INHALED ANESTHETICS AND GASES

HARRY SINGH, MD DEPT. OF ANESTHESIOLOGY UTMB

HISTORY

Horace Wells administered N2O for dental extraction in 1844 William Green Morton demonstrated use of ether for surgical anesthesia on October 16, 1846 at MGH Inventor and revealer of anesthetic inhalation Before whom in all time, surgery was agony. By whom pain in surgery was averted and annulled. Since whom science has control of pain

KEY TOPICS
Potency or MAC Factors affecting uptake and distribution Effects on various organ systems Metabolism and toxic effects N2O and Xenon Mechanisms of action

STRUCTURE OF DIETHYL ETHER

F N=N=O

F C C* Br F Cl

Cl C* C O C H H F Enflurane F

Nitrous Oxide

Halothane F F
C F F F C C O C F H

H H
F H F F C C* O C H F F F

F C C* O C H F Cl F

F
Desflurane

Isoflurane

Sevoflurane

ANESTHETIC POTENCY
MAC MAC awake: 0.3 MAC MAC BAR: 1.5XMAC MAC intubation: 2XMAC Alveolar concentration represents brain concentration after a short period of equilibration

FACTORS AFFECTING MAC

Temperature: 2%-5% for 1 0C temp. Age: Maximum at 6 months;6%/decade CNS catecholamine stimulation: MAC Benzodiazepine, opiates,alpha-2 agonists:MAC Inhaled anesthetics: additive effect 1% N2O decreases MAC by 1% Pregnancy: MAC Ethanol: acute MAC, chronic MAC Metabolic acidosis, hypoxia, hypotension: MAC Hypernatremia:MAC Hyponatremia, hypermagnesemia: MAC

MAC, BP, VAPOR PRESSURE

(200C) Halothane mmHg Enflurane mmHg Isoflurane mmHg Sevoflurane mmHg Desflurane mmHg
MAC 0.77 1.7 1.15

BP(0C) VP 50.2 56.2 48.5 241 175 238

2.0
6.0

58.5
23

160
664

UPTAKE AND DISTRIBUTION

Goal: To develop and maintain a satisfactory partial pressure or tension of anesthetic at the site of anesthetic action in brain Delivered>Inspired>Alveolar>Arterial>Brain Concentration= Partial pressure/barometric pressurex100 Brain with its high perfusion per gram rapidly equilibrates with anesthetic partial pressure in blood

1.0

Nitrous oxide Desflurane

Sevoflurane

Isoflurane

FA/F1

0.5

Halothane

0 0 10 20 30

Anesthesia administration (min)

Human Blood/Gas and Tissue/Blood Partition Coefficients (MeanSD)1-4

Tissue Desflurane Sevoflurane Isoflurane Halothane

Blood Brain Heart Liver Kidney Muscle Fat

0.420.02 1.30.1 1.30.2 1.30.1 1.00.1 2.00.6 273

0.690.05 1.70.1 1.80.2 1.80.2 1.20.2 3.11.0 486

1.460.09 1.60.1 1.60.2 1.80.2 1.20.2 2.91.0 456

2.540.18 1.90.2 1.80.3 2.10.3 1.00.2 3.41.4 5110

UPTAKE AND DISTRIBUTION

Balance between the delivery of anesthetic and its removal by uptake or metabolism determines FA/FI ratio at any given time after administration of inhaled anesthetic The rate of rise of alveolar concentration (FA) toward inspired concentration (FI) or FA/FI ratio determines speed of induction of anesthesia 1. Alveolar ventilation 2. The inspired concentration (concentration effect) 3. Second gas effect

Ventilation lit/min 1.0 Nitrous oxide 8 4 2

Halothane

0.5

8 2

Diethyl ether

0 0 0 20 40 Anesthesia administration (min) 60

UPTAKE AND DISTRIBUTION

Concentration Effect: The inspired anesthetic concentration also determines the rate of rise of alveolar concentration toward inspired concentration (FA/FI) ratio. The greater the inspired concentration, the more rapid is the rate of rise in FA/FI ratio. It results from two factors: 1. A concentrating of the residual gases 2. Increase in inspired ventilation

UPTAKE AND DISTRIBUTION

Second Gas Effect: Factors governing concentration effect also influence concentration of any gas given concomitantly with N2O (Second gas effect). It results from two factors: 1. The loss of volume associated with N2O uptake concentrates the second gas 2. Replacement of the gas taken up by an increase in inspired ventilation augments the amount of second gas in the lung.

A 1% of second gas 19 % O2 Uptake of half of the N2O

B 1.7 % of second gas

C 1% of second gas 19 % O2

31.7 % O2

Absorbed gases replaced by added ventilation

66.7 % N2O

40% N2O 7.6% O2 32% N2O

80% N2O
0.4% of second gas

1.0

Anesthesia administration (min)

65% N2O

0.9

Desflurane in 65% N2O 5% N2O

FA/F1 0.8

Desflurane in 5% N2O

0 0 10 20

UPTAKE AND DISTRIBUTION

Anesthetic Uptake Factors: Solubility x Cardiac output x Alveolar to venous partial pressure difference. Solubility: Primary factor that determines FA/FI ratio Blood/gas partition coefficient: Relative affinity or partitioning of an anesthetic between two phases at equilibrium. Larger blood/gas partition coefficient more solubilitygreater uptake FA/FI ratio Cardiac output: Cardiac output FA/FI ratio

PARTITION COEFFICIENT OF NITROUS OXIDE

UPTAKE AND DISTRIBUTION

Alveolar to venous anesthetic gradient depends on tissue uptake. Tissue uptake: 1. Tissue solubility (tissue/blood partition coefficient) 2. Tissue blood flow 3. Arterial to tissue anesthetic partial pressure difference

Tissue group characteristics

Tissue Group Characteristic Percentage of body mass Perfusion as percentage of cardiac output Vessel-Rich 10 75 Muscle 50 19 Fat 20 6 Vessel-Poor 20 0

UPTAKE AND DISTRIBUTION

Tissue Groups: Three tissue groups form depots for anesthetic within the body. Vessel rich group (VRG) : Brain, heart, splanchnic bed, liver, kidney and endocrine Equilibrates with blood in 4-8 minutes Muscle group (MG) : Muscle and skin Equilibrates with blood in 2-4 hours Fat group (FG) : Equilibration: 70-80 min for N2O 30 hours for sevoflurane Vessel poor group (VPG)) : Bone , cartilage, ligaments, tendons-no uptake

RECOVERY FROM ANESTHESIA

Recovery correlates with fall in alveolar concentration Solubility: Low solubilityRapid recovery Desflurane>Sevoflurane>Isoflurane Duration of anesthesia MAC awake: Varies with different anesthetics MAC awake of N2O> Inhlaled anesthetics Lower MAC awake: More amnestic the agent Metabolism: Alveolar washout of halothane more rapid than enflurane Residual gases in the anesthetic circuit.

CARDIOVASCULAR EFFECTS
Systolic and Diastolic Function: Dose related negative inotropic effect Halothane=Enflurane>Isoflurane=Desf lurane=Sevoflurane Dose related prolongation of isovolemic relaxation, early LV filling and filling associated with atrial systole

CARDIOVASCULAR EFFECTS

Systemic Hemodynamics: Depress baroreceptors. No change in CI except halothane (CI) Desflurane 1 MAC1.5 - 2 MAC HR and BP Sevoflurane 1 MAC1.5 - 2 MAC HR or no change Isoflurane Intermediate effect All cause concentration related decreases in BP Sevoflurane, desflurane, isoflurane SVR Halothane, enflurane Myocardial depression

CARDIOVASCULAR EFFECTS

Epinephrine induced arrhythmias: Halothane arrythmogenic Other agents safer Coronary Steal: Coronary vasodilataion with isoflurane may cause detrimental redistribution of coronary blood flow away from ischemic myocardium with hypotension leading to coronary steal No coronary steal if hypotension avoided

CARDIOVASCULAR EFFECTS

Myocardial Protection: Protect against reversible and irreversible ischemia Reduce the infarct size Decrease myocardial reperfusion injury and improve functional recovery after global ischemia Activation of intracellular transduction pathways involving A1 receptors, PKC, G proteins and mitochondrial or sarcolemmal KATP Channels

PULMONARY EFFECTS
Respiratory depression leading to MV and pCO2: : Desflurane>Isoflurane>Sevoflurane Depress ventilatory responses to hypercarbia and hypoxia in a dose dependent manner Respiratory Irritation: 2 MAC Desflurane 75% 2 MAC Isoflurane 50% 2 MAC Sevoflurane 0% 1 MAC No respiratory irritation Sevoflurane agent of choice for inhalation induction

PULMONARY EFFECTS
Potent bronchodilators in animals and human Halothane probably the most potent bronchodilator Preferential dilatation of distal airways as compared to proximal airways Action mediated through several complex mechanisms leading to intracellular Ca++

PULMONARY EFEFCTS
Depress mucociliary clearance and function of type II alveolar cells Attenuate hypoxic pulmonary vasoconstriction (HPV) in vitro Modest inhibitory effects on HPV in vivo leading to shunting and decreased oxygenation.

CENTRAL NERVOUS SYSTEM

EEG wave frequency and amplitude Higher conc. (2 MAC): Isoelectric EEG and burst suppression Protect against ischemia by CMRO2 Cerebral vasodilation leading to ICP Enflurane and sevoflurane to a lesser extent can cause convulsions Dose related amplitude and latency of evoked potentials

UTERINE AND FETAL EFFECTS

Dose dependent relaxation of uterus Increased blood loss during CD Lower concentrations (=0.5MAC safer) Inhaled anesthetics cross placenta Higher concentration: Fetal cardiovascular depression Reduction of CBF and O2 delivery to brain

NEUROMUSCULAR SYSTEM
Dose dependent muscle relaxation Can cause sufficient relaxation to permit endotracheal intubation and facilitate intra abdominal procedures Potentiate the action of muscle relaxants Non depolarizers > Depolarizers All trigger MH; Halothane worse

NITROUS OXIDE
Clear, colorless and odorless gas Supplied in pressurized cylinders Elimination through exhalation No biotransformation Uptake and elimination rapid due to low blood/gas partition coefficient (0.47)

NITROUS OXIDE

Analgesia in a dose dependent manner >60% produce amnesia Cant be used as sole anesthetic (MAC 104%) Direct negative inotropic effect Mild sympathetic nervous system agonist Modest increases in PAP and PVR Mild respiratory depression Cerebral vasodilation leading to ICP CMRO2

NITROUS OXIDE

Expansion of closed gas spaces N2O 31 times more soluble than nitrogen (nitrogen blood gas partition coefficient:0.015) Moves faster into spaces than nitrogen can move out Contraindicated in pneumothorax, air embolism, posterior fossa surgery, laparoscopy and tympanoplasty Diffusion hypoxia or Fink effect: Significant for 5-10 min after discontinuation of anesthesia during recovery 1. Large amounts of released N2O displace O2 2. Reduced alveolar ventilation due to fall in CO2

METABOLISM
Halothane: 20% Enflurane: 2.5% Isoflurane: 0.2% Desflurane: 0.01-0.02% Sevoflurane:5%

HEPATOTOXICITY
Correlates with extent of oxidative metabolism Halothane>Enflurane>Isoflurane>Desf lurane 50 case reports with enflurane Fewer case reports with isoflurane One case report with desflurane

HALOTHANE HEPATITIS
Trifluoroacetic acid, chlorine and bromine Major metabolite: Trifluoracetic acid Intermediate reactive metabolite: TFA-Cl Trifluoracetylated proteinsformation of anti-trifluoracetylated protein antibodies Subsequent exposures lead to massive hepatic necrosis Sevoflurane metabolism different from other inhaled anesthetics Sevoflurane: Inorganic fluoride and hexafluoroisopropanol

CLINICAL FEATURES
MILD FORM: Incidence: 1:5 Repeat exposure not necessary Mild elevation of ALT, AST Focal necrosis Self limited

CLINICAL FEATURES

FULMINANT FORM: Incidence: 1:10,000 Multiple exposures Marked elevation of ALT, AST, bilirubin and alkaline phosphatase Massive hepatic necrosis Mortality: 50% Antibodies to halothane altered protein antigen

NEPHROTOXICITY
Methoxyflurane: Vasopressin resistant high output renal failure Related to inorganic fluoride Subclinical nephrotoxicity: 50-80 uM/lit Overt nephrotoxicity: 80-175 uM/lit 2-4 MAC-hr enflurane: 20-30 uM/lit 2-4 MAC-hr isoflurane: 3-8 uM/lit Desflurane: Unchanged

NEPHROTOXICITY
1-2 MAC-hr sevoflurane: 10-20 uM/lit 2-7 MAC-hr sevoflurane: 20-40 uM/lit 15% sevoflurane anesthetics>50 uM/lit Absence of sevoflurane nephrotoxicity contradicts classical fluoride hypothesis of 50 uM toxic threshold

COMPOUND A

Sevoflurane decomposes to compound A in presence of CO2 absorbents (alkali) Higher compound A formation: Low FGF Higher absorbent temperature CO2 production Greater sevoflurane concentrations Baralyme > soda lime Compound A renal injury: Dose and time dependent, transient, 150 ppm-hr

CO2 Flow vs COMPOUND A and Temperature

FGF vs COMPOUND A

COMPOUND A

Toxic threshold reached after prolonged sevoflurane anesthesia Compound A nephrotoxicity more of theoretical concern Patients with preexisting renal disease should not be exposed to sevoflurane Sevoflurane should not be used with FGF < 1 lit/min For exposure greater than 2 MAC hr, FGF should be increased to 2 lit/min or above

CARBON MONOXIDE
CO

formation occurs in presence of desiccated CO2 absorbents Desflurane>Isoflurane>Enflurane Common scenario-First case Monday morning Intraoperative detection difficult Pulse oxymeters cant distinguish between carboxyhemoglobin and oxyhemoglobin

CARBON MONOXIDE
Factors influencing CO production: Choice of anesthetic agent Inspired anesthetic concentration Temperature and degree of dryness of CO2 absorbent Type of absorbent: Baralyme > Soda lime Precautions: Use of fresh absorbent, use of soda lime instead of baralyme and avoiding techniques drying CO2 absorber CO toxicity: Undetected in great proportion of cases

HEMATOPOIETIC AND NEUROLOGIC EFFECTS OF N2O

N2O by oxidation of vit B12 inhibits methionine synthetase preventing conversion of methyltetrahydrofolate to tetrahydrofolate Reduced synthesis of thymidine 50% N2O for 12 hrs-mild megaloblastic changes Marked changes after exposure for 24 hrs Complete bone marrow failure after exposure for several days Subacute combined degeneration of spinal cord after exposure for several months Should not be used in vit B12 deficient patients

XENON

Not approved for clinical use in humans yet Inert gas with anesthetic properties Obtained by fractional distillation of air Expensive to manufacture Minimal hemodynamic side effects Pulmonary airway resistance (high density) Not metabolized Doesnt trigger MH in animals Positive environmental effects

MECHANISMS OF ACTION

KEY POINTS: The structural diversity of inhaled anesthetics suggests that they all do not interact with single receptor site (multisite theory). Physical or biochemical changes important to mechanism occur within seconds and are rapidly reversible Inhaled anesthetics have inhibitory synaptic >axonal effects in the brain and spinal cord. Immobility occurs by action on the spinal cord Amnesia is achieved by action on the brain.

MECHANISMS OF ACTION
Many excitatory (e.g. glutamate) and inhibitory (GABA, glycine) neurotransmitters alter the anesthetic requirement. Gaseous agents ( N2O and xenon) exert their effect by inhibition of excitatory glutamate (NMDA) receptors Volatile agents exert their greater effect by enhancing inhibitory GABA or glycine transmission

MECHANISMS OF ACTION
Meyer Overton Hypothesis describes the correlation between lipid solubility and anesthetic potency (unitary theory of narcosis) MAC X Oil/gas partition coefficient:1.84 atm for conventional anesthetics Additive effect of inhaled anesthetics However some volatile halogenated compounds like non-immobilizers, transitional compounds and alcohols dont obey Meyer Overton hypothesis

Ca2+ Action potential entry

Neurotransmitter release (GABA, glycine)

Postsynaptic membrane

Inhibitory postsynaptic potential

CICICIVoltage

+ Anesthetic Time

A
a B

B
Extracellular

a B
4 Critical amino acids 1 Intracellular 2 3

Channel Putative pore anesthetic site

SUGGESTED READINGS
Inhaled Anesthetics in Millers Anesthesia (Vol 1), Editor Ronald D Miller, Churchill Livingstone. The Pharmacology of Inhaled Anesthetics by Edmond I Eger II, James B Eisenkraft, Richard B Weiskopf. Basic Physics and Measurement in Anaesthesia, Editor Paul D Davis and Gavin NC Kenny.

Vernal and Nevada Falls, Yosemite