4. General Anesthetics

5. Learning objectives Explain the purpose of application of GAs Classify the GAs & the typical drugs Identify the mechanism of action of GAs Analyze the characteristic ADR of GAs At the end of this class, you are able to:

6. Definition The drugs induce the state of general anesthesia, which create a reversible condition of comfort, quiescence, and physiological stability before, during, and after a surgical procedure.

7. Why we use general anesthetics? Analgesia Skeletal muscle relaxation Sedation and reduction of anxiety Lack of awareness and amnesia Suppression of troublesome reflexes

8. Pre-anesthetics Preanesthetic medications – drugs given generally prior to anesthesia (may be given during or after, as well) in order to: Œ Decrease anxiety  Sedation Ž Provide amnesia  Relieve pre-and post-operative pain  Inhibit secretion ‘ Antiemetic

9. Preanesthetic Agents Drug ClassificationGeneric Name Desired Effect BenzodiazepinesDiazepam Midazolam Reduce anxiety, Sedation, Amnesia, “Conscious sedation” AntihistaminesHydroxyzineSedation Opioid analgesicsMorphine Meperidine Fentanyl Remifentanil Sedation to decrease tension, anxiety, and provide analgesia PhenothiazinesPromethazineSedation, antihistaminic, antiemetic, decreased motor activity AnticholinergicsAtropine Glycopyrollate Inhibit secretion, bradycardia, vomiting, and laryngospasms GI DrugsOndansetron Ranitidine Metoclopramide Antiemetic Decrease gastric acidity Decrease stomach contents

10. Inhaled Nitrous oxide Desflurane Halothane Isoflurane sevoflurane Classifications of GAs Intravenous Barbiturates Benzodiazepines Dexmedetomidine Etomidate Ketamine Opioids Propofol

11. Theories of Anesthetic Action No single theory adequately explains how anesthetics exert their pharmacological effects.  Physical theories Based on physico-chemical properties of anesthetics, e.g., lipid solubility.

12. Theories of Action  Receptor theories Anesthetics exert their effects by direct interactions with proteins (membrane receptors or ion channels). Most anesthetics increase the sensitivity of the Ɣ - aminobutyric acid (GABA) and glycine receptors to GABA and glycine respectively. Anesthetics also generally inhibit the activity of excitatory transmitters acetylcholine (Nicotinic) and serotonin. Ketamine and nitrous oxide inhibit glutamate activity via its antagonism of the action of the excitatory neurotransmitter glutamic acid on the N-methyl-D- aspartate(NMDA)  Thus neurons are hyperpolarized.

13. Inhalation Anesthetic Agents General pharmacological effects CNS – dose dependent depression of all portions of CNS. Order of sensitivity (most to least) is Reticular Arousal System(RAS) and cortex → hippocampus → basal ganglia → cerebellum → spinal cord → medulla (irregularly descending anesthesia) Autonomic nervous system Inhibition of sympathetics Stimulation of parasympathetics Nausea and vomiting

14. Inhalation Anesthetic Agents General pharmacological effects Cardiovascular  Dose related negative inotropic effect  ↓ BP  Arrhythmias  Sensitization to circulating catecholamines Respiration  Dose dependent depression of medullary respiratory center

15. Inhalation Anesthetic Agents  General pharmacological effects Hypothermia  Altered thermoregulatory control and reduced metabolic rate Miscellaneous  Decrease lower esophageal sphincter tone  Post-operative cognitive dysfunction

16. Inhalation Anesthetic Agents Anesthetic gases – only one is Nitrous Oxide Volatile liquids Halothane (Fluothane) : Malignant hyperthermia; Halothane hepatitis Isoflurane (Forane) – commonly used anesthetic for adults Enflurane (Ethrane) – like isoflurane, except increased risk of seizures. Rarely used Desflurane (Suprane) – similar to isoflurane except for more rapid emergence, and more irritating to airway Sevoflurane (Ultane) – similar to desflurane except not irritating to airway

17. Anesthetic Agents Intravenous agents  Barbiturates – sodium thiopental  Propofol (Diprivan) – similar to thiopental except that it can be used for longer periods of anesthesia  Dissociative – ketamine  Benzodiazepines – diazepam, midazolam  Etomidate (Amidate)  Dexmedetomidine (Precedex)

18. Properties of Intravenous Anesthetic Agents DrugSpeed of Induction and Recovery Main Unwanted Effects Notes ThiopentalFast (accumulation occurs, giving slow recovery) Hangover Cardiovascular and respiratory depression laryngospasm Used as induction agent declining. Decreases cerebral blood flow and O2 consumption. EtomidateFast onset, fairly fast recoveryExcitatory effects during induction and recovery, including seizures Adrenocortical suppression Less cardiovascular and respiratory depression than with thiopental, Causes pain at injection site PropofolFast onset, very fast recoveryCardiovascular and respiratory depression. Pain at injection site. Most common induction agent. Rapidly metabolized; possible to use as continuous infusion. KetamineSlow onset, after-effects common during recovery Psychotomimetic effects following recovery, Postoperative nausea, vomiting and salivation Produces good analgesia and amnesia MidazolamSlower than other agentsMemory loss, specifically short- term antegrade amnesia Little respiratory or cardiovascular depression

19. Anesthetic Antagonists Naloxone (Narcan) and nalmefene (Revex) Flumazenil (Romazicon)

20. Usmle questions A 20-year-old male patient scheduled for hernia surgery was anesthetized with halothane and nitrous oxide, tubocurarine was provided for skeletal muscle relaxation. The patient rapidly developed tachycardia and became hypertensive. Generalized skeletal muscle rigidity was accompanied by marked hyperthermia. Laboratory values revealed hyperkalemia and acidosis. This unusual complication of anesthesia is lost likely caused by: A. acetylcholine release from somatic nerve endings at skeletal muscle B. activation of brain dopamine receptors by halothane C. block of autonomic ganglia by tubocurarine D. pheochromocytoma E release of calcium form the sarcoplasmic reticulum

21. The patient should be treated immediately with A. Atropine B. Baclofen C. Dantrolene D. Edrophonium E. Flumazenial