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

2. Overview Historical Perspective Definition of General Anesthesia
Mechanism of Anesthesia
Anesthetic Agents (volatile & intravenous)

3. Surgery before 1846
Hippocrates ( , BC) a treatise on surgery, but little sympathy for the patient.
Greek surgeon Dioscorides (40- 70, AD) His book “Materia Medica” described the effects of mandroga & wine to produce anesthesia.

4. Surgery before 1846
Middle ages: Alcohol fumes as an analgesic during surgery, soporific sponge (opium & scopolamine) marijuana, belladonna and jimsonweed.
Hypnosis, strangulation…

5. History Crawford Long, 1842: Ether anesthesia first ideal anesthetic.
Dt.Horace Wells, 1846: Nitrous Oxide
Unsuccessful demo in Boston Mass general

6. Public Demo of Ether Anesthesia “Gentlemen, this is no Humbug”
Dt. William Morton,
October 16, 1846
Ether anesthesia in ETHER DOME (MASS General Hospital)
Patient Gilbert Abbot

7. Ether “Letheon” Inhaler
Morton named his “creation” Letheon, after the Lethe River of Greek mythology. ..The river of forgetfulness, oblivion.
“The Letheon” In classical Greek mythology, the waters of the River Lethe expunged painful memories.

8. Ether “Letheon” Flammable Prolonged induction Unpleasant odor
High incidence of nausea-vomiting

9. Chloroform, 1847: James Simpson; Hepatotoxic, ventricular fibrillation
Cyclopropane, 1929: Most widely used general anesthetic for the following 30 years, explosive !
Halothane, 1956: Although widely replaced with new generation volatiles, it is still in use.
Methoxyflurane, 1960: Nephrotoxicity. Most potent of all the volatiles.
Sevoflurane & Desflurane, late 1960s
Thiopental, intravenous anesthetic, synthesized in the early 1930s by Ernest H Volwiler

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

11. Sleep & death are brothers (Ancient Greek proverb)
The god of Sleep “Hypnos” is the younger brother of the god of death “Thanatos”. Both of them are the children of Nyx, the goddess of night.

12. Theories of general anesthetic action
Lipid solubility-anesthetic potency correlation
“The Meyer-Overton correlation”
Anesthetic potency is related to lipid solubility. 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, Nicotinic receptors can be selectively modified by clinical concentrations of volatiles.
* Franks NP. Nature, 300: 1982.

14. Anatomic regions of brain responsible for the general anesthetic action
THALAMUS (Inhibition of Ni Ach receptors)
HIPOTHALAMUS (Histaminergic, orexinergic neurons)
BRAIN STEM (Noradrenergic neurons of LC. α2-agonists)
LIMBIC SYSTEM (Hippocampus and Amygdala; memory function and anesthetic mediated amnesia)

15. 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”, the potential result is loss of consciousness.
Existing evidence provides no basis for a single anatomic site responsible for anesthesia.

16. 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.

17. 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.

18. 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.

19. 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

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

21. BARBITURATES
Depress RAS located in the brainstem & 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 sec.

22. BARBITURATES USES 1. Anesthesia 2. Medically induced coma
3. Euthanasia
4. Lethal injection
5. Truth serum
6. Psychiatry

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

24. BENZODIAZEPINES (Diazepam, Midazolam)
Absorbtion: Oral, IM, IV, SL, rectal, buccal.
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.

25. Midazolam is used for: Emergency treatment of seizures
Sedation during medical procedures
Premedication prior to medical procedures

26. Buccal Midazolam for epilepsy treatment
Midazolam can be:
Trickled inside the cheek – buccal
Dripped into the nose – intranasal
Injected into a vein (IV) or muscle (IM)

27. KETAMINE (PHENCYCLIDINE ANALOGUE)
IV, IM, oral.
NMDA-Antagonist (glutamate subtype)
Functionally dissociates the THALAMUS from the LIMBIC cortex.
Dissociative anesthesia.
Analgesic, amnestic, hypnosis.
Ketamine anesthesia was first given to American soldiers during the Vietnam War.

28. ETOMIDATE Depresses RAS, Myoclonic activity (decreased with opioids),
Pain on injection,
Rapid onset of action,
Hydrolysed by hepatic microsomal enzyme & plasma esterases,
Excreted in urine.

29. 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.

30. PROPOFOL (2,6-DIISOPROPYLPHENOL)
Fascilitates the inhibitory neurotransmission mediated by GABA,
Pain on injection (iv),
Bacterial growth in the formula. Use within 6 hours after opening the formula

31. IV ANESTHETIC AGENTS Endocrine: PROPOFOL CVS Respiratory CNS Hepatic
Immune
Thiopental
HR 
BP 
Apne
Laryngospasm bronchospasm
Controls epilepsia
CBF ICP
CPP CMRO2
HBF
Porfiria precipitation
Histamine release (avoid in asthma)
Midazolam
Minimal effect
Insignificant depression
Apnea
CMRO2 -
Ketamine
My ischemia
CO
BP 
Minimally effected
Laryngospasm
Bronchospasm
Salivation
CBF ICP
CMRO2
Hallucinogen
Myoclonic activity
Etomidate
Less effect
Rarely apnea
CPP maintained
Endocrine:
Adrenocortical supression
PROPOFOL
HR 
Profound depression
ANTIEMETIC

32. Pharmacokinetics of Inhaled Anesthetics
Amount that reaches the brain is determined by:
Lipid solubility (oil:gas partition ratio) –its related to MAC-
Alveolar partial pressure of anesthetic
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.

33. Pathway for General Anesthetics

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

35. 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 Control
Pulmonary blood flow (function of CO)
Arterio-venous concentration gradient

36. 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.
A blood:gas PC ( oil gas partition coefficient) of 0.5 means that the concentration of the volatile agent in the blood is half that present in the alveolar gas when the partial pressure of the anesthetic is identical at both sites.
o PC in an inhalation anesthetic is most commonly used to refer to its solubility in a given solvent (e.g., oil, blood etc.). o A very potent anesthetic (e.g.methoxyflurane) has a low MAC value and a high oil/gas PC, whereas a low potency agent (e.g.N2O) has a high MAC and low oil/gas PC. o In other words, an anesthetic with a high oil solubility (i.e., high oil/gas PC) is effective at a low alveolar concentration and has a high potency.

37. 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

38. Systemic Effects of Inhaled Anesthetics
Respiration: Depress respiration and response to CO2
Kidney: Depress renal blood flow and urine output
Muscle: High concentrations relax skeletal muscle
CNS: Increased cerebral blood flow, decreased cerebral metabolism

39. Cardiovascular System
Reduced blood pressure and peripheral vascular resistance. Isoflurane maintains CO and coronary function better than other agents.

40. 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

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

42. Nitrous Oxide Its potency is low
Weak anesthetic, relatively powerful analgesic
It must be used with other agents for surgical anesthesia
Low blood solubility (quick recovery)

43. 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

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

45. Side effects (Nitrous Oxide)
N2O inhibits methionine synthetase (precursor to DNA synthesis) & vitamin B12 metabolism,
Dentists, OR personnel, abusers are at risk.

46. Methoxyflurane, 1960 Halogen substituted ethane, not flammable.
Most potent inhalational anesthetic
Prolonged induction & emergence from anesthesia
Nephrotoxic & Hepatotoxic

47. Methoxyflurane
Since the 1970s it has been used in Australia in lower doses for acute analgesia, largely by paramedic services.
Self administered by the patients.

48. Halothane, 1956 Halogen substituted ethane. Stable and nonflammable
Most potent inhalational anesthetic (except for the methoyflurane)
Very soluble in blood and adipose tissue
Prolonged emergence

49. Shallow respiration -- atelectasis
Sensitizes myocardium to effects of exogenous catecholamines-- ventricular arrhythmias
Depresses myocardium-- lowers BP and slows conduction-
Decreases respiratory drive-- central response to CO2-
Shallow respiration -- atelectasis
Depresses protective airway reflexes

50. 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).

51. 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%

52. Isoflurane Metabolized into trifluoroacetic acid
Nephrotoxicity is extremely unlikely
Coronary steal syndrome (experimental !)

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

54. 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)

55. 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

56. Desflurane Disadvantages Advantages High cost Insoluble
CNS stimulation (minor)
Not suitable for induction
CO production (not relevant)
Advantages
Insoluble
Fast induction/emergence
Low residual at the end of case

57. 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 sodalime
In general, not clinically significant
No deaths reported

58. 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)

59. 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

60. Anesthesia