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

2. 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

3. 18th Century Surgery
Original in the Royal College of Surgeons of England, London.

4. Sir Humphrey Davy at the Royal Institution

5. 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.

6. 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

7. 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

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

9. 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.

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

11. 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.

12. 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

13. 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.

14. 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!

15. 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

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

17. 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

18. 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

19. 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.

20. 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.

21. 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%

22. 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 ED 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.

23. 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.

24. 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.

25. 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

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

27. 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

28. 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.

29. 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

30. 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

31. 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

32. 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.

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

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

35. 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.

36. 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

37. 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.

38. 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

39. 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

40. 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

41. 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

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

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

44. 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

45. 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.

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

47. 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

48. 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

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

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

51. 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.

52. 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

53. Equipment used can be complex

54. Induction chambers Induction chambers Useful for small species
Minimal restraint needed

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

56. Thanks for your attention