. Heart rate and BP may rise , and pupils dilate. No stimulus should be applied or operative procedure carried out during this stage. Stage III: Surgical (continued) ─Extends from onset of regular respiration to cessation of spontaneous breathing. This has been divided into 4 planes: Plane 1 : 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. Plane4:Intercostal paralysis shallow abdominal, respiration, dilated pupils. Stage IV: Medullary Depression ─ Cardio-respiratory collapse due to depression of respiratory and vasomotor centers of medulla. Fortunately, neurons are relatively insensitive to depressant effects of GA.Observed only at toxic doses. Fixed, dilated pupils = signs of pending coma or death 4.Mechanism of action In summary , general anaesthetics inhibit excitatory channels (especially glutamate receptors) and facilitate inhibitory channels (particularly GABAA but also glycine and certain potassium channels), and these interactions are targeted at specific hydrophobic domains of channel proteins. Individual anaesthetics differ in their actions and affect cellular function in several different ways. 5. Pharmacokinetics of inhaled GAs Factors that influence the uptake and distribution of GAs : Solubility Blood/Gas Partition coefficient Oil/Gas partition coefficient GA Concentration in the inspired air: inspired anaesthetic concentration increase the rate of induction by increasing the rate of transfer into the blood. Pulmonary ventilation: hyperventilation increases the speed of induction of anesthesia with inhaled anesthetics that would normally have a slow onset Pulmonary blood flow: an increase in pulmonary BF slows the rate of rise in arterial tension particularly for those inhaled GAs with moderate to high blood solubility – speed of onset of anesthesia is reduced. Arteriovenous concentration gradient The important characteristics of Inhalational anesthetics which govern the anesthesia are : Solubility in the blood (blood/gas partition coefficient)─It is a measure of solubility in the blood.It determines the rate of induction and recovery of Inhalational anesthetics. Lower the blood/gas coefficient is faster the induction and recovery such as Nitrous oxide. Higher the blood/gas coefficient is slower induction and recovery such as Halothane. Solubility in the fat (oil/gas partition coefficient) ─It is a measure of lipid solubility. Lipid solubility - correlates strongly with the potency of the anesthetic. Minimum alveolar Concentration (MAC) ─ A measure of inhalational anesthetic potency. It is defined as the minimum alveolar anesthetic concentration ( % of the inspired air) at which 50% of patients do not respond to a surgical stimulus.Values of MAC are additive: 6.commonly used GAs (1) Ether First anesthetic (1842) Liquid at room temp, readily vaporizes & easy to administer Inflammable, explosive & irritating (2)Chloroform Next anesthetic that received wide use (1847) Have a pleasant odor, nonflammable Is hepatotoxic & severe CV depressant (3)Cyclopropane Accidentally discovered -1929 Flammable & explosive (4)HALOTHANE (Fluothane) Very widely used in children. Not so in adults due to fear of hepato-toxicity CVS ─ Decreases mean arterial pressure, decreases Cardiac output and myocardial depressant effects. Respiration system ─ Decreases TV, minute volume, mucociliary function. Increases RR. Brain ─ Increases cerebral BF, decreases cerebral vascular resistance with decreased metabolic rate of brain. Renal ─ Decreases GFR, RPF. Increases FF,RENAL vascular resistance. Liver ─ Decreases hepatic BF and is hepatotoxic Advantages ─ Good Physical properties (pleasant odor, non-explosive);Potent Anaesthetic (MAC 0.75%); Potent Inhibitor of Laryngeal and Pharyngeal Reflexes; Potent Relaxant of Masseter Muscles – easy intubation; Does not cause Laryngospasm, Bronchospasm and Coughing ; Produces Bronchodilatation (useful in asthmatic patients) ; Used to produce Controlled Hypotension è Bloodless field during plastic/vascular surgery Disadvantages ─ Poor muscle relaxant ; Respiration depressant ; Profound hypotension if given in more than 2% concentration ; Increases Parasympathetic tone cause Bradycardia; Sensitizes the ventricular muscle & conduction tissue to Adrenaline cause Arrhythmias (5) ISOFLURANE Most widely used volatile anesthetic. It is similar to Enflurane in many aspects.Resemble Halothane Except: Less incidence of hypotension Less sensitization of heart to Catecholamines Less toxic Powerful Coronary vasodilator No pro-convulsive properties Not cost effective (6) NITROUS OXIDE (N2O) Rapid onset & offset Good analgesic Entonox (50% oxygen & nitrous oxide) for labor pain Low potency (MAC >100) Used mostly as an adjuvant Second gas effect DIffusion hypoxia Toxicity Inhibits methionine synthetase Leucopenia & megaloblastic anemia Expands gas spaces in the body Advantages ─ Non-inflammable Non-irritating Very Potent Analgesic: 30 – 40 % Analgesia 65 – 70 % Loss of consciousness 80 % plane one of Surgical Anaesthesia 80 % will produce hypoxia Non-explosive, however supports combustion Rapid induction and recovery. Use in procedures of short durations (tooth extraction, obstetrical analgesia, cleaning and debridement of wounds and cauterization). First Stage of Parturition. Disadvantages ─ Not a potent anesthetic & muscle relaxant Violent excitement (laughing gas) Carbon dioxide accumulation and hypoxia Specialized apparatus to control its administration Expansion of pocket of trapped air( pneumothorax, intestinal loop, renal cyst, hepatic, pneumothorax encephalogram because Blood: Gas Partition Coefficient is 34 times higher than that of Nitrogen and a lot of it is available for exchange with Nitrogen. 80 times expansion takes place in the pockets). Increase the frequency of abortion & fetal abnormalities 7. Intravenous Induction Agents Commonly used IV induction agents include Prpofol, Sodium Thiopental and Ketamine. They modulate GABA ergic neuronal transmission. (GABA is the most common inhibitory neurotransmitter in humans). The duration of action of IV induction agents is generally 5 to 10 minutes, after which time spontaneous recovery of consciousness will occur. (1) Thiopentone sodium (Pentothal) Very high lipid solubility Rapid action because of rapid transfer across blood – brain barrier; short duration (about 5 minutes) because of redistribution, mainly to muscle and fat. Slowly metabolised and liable to accumulate in body fat; therefore, may cause prolonged effect if given repeatedly. Ease of Administration Non-explosive Induction is rapid & pleasant No irritation of mucous membranes Less incidence of vomiting & excitement No sensitization of myocardium to Adrenaline No incidence of post operative vomiting Quick recovery Low incidence of post-anaesthetic complications Stages of anaesthesia cannot be recognized Pupils remain normal or constricted During induction unpleasant and fatal reactions like Apnea, Coughing, Hiccough, Laryngospasm & Bronchospasm may develop. Depression of Respiration centre Depression of Vasomotor centre & Myocardium Rapid injection may cause Hypotension & Cardiac Arrhythmias Inadequate Muscular Relaxation (2) Propofol Most popular IV anaesthetic Rapid OOA like barbiturates Rapid recovery Reduction in postop N & V and a sense of well being Used for both induction & maintenance MOA:Facilitate GABA mediated inhibition at GABAA receptor site. GABAA receptor chloride channel is a major mediator of inhibiting Synaptic transmission. Rapid Induction Very rapid recovery as Compared to Thiopental, without any hangover effect Patient feels better in immediate post operative period – No hangover, no N & V, euphoric effect. Post operative nausea and vomiting is uncommon as has antiemetic actions. No cumulative effect But it is Very expensive; Apnoea can occur ; CVS depression ; Pain at site of injection ; Clinical infections (3) Ketamine Ketamine is a general dissociative anaesthetic. Ketamine is classified as an NMDA Receptor Antagonist. The effect of Ketamine on the respiratory and circulatory syst ems is different . When used at anaesthetic doses, it will usually stimulate rather than depress the circulatory system. MOA: Involve the blockade of the membrane effects of the excitatory NT glutamic acid at the NMDA (N – methyl – D - aspartate) receptor sub type.The drug exerts its effect by entering and blocking the open channels (4) Benzodiazepines ─Diazepam, Lorazepam & Midazolam Not normally used as GA Produce a slower onset of CNS depression-not adequate for surgical anesthesia stage Using larger doses to achieve deep sedation prolongs the postanesthetic recovery period, also can produce high incidence of anterograde amnesia Depress respiration (5) Opiod analgesics Used for pre-anaesthetic medication Used for induction of anaesthesia Used for Neurolept analgesia & Neurolept anaesthesia GAs in high doses in combination with large doses of BDZs --- in cardiac/major surgery in pts having Low circulatory reserves . For conscious sedation with BDZ. (6) Neuroleptanesthesia It is a method of IV anaesthesia which combines the use of a neuroleptic drug with a narcotic analgesic drug. A dministration of such a combination produces a state which differs from the classical general anaesthesia in that the subject is conscious and is able to cooperate during the operative procedure . The most common combination is that of Droperidol (neuroleptic) and Fentanyl (opioid analgesic) (7) Neuromuscular-blocking drugs Block neuromuscular transmission at the neuromuscular junction. Used as an adjunct to anesthesia to induce paralysis. Mechanical ventilation should be available to maintain adequate respiration.