1. Introduction to Anesthesiology Clinic
Özge Köner, MD
Anesthesiology Dept.

2. Schedule

4. 1st week
2nd week

5. Introduction to General Anesthesia
Özge Köner, MD
Anesthesiology Dept.

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

7. 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.

8. 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

9. 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

10. 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.

11. 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

12. 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 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"

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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

19. Anesthetics divide into 2 classes
Inhalation Anesthetics
Gases or Vapors
Usually Halogenated
Intravenous Anesthetics
Injections
Anesthetics or induction agents

20. 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

21. 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.

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

23. 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.

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

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

26. 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.

27. 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.

28. 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

29. 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

30. 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.

41. Pathway for General Anesthetics

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

43. 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

44. 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.

45. 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

46. 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

47. Cardiovascular System
Generalized reduction in arterial pressure and peripheral vascular resistance. Isoflurane maintains cardiac output and coronary function better than other agents

48. 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

49. Nitrous Oxide Simple linear compound Not metabolized
Only anesthetic agent that is inorganic
Colorless, odorless, tasteless

50. Nitrous Oxide Major difference is low potency
Weak anesthetic, powerful analgesic
Needs other agents for surgical anesthesia
Low blood solubility (quick recovery)

51. 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

52. Side effects (Nitrous Oxide)
Diffusion into closed spaces

53. Side effects (Nitrous Oxide)
Inhibits methionine synthetase (precursor to DNA synthesis) & vitamin B12 metabolism,
Dentists, operating room personnel, abusers are at risk.

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

55. 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

56. 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).

57. 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%

58. Isoflurane Metabolized into trifluoroacetic acid
Nephrotoxicity is extremely unlikely
NMBA are potentiated by isoflurane

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

60. 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)

61. 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

62. 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

63. 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

64. 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)

65. 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

66. 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