Michael H. Ossipov, Ph.D. Department of Pharmacology

1. General Anesthetics Michael H. Ossipov, Ph.D. Department of Pharmacology

2. Surgery Before Anesthesia

3. Fun and Frolics led to Early Anesthesia

4. History of Anesthesia (150 years old) Joseph Priestly – discovers N2O in 1773 Crawford W. Long – 1842. Country Dr. in Georgia first used ether for neck surgery. Did not publicize, in part because of concerns about negative fallout from “frolics”. Tried to claim credit after Morton’s demonstration but… Important lesson learned – if you don’t publish it, it didn’t happen. Sir Humphrey Davy – experimented with N2O, reported loss of pain, euphoria Traveling shows with N2O (1830’s – 1840’s) Colt (of Colt 45 fame) Horace Wells 1844. Demonstrated N2O for tooth extraction – deemed a failure because patient “reacted”.

5. History of Anesthesia William Morton, dentist – first demonstration of successful surgical anesthesia with ether 1846 John C. Warren, surgeon at MGH says “Gentlemen, this is no humbug!” – birth of modern anesthesia Dr. John Snow administers chloroform to Queen Victoria (1853)– popularizes anesthesia for childbirth in UK He becomes the first anesthesia specialist. Note that ether became anesthesia of choice in US, chloroform in UK

6. Anesthesia • Allow surgical, obstetrical and diagnostic procedures to be performed in a manner which is painless to the patient • Allow control of factors such as physiologic functions and patient movement

7. Anesthetic techniques • General anesthesia • Regional anesthesia • Local anesthesia • Conscious Sedation (monitored anesthesia care)

8. What is “Anesthesia” • No universally accepted definition • Usually thought to consist of: • Oblivion • Amnesia • Analgesia • Lack of Movement • Hemodynamic Stability

9. What is “Anesthesia” • Sensory • -Absence of intraoperative pain • Cognitive: • -Absence of intraoperative awareness • -Absence of recall of intraoperative events • Motor: • -Absence of movement • -Adequate muscular relaxation • Autonomic: • -Absence of hemodynamic response • -Absence of tearing, flushing, sweating

10. Goals of General Anesthesia • Hypnosis (unconsciousness) • Amnesia • Analgesia • Immobility/decreased muscle tone • (relaxation of skeletal muscle) • Inhibition of nociceptive reflexes • Reduction of certain autonomic reflexes • (gag reflex, tachycardia, vasoconstriction)

11. Rapid induction Sleep Analgesia Secretion control Muscle relaxation Rapid reversal Desired Effects Of General Anesthesia (Balanced Anesthesia)

12. Phases of General Anesthesia Stages Of General Anesthesia • Induction- initial entry to surgical anesthesia • Maintenance- continuous monitoring and medication • Maintain depth of anesthesia, ventilation, fluid balance, hemodynamic control, hoemostasis • Emergence- resumption of normal CNS function • Extubation, resumption of normal respiration

13. Stages Of General Anesthesia Phases of General Anesthesia Stage I: Disorientation, altered consciousness Stage II: Excitatory stage, delirium, uncontrolled movement, irregular breathing. Goal is to move through this stage as rapidly as possible. Stage III: Surgical anesthesia; return of regular respiration. Plane 1: “light” anesthesia, reflexes, swallowing reflexes. Plane 2: Loss of blink reflex, regular respiration (diaphragmatic and chest). Surgical procedures can be performed at this stage. Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation needed. Level of anesthesia for painful surgeries (e.g.; abdominal exploratory procedures). Plane 4: Diaphragmatic respiration only, assisted ventilation is required. Cardiovascular impairment. Stage IV: Too deep; essentially an overdose and represents anesthetic crisis. This is the stage between respiratory arrest and death due to circulatory collapse.

14. Routes of Induction • Intravenous • Safe, pleasant and rapid • Mask • Common for children under 10 • Most inhalational agents are pungent, evoke coughing and gagging • Avoids the need to start an intravenous catheter before induction of anesthesia • Patients may receive oral sedation for separation from parents/caregivers • Intramuscular • Used in uncooperative patients

15. Anesthetic Techniques • Inhalation anesthesia • Anesthetics in gaseous state are taken up by inhalation • Total intravenous anesthesia • Inhalation plus intravenous (“Balanced Anesthesia”) • Most common

16. Anesthetic drugs have rapid onset and offset • “Minute to minute” control is the “holy grail” of general anesthesia • Allows rapid adjustment of the depth of anesthesia • Ability to awaken the patient promptly at the end of the surgical procedure • Requires inhalation anesthetics and short-acting intravenous drugs

17. Anesthetic Depth • During the maintenance phase, anesthetic doses are adjusted based upon signs of the depth of anesthesia • Most important parameter for monitoring is blood pressure • There is no proven monitor of consciousness

18. Selection of anesthetic technique • Safest for the patient • Appropriate duration • i.v. induction agents for short procedures • Facilitates surgical procedure • Most acceptable to the patient • General vs. regional techniques • Associated costs

19. MAC – Minimal Alveolar Concentration • "The alveolar concentration of an inhaled anesthetic that prevents movement in 50% of patients in response to a standardized stimulus (eg, surgical incision)." • A measure of relative potency and standard for experimental studies. • MAC values remain constant regardless of stimuli, weight, sex, and even across species • Steep DRC: 50% respond at 1 MAC but 99% at 1.3 MAC • MAC values for different agents are approximately additive. (0.7 MAC N2O + 0.6 MAC halothane = 1.3 MAC total) • "MAC awake," (when 50% of patients open their eyes on request) is approximately 0.3. • Light anesthesia is 0.8 to 1.2 MAC, often supplemented with adjuvant i.v. drugs

20. Factors Affecting MAC • Circadian rhythm • Body temperature • Age • Other drugs • Prior use • Recent use

21. How do Inhalational Anesthetics Work? • Surprisingly, the mechanism of action is still largely unknown. • "Anesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience," James Sonner, M.D. (UCSF) • Anesthesia research "has been for a long time a science of untestable hypotheses," Neil L. Harrison, M.D. (Cornell University)

22. How do Inhalational Anesthetics Work? Meyer-Overton observation: There is a strong linear correlation between lipid solubility and anesthetic potency (MAC)

23. How do Inhalational Anesthetics Work? • Membrane Stabilization Theory: • Site of action in lipid phase of cell membranes (membrane stabilizing effect) or • Hydrophobic regions of membrane-bound proteins • May induce transition from gel to liquid crystalline state of phospholipids • Supported by NMR and electron-spin resonance studies • Anesthesia can be reduced by high pressure

24. How do Inhalational Anesthetics Work? • Promiscuous Receptor Agonist Theory: Anesthetics may act at GABA receptors, NMDA receptors, other receptors • May act directly on ion channels • May act in hydrophobic pouches of proteins associated with receptors • May effect allosteric interaction to alter affinity for ligands • Immobility is due to a spinal mechanism, but site is unknown • “Overall, the data can be explained by supposing that the primary target sites underlying general anesthesia are amphiphilic pockets of circumscribed dimensions on particularly sensitive proteins in the central nervous system.” – Franks and Lieb, Environmental Health Perspectives 87:199-205, 1990.

26. Potentiation of inhibitory ‘receptors’ GABAA Glycine Potassium channels Inhibition of excitatory ‘receptors’ NMDA (glutamate) AMPA (glutamate) Nicotinic acetylcholine Sodium channels Receptors Possibly Mediating CNS Effects Of Inhaled Anesthetics Inferred from demonstration of effect on receptor at clinically relevant concentrations and lack of effect in absence of receptor

27. Inhaled Anesthetics • Gases • Nitrous oxide • Present in the gaseous state at room temperature and pressure • Supplied as compressed gas

28. Inhaled Anesthetics • Volatile anesthetics • Present as liquids at room temperature and pressure • Vaporized into gases for administration

29. Inhaled Anesthetics • Volatile anesthetics • Present as liquids at room temperature and pressure –BUT NOT ALWAYS! • Vaporized into gases for administration

30. Concentration of Inhaled Anesthetics Determines Dose • Partial pressure (mmHg) • Applies to gas phase or to dissolved gases • Volumes % • Percentage of total gas volume contributed by anesthetic • Percentage of total gas molecules contributed by anesthetic • Partial pressure/atmospheric pressure

31. Solubility of Inhaled Anesthetics Determines Dose and Time-course • Ratio of concentration in one phase to that in a second phase at equilibrium • Important solubility coefficients for inhaled anesthetics • Lower blood-gas partition coefficient leads to faster induction and emergence • Higher oil-gas partition coefficient leads to increased potency

32. Chemistry (CF3)2CH-O-CH3 10%, excellent anesthesia CF3CHFCF2-O-CH3 5%, light anesthesia, tremors CF3CH2-O-CF2CH2F 3%, convulsions CF3CH2-O-CH2CF3 (Indoklon) 0.25%, marked convulsions CF3CF2-O-CF2CF3 Inert From: F.G. Rudo and J.C. Krantz, Br. J. Anaesth. (1974), 46, 181

33. Inhaled Anesthetics

34. Inhaled Anesthetics - Historical • Ether – Slow onset, recovery, explosive • Chloroform – Slow onset, very toxic • Cyclopropane – Fast onset, but very explosive • Halothane (Fluothane) – first halogenated ether (non-flammable) • 50% metabolism by P450, induction of hepatic microsomal enzymes; TFA, chloride, bromide released • Myocardial depressant (SA node), sensitization of myocardium to catecholamines • Hepatotoxic • Methoxyflurane (Penthrane) - 50 to 70% metabolized • Diffuses into fatty tissue • Releases fluoride, oxalic acid • Renotoxic

35. Inhaled Anesthetics – Currently • Enflurane (Ethrane) Rapid, smooth induction and maintenance • 2-10% metabolized in liver • Introduced as replacement for halothane, “canabilized” to make way for isoflurane • Isoflurane (Forane) smooth and rapid induction and emergence • Very little metabolism (0.2%) • Control of Cerebral blood flow and Intracranial pressure • Potentiates muscle relaxants, Uterine relaxation • CO maintained, arrhythmias uncommon, epinephrine can be used with isoflurane; Preferential vasodilation of small coronary vessels can lead to “coronary steal” • No reports of hepatotoxicity or renotoxicity • Most widely employed

36. Inhaled Anesthetics – New Kids on the Block • Desflurane (Suprane) – Very fast onset and offset (minute-to minute control) because of its low solubility in blood • Differs from isoflurane by replacing one Cl with F • Minimal metabolism • Very pungent - breath holding, coughing, and laryngeal spasm; not used for induction • No change in cardiac output; tachycardia with rapid increase in concentration, No coronary steal • Degrades to form CO in dessicated soda-lime (Ba2OH /NaOH/KOH; not Ca2OH) • Fast recovery – responsive within 5-10 minutes

37. Inhaled Anesthetics – New Kids on the Block • Sevoflurane (Ultane) – Low solubility and low pungency = excellent induction agent • Significant metabolism (5%; 10x > isoflurane); forms inorganic fluoride and hexafluoroisopropranolol • No tachycardia, Prolong Q-T interval, reduce CO, little tachycardia • Soda-lime (not Ca2OH) degrades sevoflurane into “Compound A” • Nephrotoxic in rats • Occurs with dessicated CO2 absorbant • Increased at higher temp, high conc, time • No evidence of clinical toxicity • Metallic/environmental impurities can form HF

38. Inhaled Anesthetics – Currently • Nitrous Oxide is still widely used • Potent analgesic (NMDA antagonist) • MAC ~ 120% • Used ad adjunct to supplement other inhalationals • Xenon • Also a potent analgesia (NMDA antagonist) • MAC is around 80% • Just an atom – what about mechanism of action?

39. Malignant Hyperthermia Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic state of skeletal muscle induced in susceptible individuals by inhalational anesthetics and/or succinylcholine (and maybe by stress or exercise). • Genetic susceptibility-Ca+ channel defect (CACNA1S) or RYR1 (ryanodine receptor) • Excess calcium ion leads to excessive ATP breakdown/depletion, lactate production, increased CO2 production, increased VO2, and, eventually, to myonecrosis and rhabdomyolysis, arrhythmias, renal failure • May be fatal if not treated with dantrolene – increases reuptake of Ca++ in Sarcoplasmic Reticulum • Signs: tachycardia + tachypnea + ETCO2 increasing + metabolic acidosis; also hyperthermia, muscle rigidity, sweating, arrhythmia • Detection: • Caffeine-halothane contracture testing (CHCT) of biopsied muscle; • Genetic testing for 19 known mutations associated with MH

40. Intravenous Anesthetics • Most exert their actions by potentiating GABAA receptor • GABAergic actions may be similar to those of volatile anesthetics, but act at different sites on receptor • High-efficacy opiods (fentanyl series) also employed • Malignant hyperthermia is NOT a factor with these

41. Intravenous Anesthetics

42. Organ Effects • Most decrease cerebral metabolism and intracranial pressure. Often used in the treatment of patients at risk for cerebral ischemia or intracranial hypertension. • Most cause respiratory depression • May cause apnea after induction of anesthesia

43. Cardiovascular Effects • Barbiturates, benzodiazepines and propofol cause cardiovascular depression. • Those drugs which do not typically depress the cardiovascular system can do so in a patient who is compromised but compensating using increased sympathetic nervous system activity.

44. Intravenous Anesthetics - Barbiturates Ideal: Rapid Onset, short-acting Thiopental (pentathol)- previously almost universally used For over 60 years was the standard against which other injectable induction agents/anesthetics were compared Others: Suritol (thiamylal); Brevital (methohexital) Act at GABA receptors (inhibitory), potentiate endogenous GABA activity at the receptor, direct effect on Cl channel at higher concentrations. Effect terminated not by metabolism but by redistribution repeated administration or prolonged infusion approached equlibrium at redistribution sites. Redistribution not effective in terminating action, led to many deaths. Build-up in adipose tissue = very long emergence from anesthesia (e.g.; one case took 4 days to emerge)

45. Propofol (Diprivan) • Originally formulated in egg lecithin emulsion • anaphylactoid reactions • Current formulation: 1% propofol in 10% soybean oil, 2.25% glycerol, 1.2% egg phosphatide • Pain on injection • Onset within 1 minute of injection • Not analgesic • Enhances activity of GABA receptors (probably) • Vasodilation, respiratory depression, apnea (25% to 40%) • Induction and maintenance of anesthesia or sedation • Rapid emergence from anesthesia • Antiemetic effect • Feeling of well-being • Widely used for ambulatory surgery

46. Etomidate (Amidate) • Insoluble in water, formulated in 35% propylene glycol (pain on injection) • Little respiratory depression • Minimal cardiovascular effects • Rapid induction (arm-to-brain time), duration 5 to 15 minutes • Most commonly used for induction of anesthesia in patients with cardiovascular compromise; or where cardiovascular stability is most important • Metabolized to carboxylic acid, 85% excreted in urine, 15% in bile • Rapid emergence from anesthesia • Adverse effects: Pain, emesis, involuntary myoclonic movements, inhibition of adrenal steroid synthesis

47. Ketamine • Chemically and pharmacologically related to PCP • Inhibits NMDA receptors • Analgesic, dissociative anesthesia • Cataleptic appearance, eyes open, reflexes intact, purposeless but coordinated movements • Stimulates sympathetic nervous system • Indirectly stimulates cardiovascular system, Direct myocardial depressant • Increases cerebral metabolism and intracranial pressure • Lowers seizure threshold • Psychomimetic – “emergence reactions” • vivid dreaming extracorporeal (floating "out-of-body") experience misperceptions, misinterpretations, illusions • may be associated with euphoria, excitement, confusion, fear

48. Benzodiazepines • Diazepam (Valium, requires non-aqueous vehicle, pain on injection); Replaced by Midazolam (Versed) which is water-soluble. • Rapidly redistributed, but slowly metabolized • Useful for sedation, amnesia • Not analgesic, can be sole anesthetic for non-painful procedures (endoscopies, cardiac catheterization) • Does not produce surgical anesthesia alone • Commonly used for preoperative sedation and anxiolysis • Can be used for induction of anesthesia • Safe – minimal respiratory and cardiovascular depression when used alone, but they can potentiate effects of other anesthetics (e.g.; opioids) • Rapid administration can cause transient apnea

49. Opioids • i.v. fentanyl, sufentanil, alfentanil, remifentanyl or morphine • Usually in combination with inhalant or benzodiazepine • Respiratory depression, delayed recovery, nausea and vomiting post-op • Little cardiovascular depression; Provide more stable hemodynamics • Smooth emergence (except for N & V) • Excellent Analgesic: intra-operative analgesia and decrease early postoperative pain • Remifentanil: has ester linkage, metabolized rapidly by nonspecific esterases (t1/2 = 4 minutes; fentanyl t1/2 = 3.5 hours) • Rapid onset and recovery • Recovery is independent of dose and duration – offers the high degree of “minute to minute” control

50. Conscious sedation • A term used to describe sedation for diagnostic and therapeutic procedures throughout the hospital. • Ambiguous because no one really knows how to measure consciousness in the setting of a patient receiving sedation.