Introduction to General Anesthesia
Özge Köner, MDAnesthesiology Dept.
Overview
Historical Perspective
Definition of General Anesthesia
Mechanism of Anesthesia
Anesthetic Agents (volatile & intravenous)
Surgery before 1846
Hippocrates (460-377, BC) a treatise on surgery but little sympathy for the patient.
Greek surgeon Dioscorides (40-70, AD) His book “Materia Medica” described the effects of mandroga & wine to produce anesthesia.
Surgery before 1846
Middle ages: Alcohol fumes as an analgesic during surgery, soporific sponge (opium & scopolamine). marijuana, belladonna and jimsonweed-
Mesmerism, hypnosis, strangulation…
History
Crawford Long, 1842: Ether
anesthesia: first ideal anesthetic.
Dt.Horace Wells, 1846: Nitrous Oxide
Unsuccessful demo in Boston Mass general
Public Demo of Ether Anesthesia“Gentlemen, this is no Humbug”
• Dt. William Morton, October 16, 1846
Ether anesthesia in ETHER DOME (MASS General Hospital)
Patient Gilbert Abbot
Ether “Letheon” Inhaler
"The Letheon”: In classical Greek
mythology, the waters of the River Lethe expunged
painful memories.
Ether “Letheon”
• Flammable
• Prolonged induction
• Unpleasant odor
• High incidence of nausea-vomiting
Cyclopropane, 1929: Most widely used general anesthetic for the following 30 yrs, explosive !
Halothane, 1956: British Research Council & Chemists at Imperial Chemical Industries. Although widely replaced with new generation volatiles, it is still in use
Methoxyflurane, 1960: Nephrotoxicity. Most potent of all the volatiles.
Sevoflurane & Desflurane, late 1960s
Thiopental, intravenous anesthetic, synthesized in the early 1930s by Ernest H Volwiler
Chloroform, 1847: James Simpson; Hepatotoxic, ventricular fibrillation
• Greek: an- “without” & aisthesis- “sensation”. Blocked or temporarily taken sensation (including the feeling of pain). Name is suggested by Oliver W. Holmes.
Reversible, drug-induced loss of consciousness.
Amnesia & unconsciousness
Analgesia
Muscle relaxation
Attenuation of autonomic responses to noxious stimulation
Anesthesia
Sleep & death are brothers(Ancient Greek proverb)
• The god of Sleep “Hypnos” is the younger brother of the god of death, Thanatos; both children of Nyx, the goddess of night.
Theories of general anesthetic action
1. Lipid solubility-anesthetic potency correlation
• “The Meyer-Overton correlation”
• Meyer HH; First experimental evidence: anesthetic potency is related to lipid solubility. A similar theory was published independently by Overton in 1901. The greater is the lipid solubility of the compound in olive oil the greater is its anesthetic potency.
• Modern interpretation of the theory; general anesthetics dissolve in lipid-bilayer regions of nerve cell membranes and alter the properties of lipids surrounding crucial membrane proteins that protein function is compromised.
Meyer HH: "Zur Theorie der Alkoholnarkose". 1899.
Theories of general anesthetic action
Alternative idea that proteins are directly affected:
2. Membrane protein hypothesis*:
• Some class of proteins might be sensitive to general anesthetics. Inhalation agents may primarily interact with receptor proteins & produce conformational changes in their molecular structure. These changes affect the function of ion channels or enzymes.
• GABAA, glycine, glutamate, Ni receptors can be selectively modified by clinical concentrations of volatiles.
* Franks NP. Nature, 300: 1982.
Anatomic regions of brain responsible for the general anesthetic action
• THALAMUS (Inhibition of Ni Ach receptors)
• HIPOTHALAMUS (Histaminergic, orexinergic neurons)
• BRAIN STEM (Noradrenergic neurons of LC. α2-agonists)
• LIMBIC SYSTEM (Hippocampus and Amygdala; memory function and anesthetic mediated
amnesia)
Mechanism of Anesthesia
Anesthetic action on spinal cord probably inhibits purposeful responses to noxious stimulation.
Inhalational agents can
“depress the exitability ofexitability of thalamic neurons”,
“block thalamocortical communication”, the potential result is loss of consciousness.
Existing evidence provides no basis for a single anatomic site responsible for anesthesia.
Anesthetic effects on synaptic level:Cellular mechanism
•SYNAPSE is thought to be the most relevant site of anesthetic action: (by means of anesthetic effects on sodium channels)
Presynaptic inhibition of neurotransmitter release,
Inhibition of excitatory neurotransmitter effect,
Enhancement of inhibitory neurotransmitter effect.
Molecular mechanismGABAA receptor, ligand gated ion channel
GABA is the major inhibitory neurotransmitter. GABAA receptor is abundant in brain and located in the post-synaptic membrane.
Glycine,
5-HT3,
Neuronal nicotinic receptors.
GABA receptor binding & anesthetic action
Binding of GABA causes a conformational change in the receptor. The central pore is opened,
Chloride ions are passed down electrochemical gradient,
Net inhibitory effect is the reduced neuronal activity.
EtomidatePropofol
Barbiturates
Volatile Anesthetics
N2OXenon
Ketamine
GABAA receptors
Na channels
K channels NMDA receptors
Neuronal excitability
Excitatory neuro-
transmission
ConsciousnessMovement
Anesthetics divide into 2 classes
• Inhalation Anesthetics
• Gases or Vapors
• Usually Halogenated
• Intravenous Anesthetics
• Injections
• Anesthetics or induction agents
BARBITURATES
• Depress RAS located in the brainstem.
• Clinical concentrations affect the synaptic function.
• Sodium salt is alkaline, pH=10.
• IV or rectal application is possible.
• Duration of action is determined by redistribution.
• Onset time of action 30-45 sec.
BARBITURATES USES
1. Anesthesia2. Medically induced coma3. Euthanasia4. Lethal injection5. Truth serum6. Psychiatry
Related Neurotransmitters
GABA
• Benzodiazepines facilitate GABA binding
• Agonistic action on GABA may account for the sedative-hypnotic and anesthetic properties
BENZODIAZEPINES
• Absorbtion: Oral, IM, IV, SL, rectal, buccal.
• Highly protein bounded, rapid of onset & duration of action
relatively long. Metabolized in liver, excreted in the urine.
• Midazolam: elimination half life 2 hrs. Renal failure prolongs
sedation (α-OH-midazolam)
• Controls grand mal seizures. Antegrade amnesia. Mild muscle
relaxation, anxiolysis, sedation.
BENZODIAZEPINES(Diazepam, Midazolam)
Midazolam is used for:
• Emergency treatment of seizures• Sedation during medical procedures• Premedication prior to medical
procedures
Buccal Midazolam for epilepsy treatment
Midazolam can be:
•Trickled inside the cheek – buccal•Dripped into the nose – intranasal•Injected into a vein (IV) or muscle (IM)
• IV, IM, oral.
• NMDA-Antagonist (glutamate subtype)
• Functionally dissociates the THALAMUS from the LIMBIC cortex.
• Dissociative anesthesia.
• Analgesic, amnestic, hypnosis.
• Ketamine anesthesia was first given to American soldiers during the Vietnam War.
KETAMINE(PHENCYCLIDINE ANALOGUE)
• Depresses RAS,
• Myoclonic activity (decreased with opioids),
• Pain on injection,
• Rapid onset of action,
• Hydrolyse by hepatic microsomal enzyme & plasma esterases,
• Excreted in urine.
ETOMIDATE
• ENDOCRINE EFFECTS:
• Long term infusion leads to adrenocortical suppression
and increased mortality in critically ill patients.
Transient inhibition of enzymes involved in “cortisol and
aldosterone” synthesis.
PROPOFOL(2,6-DIISOPROPYLPHENOL)
• Fascilitation of inhibitory neurotransmission
mediated by GABA,
• Pain on injection (iv),
• Bacterial growth in the formula. Use within 6 hours
after opening the formula
IV ANESTHETIC AGENTS
CVS Respiratory CNS Hepatic Immune
Thiopental HR BP
ApneLaryngospasm bronchospasm
Controls epilepsiaCBF ICPCPPCMRO2
HBFPorfiria precipitation
Histamine release (avoid in asthma)
Midazolam Minimal effect
Insignificant depressionApnea
Controls epilepsiaCBF ICPCMRO2
-
Ketamine My ischemiaCOHR BP
Minimally effectedLaryngospasmBronchospasmSalivation
CBF ICPCMRO2HallucinogenMyoclonic activity
-
Etomidate Minimal effect
Less effect Rarely apnea
CBF ICPCMRO2CPP maintained
Endocrine:Adrenocortical supression
PROPOFOL
HR BP
Profound depressionApnea
CBF ICPCMRO2CPP maintained
ANTIEMETIC
Amount that reaches the brain is determined by:
1. Oil:gas partition ratio (lipid solubility) –its related to MAC-
2. Alveolar partial pressure of anesthetics
3. Solubility of gas into blood
The rate of onset of action is determined by solubility in blood. The lower the solubility in blood, the more anesthetics will arrive at the brain
4. Cardiac Output: If increased induction time delays.
Pharmacokinetics of Inhaled Anesthetics
Pathway for General Anesthetics
Rate of Entry into the Brain: Influence of Blood and Lipid Solubility
• Direct Physician's Control
• Solubility of agent
• Concentration of agent in inspired gas
• Magnitude of alveolar ventilation
• Indirect Physician’s Control
• Pulmonary blood flow (function of CO)
• Arterio-venous concentration gradient
Control of volatile Partial Pressure in Brain
MAC (minimal alveolar concentration)
• A measure of potency
• 1 MAC is the concentration necessary to prevent movement in response to painful stimulus in 50% of population.
• Values of MAC are additive:
• Avoid cardiovascular depressive concentration of potent agents.
Agent 1 MAC (ED50)Blood/Gas
Partition coeff.
Halothane 0.75 % 2.4
Isoflurane 1.2 % 1.4
Sevoflurane 2% 0.65
Desflurane 6% 0.42
Nitrous Oxide 105% 0.47
• Respiration: Depress respiration and response to CO2
• Kidney: Depress renal blood flow and urine output
• Muscle: High concentrations will relax skeletal muscle
• CNS: Increased cerebral blood flow, decreased cerebral metabolism
General Actions of Inhaled Anesthetics
• Cardiovascular System
• Generalized reduction in arterial pressure and peripheral vascular resistance. Isoflurane maintains CO and coronary function better than other agents
Drug Liver Enzyme Kidney
Halothane 25%CYP2E1, CYP2A6,
CYP3A4minimal
Sevoflurane 5% CYP2E1 <1%, Some metabolism
Isoflurane 0.025% CYP2E1 none
Desflurane minimal CYP2E1 ? none
Enflurane <1% CYP2E1 (minor)2%, Major place, F-
toxicity no longer on market
Nitrous Oxide
• Simple linear compound
• Not metabolized
• Only anesthetic agent that is inorganic
• Colorless, odorless, tasteless
Nitrous Oxide
• Major difference is low potency
• Weak anesthetic, relatively powerful analgesic
• Needs other agents for surgical anesthesia
• Low blood solubility (quick recovery)
Nitrous Oxide
• Minimal effects on heart rate and blood pressure
• May cause myocardial depression
• Little effect on respiration
• Beginning of case: second gas effect
• End of case: diffusion hypoxia
Side effects (Nitrous Oxide)
• Diffusion into closed spaces
Side effects (Nitrous Oxide)
• Inhibits methionine synthetase (precursor to DNA synthesis) & vitamin B12 metabolism,
• Dentists, OR personnel, abusers are at risk.
Methoxyflurane, 1960
• Halogen substituted ethane, not flammable.
• Most potent inhalational anesthetic
• Prolonged induction & emergence from anesthesia
• Nephrotoxic & Hepatotoxic
Methoxyflurane
• Since the 1970s it has been used in Australia in lower doses for acute analgesia (up to 6 mL), largely by paramedic services.
• Self administered by the patients.
Halothane, 1956
• Halogen substituted ethane. Stable and nonflammable
• Most potent inhalational anesthetic (except for the methoyflurane)
• Very soluble in blood and adipose tissue
• Prolonged emergence
• Sensitizes myocardium to effects of exogenous catecholamines-- ventricular arrhythmias
• Depresses myocardium-- lowers BP and slows conduction-
• Decreases respiratory drive-- central response to CO2-
• Shallow respiration -- atelectasis
• Depresses protective airway reflexes
• “Halothane Hepatitis” -- 1/10,000 cases (immunologically mediated)
• fever, jaundice, hepatic necrosis, death
• exposure dependent
• metabolic breakdown products are hapten-protein conjugates
• Malignant Hyperthermia-- 1/60,000 (with succinylcholine to 1/260,000).
Halothane (Side Effects)
Volatile Agents
CVS Respiratory
CNSSeizures
Renal Hepatic Metabolism
Halothane HR BP CO
TV RR
CBF ICP CMRO2
RBF GFR Urine output
HBF 15-20%
Isoflurane HR BP CO nc
TV RR
CBF ICP CMRO2
RBF GFR Urine output
HBF 0.2%
Sevoflurane
HR NC BP CO
TV RR
CBF ICP CMRO2
RBF GFR ?Urine output ?
HBF 5%
Desflurane HR NC/BP CO NC/
TV RR
CBF ICP CMRO2
RBF GFR ?Urine output ?
HBF <0.1%
N2O HR ncBP ncCO nc
TV RR
CBF ICP CMRO2
RBF GFR Urine output
HBF 0.004%
Isoflurane
• Metabolized into trifluoroacetic acid
• Nephrotoxicity is extremely unlikely
• NMBA are potentiated by isoflurane
Sevoflurane
• A potent inhalational anesthetic
• Very soluble in blood and adipose tissue
• Smooth and rapid induction
• Fast emergence
Sevoflurane
• Advantages
• It can be used for anesthesia induction
• Less CNS activation
• Cardio-protective
• Disadvantages
• High cost
• Compound A (possible nephrotoxicity)
Sevoflurane & Compound A
• Sevoflurane reacts with sodalime (used in anesthetic circuit to absorb CO2) to form a renal toxin “compound A”
(Trifluoromethyl- vinyl ether)
• Some reports of fire and explosion
• Little evidence of harm unless
• Low gas flow (≥2 L/min gas flow rate is recommended)
• Prolonged exposure
• Some evidence for changes in renal damage markers but not clinically significant
Desflurane
• Advantages
• Insoluble
• Fast on/off
• Low residual at the end of case
• Disadvantages
• High cost
• CNS stimulation (minor)
• Not suitable for induction
• CO production (not relevant)
Anesthetics & Carbon Monoxide
• All anesthetic agents react with sodalime to produce CO
• CO is toxic and binds to Hb in preference to oxygen
Desflur > enflur >>> isoflur > sevoflur > halothane
• Risk Factors
• Dryness & high temperature of soda lime
• In general, not clinically significant
• No deaths reported
Fluoride Nephrotoxicty
Methoxy > enflur > sevoflur > isoflur > desflur
• F- is a nephrotoxic byproduct of metabolism in liver & kidney
• F- opposes ADH leading to polyuria
• Methoxyflurane 2.5 MAC/hours (no longer used)
• Enflurane 9.6 MAC/hours (rarely used)
XENON
• An inert gas, nonexplosive
• No metabolism
• Minimal cardiovascular effects
• Low blood solubility
• Rapid induction & recovery
• Doesn’t trigger malign hyperthermia
• EXPENSIVE
• NOT AVAILABLE FOR THE CLINICAL USE YET
Anesthesia