Introduction to General Anesthesia Özge Köner, MD Anesthesiology 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. 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 Morton named his “creation” Letheon, after the Lethe River of Greek mythology. ..The river of forgetfulness, oblivion. “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

Chloroform, 1847: James Simpson; Hepatotoxic, ventricular fibrillation Cyclopropane, 1929: Most widely used general anesthetic for the following 30 years, explosive ! Halothane, 1956: 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

Anesthesia Reversible, drug-induced loss of consciousness. 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

Sleep & death are brothers (Ancient Greek proverb) The god of Sleep “Hypnos” is the younger brother of the god of death “Thanatos”. Both of them are the children of Nyx, the goddess of night.

Theories of general anesthetic action Lipid solubility-anesthetic potency correlation “The Meyer-Overton correlation” Anesthetic potency is related to lipid solubility. 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: 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, Nicotinic 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 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 mechanism GABAA 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.

Neuronal excitability Consciousness Movement Excitatory neuro- transmission Neuronal excitability GABAA receptors Na channels NMDA receptors K channels Etomidate Propofol Barbiturates Volatile Anesthetics N2O Xenon Ketamine

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 & 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. Anesthesia 2. Medically induced coma 3. Euthanasia 4. Lethal injection 5. Truth serum 6. Psychiatry

BENZODIAZEPINES Related Neurotransmitters GABA Benzodiazepines facilitate GABA binding Agonistic action on GABA may account for the sedative-hypnotic and anesthetic properties

BENZODIAZEPINES (Diazepam, Midazolam) 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.

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)

KETAMINE (PHENCYCLIDINE ANALOGUE) 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.

ETOMIDATE Depresses RAS, Myoclonic activity (decreased with opioids), Pain on injection, Rapid onset of action, Hydrolysed by hepatic microsomal enzyme & plasma esterases, Excreted in urine.

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) Fascilitates the 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 Endocrine: PROPOFOL CVS Respiratory CNS Hepatic Immune Thiopental HR  BP  Apne Laryngospasm bronchospasm Controls epilepsia CBF ICP CPP CMRO2 HBF Porfiria precipitation Histamine release (avoid in asthma) Midazolam Minimal effect Insignificant depression Apnea CMRO2 - Ketamine My ischemia CO BP  Minimally effected Laryngospasm Bronchospasm Salivation CBF ICP CMRO2 Hallucinogen Myoclonic activity Etomidate Less effect Rarely apnea CPP maintained Endocrine: Adrenocortical supression PROPOFOL HR  Profound depression ANTIEMETIC

Pharmacokinetics of Inhaled Anesthetics Amount that reaches the brain is determined by: Lipid solubility (oil:gas partition ratio) –its related to MAC- Alveolar partial pressure of anesthetic 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 Cardiac Output: If increased induction time delays.

Pathway for General Anesthetics

Rate of Entry into the Brain: Influence of Blood and Lipid Solubility

Control of Volatile Partial Pressure in Brain Direct Physician's Control Solubility of agent Concentration of agent in inspired gas Magnitude of alveolar ventilation Indirect Control Pulmonary blood flow (function of CO) Arterio-venous concentration gradient

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. A blood:gas PC ( oil gas partition coefficient) of 0.5 means that the concentration of the volatile agent in the blood is half that present in the alveolar gas when the partial pressure of the anesthetic is identical at both sites. o PC in an inhalation anesthetic is most commonly used to refer to its solubility in a given solvent (e.g., oil, blood etc.). o A very potent anesthetic (e.g.methoxyflurane) has a low MAC value and a high oil/gas PC, whereas a low potency agent (e.g.N2O) has a high MAC and low oil/gas PC. o In other words, an anesthetic with a high oil solubility (i.e., high oil/gas PC) is effective at a low alveolar concentration and has a high potency.

Blood/Gas Partition coeff. 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

Systemic Effects of Inhaled Anesthetics Respiration: Depress respiration and response to CO2 Kidney: Depress renal blood flow and urine output Muscle: High concentrations relax skeletal muscle CNS: Increased cerebral blood flow, decreased cerebral metabolism

Cardiovascular System Reduced blood pressure and peripheral vascular resistance. Isoflurane maintains CO and coronary function better than other agents.

2%, Major place, F- toxicity no longer on market Drug Liver Enzyme Kidney Halothane 25% CYP2E1, CYP2A6, CYP3A4 minimal Sevoflurane 5% CYP2E1 <1%, Some metabolism Isoflurane 0.025% none Desflurane CYP2E1 ? 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 Its potency is low Weak anesthetic, relatively powerful analgesic It must be used with 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) N2O 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, 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

Shallow respiration -- atelectasis 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 (Side Effects) “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).

Volatile Agents Halothane Isoflurane Sevoflurane Desflurane N2O 15-20% CVS Respiratory CNS Seizures Renal Hepatic Metabolism Halothane HR  BP  CO  TV  RR  CBF  ICP  CMRO2  RBF  GFR  Urine output HBF  15-20% Isoflurane HR  CO nc RR  CBF  ICP  CMRO2  RBF  GFR  Urine output  HBF  0.2% Sevoflurane HR NC BP  CO  TV  RR  CBF  ICP  RBF  GFR ? Urine output ? 5% Desflurane HR NC/ CO NC/ CBF  <0.1% N2O HR nc BP nc CO nc CMRO2  0.004%

Isoflurane Metabolized into trifluoroacetic acid Nephrotoxicity is extremely unlikely Coronary steal syndrome (experimental !)

Sevoflurane A potent inhalational anesthetic Very soluble in blood and adipose tissue Smooth and rapid induction Fast emergence

Sevoflurane It can be used for anesthesia induction 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 Disadvantages Advantages High cost Insoluble CNS stimulation (minor) Not suitable for induction CO production (not relevant) Advantages Insoluble Fast induction/emergence Low residual at the end of case

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 sodalime 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)

NOT AVAILABLE FOR THE CLINICAL USE YET 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