Introduction to Anesthesiology Clinic Özge Köner, MD Anesthesiology Dept.

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1st week 2nd week

Introduction to General Anesthesia Özge Köner, MD Anesthesiology Dept.

Learning Objectives Historical Perspective Definition of General Anesthesia Theories & Mechanism of Action of General Anesthesia Anesthetic Agents (volatile & intravenous)

History Crawford Long, 1842: Horace Wells, 1846: American surgeon & pharmacist best known for his first use of inhaled diethyl ether as an anesthetic. Horace Wells, 1846: Dentist. Unsuccessful demo with Nitrous Oxide in Boston Mass general. James Simpson, 1847: Scottish obstetrician who discovered the properties of chloroform during an experiment with friends in which he learnt that it could be used to put one to sleep.

Public Demo of Ether Anesthesia “Gentlemen, this is no Humbug” William Morton, October 16, 1846 Morton christened his ether inhaler "The Letheon". In classical Greek mythology, the waters of the River Lethe expunged painful memories. In Greek mythology, Lethe (Greek: Λήθη, Lḗthē; Classical Greek [lɛː́tʰɛː], modern Greek: [ˈliθi]) was one of the five rivers of Hades. Also known as the Ameles potamos (river of unmindfulness), the Lethe flowed around the cave of Hypnos and through the Underworld, where all those who drank from it experienced complete forgetfulness. Lethe was also the name of the Greek spirit of forgetfulness and oblivion, with whom the river was often identified. In Classical Greek, the word lethe literally means "oblivion", "forgetfulness", or "concealment".[1] It is related to the Greek word for "truth", aletheia (ἀλήθεια), which through the privative alpha literally means "un-forgetfulness" or "un-concealment". Ether anesthesia in ETHER DOME (MASS General Hospital) Patient Gilbert Abbot

OLIVER WENDELL HOLMES, Sr (1809-1894) “Everybody wants to have a hand in a great discovery. All I will do is to give you a hint or two as to names—or the name—to be applied to the state produced and the agent. The state should, I think, be called ‘Anaesthesia’ (from the Greek word anaisthesia, ‘lack of sensation’). This signifies insensibility.... The adjective will be ‘Anaesthetic’. Thus we might say the state of Anaesthesia, or the Anaesthetic state.” Oliver Wendell Holmes 21 November 1846

Cyclopropane, 1929: Most widely used general anesthetic for the following 30 yrs, 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. Sevoflurane & Desflurane, late 1960s Thiopental, intravenous anesthetic.

Anesthesia Reversible, drug-induced loss of consciousness. Greek: an- “without” & aisthesis- “sensation”. Blocked or temporarily taken sensation (including the feeling of pain). Reversible, drug-induced loss of consciousness. Amnesia & unconsciousness Analgesia Muscle relaxation Attenuation of autonomic responses to noxious stimulation

Theories of general anesthetic action 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: 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.

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” and 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. 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 seconds

BARBITURATES (Thiopental) Hypovolemic shock Low serum albumin (severe liver disease) Increased non-ionized fraction (acidosis) will increase the brain & heart concentrations for a given dose.

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

BENZODIAZEPINES (Midazolam) Absorbtion: Oral, IM, IV, SL, rectal, nasal (pH<6: water, pH>6: lipid soluble). 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.

Volatile anesthetic agents, ethanol, barbiturates, Volatile anesthetic agents, ethanol, barbiturates, .. potentiate their sedative effects. Volatile MAC is reduced 30% with concomittant benzodiazepines.

KETAMINE (PHENCYCLIDINE ANALOGUE) IV, IM, oral. NMDA-ANTAGONIST (glutamate subtype) Functionally dissociates the THALAMUS from the LIMBIC cortex. Dissociative anesthesia. Analgesic, amnestic, hypnosis.

ETOMIDATE Depresses RAS, Myoclonic activity (decreased with opioids), Pain on injection, Rapid onset of action, Hydrolyse 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) 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 Endocrine: PROPOFOL CVS Respiratory CNS Hepatic Immune Thiopental HR increased BP decreased Apne Laryngospasm bronchospasm Controls epilepsia CBF, ICP CPP, CMRO2 HBF Porfiria precipitation Histamine release (avoid in asthma) Midazolam Minimal effect Insignificant depression Apnea CBF , ICP CMRO2 - Ketamine My ischemia CO HR BP Minimally effected Laryngospasm Bronchodilatator Salivation CBF ICP CMRO2  Hallucinogen Myoclonic activity Etomidate Less effect Rarely apnea DECREASED: CBF, ICP,CMRO2 CPP : maintained Endocrine: Adrenocortical supression PROPOFOL Profound depression CBF ICP CMRO2 CPP maintained ANTIEMETIC

Pharmacokinetics of Inhaled Anesthetics Amount that reaches the brain is determined by: Oil:gas partition ratio (lipid solubility) –its related to MAC- Alveolar partial pressure of anesthetics 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 Physician’s 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. Values of MAC are additive: Avoid cardiovascular depressive concentration of potent agents.

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

General Actions of Inhaled Anesthetics 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

Cardiovascular System Generalized reduction in arterial pressure and peripheral vascular resistance. Isoflurane maintains cardiac output 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 Major difference is low potency Weak anesthetic, 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, operating room personnel, abusers are at risk.

Halothane, 1956 Halogen substituted ethane. Stable, and nonflammable Most potent inhalational anesthetic Very soluble in blood and adipose tissue Prolonged emergence

Shallow respiration -- atelectasis Sensitizes myocardium to effects of exogenous catecholamines-- ventricular arrhythmias Depresses myocardium-- lowers blood pressure 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 NMBA are potentiated by isoflurane

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 on/off 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 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)

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

PREMEDICATION Anticholinergics- atropine, glycopyrolat Reduce vagal response Reduce pulmonary secretions Reduce gastric motility Analgesics- to reduce pain, anxiety Tranquilizer (benzodiazepines)- to reduce anxiety H1,2 antihistamine- to avert emesis