2Objectives Define sleep, amnesia, analgesia, general anesthesia List different phases/planes of GAClassify the agents used for general anesthesiaDescribe the mechanism of action, pharmacokinetics, therapeutics and adverse effects and drug interactions of different anesthetic drugsCompare the pharmacological effects of thiopental sodium, propofol, and ketamine
5What are General Anesthetics? A drug that brings about a reversible loss of consciousnessgenerally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery.Can be viewed as a pharmacological intervention used to prevent psychological and somatic adverse effects of surgical trauma and also to create convenient conditions for surgery.
6General Anaesthesia (GA) unconsciousnessamnesiaanalgesia.A variety of drugs are given to the patient that have different effects with the overall aim of ensuring unconsciousness, amnesia and analgesia.
7Stages Of General Anesthesia Stage I: Disorientation, altered consciousnessStage II: Excitatory stage, delirium, uncontrolled movement, irregular breathing. Goal is to move through this stage as rapidly as possible.Stage III: Surgical anesthesia; return of regular respiration.Plane 1: “light” anesthesiaPlane 2: Loss of blink reflex, regular respiration . Surgical procedures can be performed at this stage.Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation needed. Level of anesthesia for painful surgeriesPlane 4: Diaphragmatic respiration only, assisted ventilation is required. Cardiovascular impairment.Stage IV: Too deep; essentially an overdose and represents anesthetic crisis. This is the stage between respiratory arrest and death due to circulatory collapse.
8Anesthetics divide into 2 classes Inhalation AnestheticsGasses or VaporsUsually HalogenatedIntravenous AnestheticsInjectionsAnesthetics or induction agents
9Anesthetics divide into 2 classes Inhalation AnestheticsGasses or VaporsUsually HalogenatedIntravenous AnestheticsInjectionsAnesthetics or induction agents
11Mechanism of Action Interaction with protein receptors Volatile A – increase GABA and Glycine( inhibitory neurotransmitters)
12MAC(minimum alveolar concentration) A measure of potency of inhaled anestheticsMAC is the concentration necessary to prevent responding in 50% of population.MAC is the “gold standard” for measuring anesthesia!!!!!!!!!!!!!!!!!!!!MINIMUM ___ ALVEOLAR_____ CONCENTRATION
13Pathway for General Anesthetics Partial Pressure in brain quickly equilibrates with partial pressure in arterial blood which has equilibrated with partial pressure perused alveoli. Furthermore, the DEPTH of anesthesia induced by an inhaled anesthetic depends primarily on the PARTIAL PRESSURE!!! Of the anesthetics in the brain, and the rate of induction and recovery from anesthesia depends on the rate of change of partial pressure in the brain. These drugs are small lipid-soluble molecules that cross the alveolar membrane easily. Move into and out of the blood based on the partial pressure gradient.
14Pharmacokinetics of Inhaled Anesthetics Amount that reaches the brainIndicated by oil:gas ratio (lipid solubility)Solubility of gas into bloodThe lower the blood:gas ratio, the more anesthetics will arrive at the brainFactors influencing the effects of inhaled anesthetics included:
15Rate of Entry into the Brain: Influence of Blood and Lipid Solubility LOW solubility in blood= fast induction and recoveryHIGH solubility in blood= slower induction and recovery.
16General Actions of Inhaled Anesthetics RespirationDepressed respiration and response to CO2KidneyDepression of renal blood flow and urine outputMuscleHigh enough concentrations will relax skeletal muscleGeneral anesthetics work by altering the flow of sodium molecules in to nerve cells or neurons through the cell membrane. Exactly how they do this is not understand since the drug apparently does not bind
17Cont’ Cardiovascular System Central Nervous System Generalized reduction in arterial pressure and peripheral vascular resistance.Isoflurane maintains CO and coronary function better than other agentsCentral Nervous SystemIncreased cerebral blood flow and decreased cerebral metabolism
18Nitrous Oxide Inhaled Anesthetics widely used Potent analgesic Produce a light anesthesiaDo not depress the respiration/vasomotor centerUsed ad adjunct to supplement other inhalationals
19Halothane Inhaled Anesthetics non-flammable 20% metabolism by P450 induction of hepatic microsomal enzymesMyocardial depressant (SA node), sensitization of myocardium to catecholamines - arrhythmia90
21Malignant Hyperthermia Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic state of skeletal muscle induced in susceptible individuals by inhalational anesthetics and/or succinylcholine (and maybe by stress or exercise).114
22Malignant Hyperthermia Genetic susceptibility-Ca+ channel defect (CACNA1S) or RYR1 (ryanodine receptor)Excess calcium ion leads to excessive ATP breakdown/depletion
23Malignant Hyperthermia Signs: tachycardia, tachypnea, metabolic acidosis, hyperthermia, muscle rigidity, sweating, arrhythmiaMay be fatalTreated with dantrolene
24Enflurane Rapid, smooth induction and maintenance Inhaled AnestheticsEnfluraneRapid, smooth induction and maintenance2-10% metabolized in liverIntroduced as replacement for halothane24
25Isoflurane smooth and rapid induction and recovery Inhaled AnestheticsIsofluranesmooth and rapid induction andrecoveryvery little metabolism (0.2%)no reports of hepatotoxicity or renotoxicitymost widely employed
26Anesthetics divide into 2 classes Inhalation AnestheticsGasses or VaporsUsually HalogenatedIntravenous AnestheticsInjectionsAnesthetics or induction agents
27Intravenous Induction Agents Commonly used IV induction agentsPropofolThiopental sodiumKetamine
28Intravenous Anesthetics Most exert their actions by potentiating GABAA receptorGABAergic actions may be similar to those of volatile anesthetics, but act at different sites on receptor117
29Organ EffectsMost decrease cerebral metabolism and intracranial pressureMost cause respiratory depressionMay cause apnea after induction of anesthesia118
30Cardiovascular Effects Barbiturates, benzodiazepines and propofol cause cardiovascular depression.119
32Effect terminated not by metabolism but by redistribution Thiopental sodiumEffect terminated not by metabolism but by redistributionrepeated administration or prolonged infusion approached equilibrium at redistribution sitesBuild-up in adipose tissue = very long emergence from anesthesia
40Induction Faster onset intravenous avoiding the excitatory phase of anaesthesiainhalationalwhere IV access is difficultAnticipated difficult intubationpatient preference (children)
41Maintenance In order to prolong anaesthesia for the required duration breathe to a carefully controlled mixture of oxygen, nitrous oxide, and a volatile anaesthetic agenttransferred to the patient's brain via the lungs and the bloodstream, and the patient remains unconscious
42MaintenanceInhaled agents are supplemented by intravenous anaesthetics, such as opioids (usually fentanyl or morphine)
43What is Balanced Anesthesia? Use specific drugs for each component1. SensoryN20, opioids, ketamine for analgesia2. CognitiveProduce amnesia, and preferably unconsciousnessinhaled agentIV hypnotic (propofol, midazolam, diazepam, thiopental)3. MotorMuscle relaxants43
44Simple Combinations Morphine Propofol N2O Sevoflurane Relaxant of choice44
45Simple Combinations Fentanyl Thiopental sodium N2O Halothane Relaxant of choice45