compiled by: Dr. saeed kolahian GENERAL ANESTHETICS compiled by: Dr. saeed kolahian

History of Anesthesia Ether synthesized in 1540 by Cordus Ether used as anesthetic in 1842 by Dr. Crawford W. Long Ether publicized as anesthetic in 1846 by Dr. William Morton Chloroform used as anesthetic in 1853 by Dr. John Snow

18th Century Surgery Original in the Royal College of Surgeons of England, London.

Sir Humphrey Davy at the Royal Institution

William T.G. Morton’s Ether Inhaler October 17, 1846: First public demonstration of the use of ether in anesthesia at Massachusetts Gen Hosp. with Dr. J.C. Warren in attendance.

Operation Under Ether1852 “The effect of the gaseous inhalation in neutralizing the sentient faculty was made perfectly distinct to my mind..” Massachusetts General Hospital, Boston

What is “general” anesthesia? A generalized reversible depression of the central nervous system such that perception of all senses is removed. Pharmacological actions of anesthetics include: unconsciousness Paralysis (Immobility to noxious stimuli, including loss of protective reflexes) Amnesia (loss of memory) with unconsciousness Analgesia (relief of pain) Sedation/Anxiolysis

General Anesthesia Stages of Anesthesia Stage I Stage II Stage III Analgesia Stage II Disinhibition Stage III Surgical anesthesia Stage IV Medullary depression

Stages of anesthesia Defined in 1920 by Arthur E. Guedel on the basis of responses to ether. Stage I- Analgesia Subject is sedated—conscious but drowsy; amnesia and variable analgesia. Stage II- Excitement (delirium) Subject experiences delirium and violent combative behavior; rise and irregularity in blood pressure and respiration; hyper-reactive. Risk of laryngospasm. Efforts are made to limit this stage. Stage III- Surgical anesthesia No spontaneous movement; regular respiration; gradual loss of muscle tone and reflexes as the CNS is further depressed; ideal stage for surgery. Stage IV- Medullary depression/paralysis Loss of respiration and vasomotor control; death. The ideal general anesthetic should result in the induction of Stage III as rapidly as possible. Careful monitoring is required to prevent progression into Stage IV.

Types of anesthetics I. Inhalation anesthetics II. Intravenous anesthetics III. Local anesthetics

Modern Anesthetics 2 principal classes Inhalational anesthetics Intravenous anesthetics Mostly used in conjunction with each other, seldom alone. Also administered in combination with other drug classes.

The ideal general anesthetic anterograde amnesia.(cause no systemic amnesia.) Analgesia (inhibition of sensation and pain) Loss of consciousness Skeletal muscle relaxation Reduction of reflex activity Quick acting and rapidly eliminated No toxic effects – large margin of safety Since no single drug has all these desirable properties, several drugs are used in combination to achieve these goals. Surgeon wants a quick turnover time (rapid induction?) and an immobile patient with cadaveric relaxation. Anesthesiologist wants what a patient wants - a smooth induction, normal patient physiology, and quick recovery with little PO pain and no PONV

Types of General Anesthetics Inhalational (gases and volatile liquids) Intravenous Oral These are almost always used in combination with each other to provide rapid induction and maintenance of surgical anesthesia.

Typical Progression of General Anesthesia Sedation (Pre-operative patient management) Reduce anxiety and aid in amnesia; facilitate a smooth and rapid induction of anesthesia Induction Sedation and rapid loss of consciousness Paralysis Intubation/muscle relaxation/immobility Maintenance - with gas Recovery Obtaining an accurate patient history is absolutely critical for proper drug selection for general anesthesia. Also add “Recovery” after Maintenance. Each one of these effects the next step, and they are all part of a continuum. Pt should be terrified – they’re about to enter a state of a total loss of control – everything is controlled by the anesthesia provider: brain, heart, respiration, circulation, muscles. Dangers include: mutilation, pain, and death!

Inhalational Anesthetics Inhalational general anesthetics are among the most dangerous drugs administered to humans Very steep dose-response curves and no antagonists exist The difference between no effect, surgical anesthesia, and severe cardiac and respiratory depression is small

Inhalation Anesthetics Original agents were vapours from volatile liquids: ether (diethylether), chloroform,halothane,… or gases :Nitrous oxide, cyclopropane

Inhalational Anesthetic Agents Inhalational anesthesia refers to the delivery of gases or vapors from the respiratory system to produce anesthesia Pharmacokinetics--uptake, distribution, and elimination from the body Pharmacodyamics-- MAC value

Factors Affecting Alveolar Concentration Inflow of anesthetic gas to the alveoli: Ventilation Increased ventilation = faster induction Concentration Increased concentration of anesthetic = faster induction (“overpressure”) Concentration effect Second gas effect Uptake of anesthetic gas from the alveoli: high uptake = slower induction Blood solubility – high blood solubility = slower induction Cardiac output High cardiac output = slower induction

Factors that influence anesthetic uptake by the body Blood solubility Solubility describes the affinity of the gas for a given substance. For inhaled anesthetics, think of blood as a pharmacologically inactive reservoir. If the anesthetic gas is very soluble in blood, the gradient driving transfer from blood to brain will be decreased. Therefore, blood solubility is critically important in determining rate of uptake. An agent that is more soluble in blood exerts its effect more slowly. The blood:gas paritition coefficient (l) describes how the gas will partition itself between the two phases at equilibrium What is solubility? We normally think of solubility in terms of how much of a substance will dissolve in a fluid, e.g. how much sugar can I get to dissolve in my iced tea? For gases, we need to think more in terms of affinity of the gas for a particular fluid, in this case, blood. Does the gas have a high affinity for blood, and thus does not want to leave the blood and diffuse into the brain? If so, this gas would have a slower induction time than a gas that was poorly soluble in blood.

Factors that influence anesthetic uptake by the body Solubility of the gas in tissue Inhalational anesthetics have a high affinity for tissues with high lipid content, which increase uptake and slow induction. Transfer of anesthetic from blood to tissue Tissues with high blood flow (e.g. brain, heart, liver, kidney) equilibrate first, whereas tissues with poor perfusion (e.g. fat) equilibrate slowest.

How are inhalational anesthetics measured? The exact concentration of the anesthetic gas in the brain is difficult to measure. To standardize the method of determining potencies of the inhalation anesthetic, the MAC value is used. Potency of inhaled anesthetics are defined by minimal alveolar concentration (MAC). 100 1 MAC is the partial pressure that gives an ED50 ; i.e., the percentage of anesthetic that prevents the muscular response to a standard painful stimulus (surgical skin incision) in 50% of unparalyzed subjects. MAC value is inversely related to lipid solubility of the agent. MAC is small for potent anesthetics such as halothane and large for less potent agents, such as nitrous oxide. % anesthetized 50 1 1.3 MAC Halothane 1MAC = 0.75% Nitrous oxide 1MAC = 105%

Minimum Alveolar Concentration (MAC) Partition Coefficient Agent MAC blood:gas blood lipid (%) (l) solubility solubility Halothane 0.75 2.4 High Isoflurane 1.2 1.4 Sevoflurane 2.0 0.65 Desflurane 6.0 0.42 Nitrous oxide 105 0.47 Low 1 MAC is ED50. 1.3 X MAC is ED95, i.e. the percentage of gas that prevents response to surgical incision in 95% of patients. However, MAC values should be considered simply as a guide as each patient responds to inhaled anesthetics differently. MAC for skin incision does not predict the concentration of anesthetic necessary to avoid responses to other painful stimuli, e.g. endotracheal intubation. Inhalational anesthetics alone are not able to suppress hemodynamic responses to painful stimuli.

Theories regarding mechanisms of action of inhalational anesthetics The exact mechanism of action of inhalational anesthetics is unknown, but several theories have been introduced: Meyer-Overton- Lipoid solubility theory (1901). The structure of cell membranes was not known at the time, but this theory proposed that there was some lipoid component in the brain. The anesthetics partitioned into this lipoid environment and caused anesthesia. Supporting this theory is the fact that compounds that are more lipophillic are more potent anesthetics. -membrane expansion Hypothesis. Anesthesia is induced when the agent occupies a critical volume in the membrane. -Membrane fluidity Hypothesis. Anesthetics enhance membrane fluidity, increase lateral compression, and thus decrease ion movement through channels. Anesthetic Protein Interaction. Anesthetics bind to hydrophobic sites on proteins, thereby altering membrane signal transduction.

More Jargon and Concepts Second gas effect: When two gases of different solubility exist together in the alveolus, the more soluble dissolves in plasma first, leaving the less soluble now a bigger fraction of alveolar gas. The second gas now dissolves more rapidly than would otherwise be the case.

I. Inhalation anesthetics Ether (diethyl ether) Spontaneously explosive Irritant to respiratory tract High incidence of nausea and vomiting during induction and post-surgical emergence The best muscle relaxant effect No cardiac side effet Shows 4 strages Safe metabolits

chloroform not explosive Not Irritant to respiratory tract cardiac side effet liver side effet

Nitrous Oxide Prepared by Priestly in 1776 Anesthetic properties described by Davy in 1799 Characterized by inert nature with minimal metabolism Colorless, odorless, tasteless, and does not burn

Nitrous oxide (N2O) (Laughing gas) Commonly used but least potent. MAC for true anesthesia = 105 % Really used as an analgesic attaining only Stage I Used as an adiuvant for the second gas effect. Low solubility in the blood – rapid onset, rapid recovery Few undesirable side effects:- Respiration - no irritation BUT risk of hypoxia. Common conc in alveolar air is 70%+ 25%O2+5%CO2 Cardiovascular system - none, no sensitization to catecholamines. Risk of Abuse in anesthetists, dentists, nurses.

Nitrous Oxide Side Effects Gastrointestinal: Nausea and vomiting are uncommon but can occur; more frequent when >50% given Kidneys and liver: No major effects Inhibits methionine synthetase (precursor to DNA synthesis) Inhibits vitamin B-12 metabolism (megaloblastic anemia) Dentists, OR personnel, abusers at risk

Nitrous Oxide Metabolism and Excretion: 99% is exhaled through the lungs within 3-5 min 1% is eliminated over 24 h through lungs and skin

Nitrous Oxide Diffusion hypoxia: N2O stopped and pt breaths room air Diffusion of N2O into alveoli from blood and tissues dilutes subsequent breaths of oxygen and pt becomes hypoxic Routine administration of 100% O2 for a minimum of 3 to 5 minutes at the end of the procedure will prevent diffusion hypoxia

Volatile Inhalational Anesthetics Most commonly used volatile inhalational agents used today: desflurane, sevoflurane, isoflurane, and to a very limited extent, halothane. All volatile anesthetics are triggering agents for malignant hyperthermia (MH). All volatile anesthetics cause dose-dependent drop in BP and systemic vascular resistance All are moderate bronchodilators and relax skeletal muscle All volatile anesthetics are respiratory depressants Primary mechanism of elimination is ventilation; minimal metabolism of most inhaled anesthetics Nitrous—associated with nausea and vomiting; contraindicated in bowel cases.

Halothane Synthesized in 1956 by Suckling Halogen substituted ethane Volatile liquid easily vaporized, stable, and nonflammable

Halothane Most potent inhalational anesthetic MAC of 0.75% Efficacious in depressing consciousness Very soluble in blood and adipose

Halothane MAC = 0.3% Volatile liquid. Widely used - good control, smooth induction & recovery Problems: At MAC little involvement of CVS sensitizes myocardium to catecholamines via action on beta-adrenoceptors. Risk of dysrhythmia; Vasodilation → hypotension; Depression of ventilation: increased bronchial secretions Neuromuscular block (slight) potentiates curariform drugs.

Halothane Systemic Effects Decreases respiratory drive-- central response to CO2 and peripheral to O2 Respirations shallow-- atelectasis Depresses protective airway reflexes (good agent for asthmatic patient) Depresses myocardium-- lowers BP and slows conduction Mild peripheral vasodilation

Risks with Halothane Malignant hyperthermia in susceptible individuals. 1:12,000 in children to 1:40,000 in adults. Locus on chromosome 19; Ryanodine receptor defective. Inhalation anesthetics excessive Ca2+ release in skeletal muscle contracture and a malignant hyperthermia Risk of spontaneous abortion in pregnant OR staff. 20% metabolism "toxic" products causing hepatic damage with repeated exposure.

Halothane Side Effects Hepatic blood flow decreased “Halothane Hepatitis” -- 1/10,000 cases fever, jaundice, hepatic necrosis, death metabolic breakdown products are hapten-protein conjugates immunologically mediated assault exposure dependent

Halothane Side Effects Malignant Hyperthermia (continued) high association with muscle disorders autosomal dominant inheritance diagnosis--previous symptoms, increase CO2, rise in CPK levels, myoglobinuria, muscle biopsy physiology--hypermetabolic state by inhibition of calcium reuptake in sarcoplasmic reticulum

Halothane Side Effects Malignant Hyperthermia (continued) treatment--early detection, d/c agents, hyperventilate, bicarb, IV dantrolene (2.5 mg/kg), ice packs/cooling blankets, lasix/mannitol/fluids. ICU monitoring Susceptible patients-- preop with IV dantrolene, keep away inhalational agents and succinylcholine

Kidney and ICP Kidney -Dose dependant decreases in: Renal blood flow GFR Urine Output -Increase intracranial pressure with vasodilation Contraindicated in patients whit head injury and bleeding

methoxyfluorane Least MAC=very potent High solubility in blood=Delayed induction and recovery Harmful to kidney because of fluorine metabolites Store in rubber

Enflurane Developed in 1963 by Terrell, released for use in 1972 Stable, nonflammable liquid MAC 1.68%

Enflurane Systemic Effects Potent inotropic and chronotropic depressant and decreases systemic vascular resistance-- lowers blood pressure and conduction dramatically Sensitizes myocardium to effects of exogenous catecholamines-- arrhythmias

Enflurane Less soluble In blood than halothane (faster induction & recovery) Less chance of dysrhythmia than with halothane but caution is still warranted. more hypotension and respiratory depression; BP on induction but recovers with the start of surgery. Cardiac output may fall slightly with a rise in central venous pressure. More neuromuscular depression. Less liver damage: 17% dose is metabolized, some to fluorine containing compounds. Nausea on recovery Occasional seizure like effect.

Isoflurane Synthesized in 1965 by Terrell, introduced into practice in 1984 Not carcinogenic Nonflammable Less soluble than halothane or enflurane MAC of 1.30 %

Isoflurane Systemic Effects Depresses respiratory drive and ventilatory responses-- less than enflurane Depresses protective airway reflexes (good agent for asthmatic patient) Myocardial depressant-- less than enflurane Sensitizes myocardium to catecholamines -- less than halothane or enflurane

Isoflurane Systemic Effects Produces most significant reduction in systemic vascular resistance-- increased ICP but less than halothane Excellent muscle relaxant-- potentiates effects of neuromuscular blockers

Isoflurane Side Effects Little metabolism (0.02%) -- low potential of organotoxic metabolites No EEG activity like enflurane Bronchoirritating, laryngospasm Coronary ischemic effect

Sevoflurane and Desflurane Low solubility in blood-- produces rapid induction and emergence Minimal systemic effects-- mild respiratory and cardiac suppression Few side effects Expensive

Desflurane Chloro analogue of Isoflurane. Least blood soluble of all the anesthetics - most rapid induction. Very pungent - severe laryngospasm, secretion, apnea. Rapid recovery (5 minutes) - CAUTION - ensure adequate analgesia is in place. Virtually no metabolism - no liver toxicity, but respiratory depressant. Malignant hyperthermia still a risk.

Sevoflurane Nonpungent, no respiratory tract irritation. Poor solubility - rapid induction and offset. 5% metabolism. Few real problems but should not be used in closed circulatory systems at low gas delivery rates (due to formation of toxic Compound A with soda lime). Malignant hyperthermia still a risk

Equipment used can be complex

Induction chambers Induction chambers Useful for small species Minimal restraint needed

Face masks Facemasks Need close restraint Or Induction chamber first Injectable agents first

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