The document provides a history of anesthetic agents, beginning with diethyl ether in 1846 and progressing to modern volatile agents like sevoflurane. It discusses the properties of each agent that made them viable or led to their discontinuation. It also defines the minimum alveolar concentration (MAC) concept for measuring anesthetic potency based on immobilization during incision. Factors that increase or decrease MAC values are outlined.

2. HISTORY
• Diethyl ether first used by William T.G. Morton in the USA in
1846
• Ether survived as a viable agent for many years because it,
a. is readily made in pure form
b. is a volatile liquid, therefore easily vaporized
c. is potent, only a few volumes % required, averting hypoxia
d. supported respiration and the circulation
• Chloroform was the next agent to receive attention, by James
Simpson in 1847
• Apart from its pleasant odour and nonflammability, it had
major problems,
a. severe cardiovascular depression (sudden death ? VF)

3. • Cyclopropane was discovered accidentally in 1929 and was very
popular for almost 30 years.
• However, the increasing use of electronic equipment
necessitated the production of a nonflammable agent
• A variety of other agents were investigated but discarded for
various reasons,
a. explosive mixtures with oxygen:
diethyl ether
ethyl chloride
divinyl ether
cyclopropane
b. postoperative liver necrosis / sudden death - chloroform
c. postoperative renal failure - methoxyflurane

4. • Halothane, developed by ICI, was introduced in 1956 and
revolutionized anesthetic practice
• It has come in to some disrepute for postoperative liver failure
• Enflurane has been in use since 1970
• Difficulties with purification and suspected cardiotoxicity delayed the
introduction of its isomer, isoflurane, until 1981.
• Desflurane was introduced in 1992.
• It has the highest onset and offset of action of the volatile anesthetic
drugs. However, it has a low potency, and its high cost prohibits its
use in less developed countries.
• Sevoflurane was introduced in 1994 and is currently the most
commonly used volatile anesthetic agent worldwide.

5. MINIMUM ALVEOLAR
CONCENTRATION
• Eger and colleagues defined this concept in the
1960s.
• Definition: the minimum alveolar concentration of
anesthetic, at equilibrium, at one atmosphere
pressure, which produces immobility in 50% of
subjects exposed to a standard noxious stimulus,
which, for humans is surgical incision of the skin.
• It is a measure of anesthetic potency.

6. • The rationale for this measure of anesthetic potency
is,
a. alveolar concentration can be easily measured
b. near equilibrium, alveolar and brain tensions are virtually
equal
c. the high cerebral blood flow produces rapid equilibration
• Factors which support the use of this measure are,
a. MAC is invariant with a variety of noxious stimuli
b. individual variability is small
c. sex, height, weight & anaesthetic duration do not alter MAC
d. doses of anaesthetics in MAC's are additive

7. • Analogous to ED50 expressed for intravenous drugs.
• Although only 50% of subjects do not respond at 1
MAC, 99% are unresponsive at 1.3 MAC
• For a number of anesthetic gases, 1.3 MAC ~ 21
mmol/l in brain lipids
• MAC represents only a single point on the dose
response curve for the production of anesthesia; other
effects, such as cardiovascular depression, may not be
proportional

8. FACTORS WHICH AFFECT MAC
Increase MAC
i. hyperthermia
ii. hypernatremia
iii. drug induced elevation of CNS catecholamine
stores
iv. chronic alcohol abuse ? chronic opioid abuse
(MCQ)
v. increases in ambient pressure (experimental)

9. Decrease MAC
i. hypothermia:
halothane MAC27°C ~ 50% MAC37°C
decrease is ~ linear
ii. hyponatremia
iii. increasing age:
MACHal < 3 mths ~ 1.1 %
MACHal > 60 yrs ~ 0.64 %
iv. Hypoxemia:
PaO2 ≤ 40 mmHg

10. v. hypotension
vi. anemia
vii. pregnancy ? progesterone
viii. CNS depressant drugs:
Opioids
Benzodiazepines
major tranquilizers
TCA's
ix. other drugs:
Lithium
Lignocaine
Magnesium
pancuronium (?)
x. acute alcohol abuse

11. No Change in MAC
i. sex
ii. weight, BSA
iii. type of supramaximal stimulus
iv. duration of anesthesia
v. hypo/hyperkaliemia
vi. hypo/hyperthyroidism
vii. PaCO2 ~ 15-95 mmHg
viii. PO2 > 40 mmHg
ix. MAP > 40 mmHg

12. SIGNIFICANCE OF MAC
• The concept of MAC evolved within a unitary paradigm of
anesthetic action and reflected the priorities of clinical practice.
• As a result, prevention of movement (immobility) became a
universal yardstick for anesthetic effects.
• Because inhaled anesthetic concentrations reflect
concentrations in the tissues after equilibration, which is most
rapidly achieved for well-perfused organs such as the brain and
heart, MAC is analogous to the plasma concentration for 50%
effect (EC50) for intravenous anesthetics.

13. • In clinical applications, MAC is usually expressed as volume
percent (vol%), which varies considerably with temperature and
atmospheric pressure caused by changes in aqueous solubility,
whereas the equivalent liquid phase molar concentration is
temperature- and pressure-independent.
• The MAC concept provided researchers and clinicians with a
universal standard to measure a defined anesthetic end point
(immobility), making meaningful comparisons of experimental
results possible and accelerating clinical and laboratory
research into anesthetic mechanisms.
• Today, a more nuanced understanding of MAC takes into
account the structural and functional diversity of the

14. MAC Awake
•MAC of anaesthetic that would allow opening of
eyes on verbal commands during emergence
from anaesthesia
•~0.3-0.4 MAC
MAC Intubation
•MAC that would inhibit movement and
coughing during endotracheal intubation.
•~1.3 MAC

15. MAC Bar
•MAC of anaesthetic necessary to prevent
adrenergic response to skin incision, as measured
by conc. Of catecholamine in venous blood
•~1.5 MAC
•When different agents are compared the ratio of
MAC skin incision to MAC intubation or MAC
awake is relatively constant

17. HISTORICAL AGENTS

18. DIETHYL ETHER

19. • First prepared by V. Cordus in 1540 by condensation
with sulphuric acid
• Used for tooth extraction by W.E. Clarke in 1842
• First public demonstration by W. Morton in 1846 in
Boston
• Highly volatile and poor stability, therefore avoid light,
heat, air
• Excellent analgesic : stages/planes of anesthesia
• Stimulates respiration, therefore less danger of
hypoxia

20. WHY ETHER WENT OUT OF USE?
• Unwanted effects of exposure to ether can include a
cough, sore throat, painful red eyes, a headache,
drowsiness, laboured breathing and nausea. Vomiting
is quite common.
• Ether is not just flammable, it is explosive. With
electrocautery in widespread use these days, you just
couldn’t use ether without serious risk of a fire in the
operating room.
• Because of high solubility in body tissues, recovery is
slow and agonizing.

21. CHLOROFORM

22. •Anesthetic action discovered by P. Flourens in
France 1847
•First employed by Simpson, in Scotland 1847
•Nonflammable
•In 1864, the Report of Chloroform Committee
of Royal Medical and Chirurgical Society
endorsed chloroform as Britain's favorite
anesthetic. But ether was safer for patients.

23. WHY CHLOROFORM WENT OUT OF USE?
• A substantial but variable percentage of chloroform from
inspired air is retained in the body; it is extensively
metabolized by the liver.
• Metabolites of chloroform include phosgene, carbene and
chlorine, all of which may contribute to its cytotoxic activity.
• Prolonged administration of chloroform as an anesthetic can
cause toxaemia. Acute poisoning is associated with headache,
altered consciousness, convulsions, respiratory paralysis and
disturbances of the autonomic nervous system: dizziness,
nausea, and vomiting are common. Chloroform may also cause
delayed-onset damage to the liver, heart and kidneys.
• Chloroform has modest "abuse potential".

24. CYCLOPROPANE

25. • First prepared by Freud, in Germany in 1881
• First used for anesthesia by R.M. Waters, in U.S.A.
• Must use in closed circuit to minimize cost and reduce danger
of explosion
• Incompatible for use with nitrous oxide, as supports
combustion
• Very rapid induction
• SNS stimulant - "cyclopropane shock"
• Respiratory depressant
• Arrhythmogenic, therefore must avoid adrenaline
• Good muscle relaxant

26. WHY CYCLOPROPANE WENT OUT OF USE?
• Explosive: This property makes it incompatible for use with
nitrous oxide, which supports combustion.

27. TRICHLORETHYLENE

28. • first manufactured by Fischer in Germany in 1864
• first used clinically by Jackson in U.S.A. in 1934
• nonflammable
• potent analgesic

29. WHY TRICHLOROETHYLENE WENT OUT OF USE?
• Unstable in soda lime circuit – dichloracetylene: this causes
cranial nerve palsies, esp. V & VII.
• Arrhythmogenic
• Causes significant nausea and vomiting.

30. NEWER VOLATILE AGENTS

31. HALOTHANE

32. Advantages
a. moderately high potency
b. moderately low blood: gas partition coefficient: induction and recovery not
prolonged
moderately rapid changes in depth of anesthesia
c. relatively non-irritant and bronchodilator: laryngospasm and bronchospasm
uncommon
d. nonflammable & nonexplosive in combination with O2
e. hypotensive effect sometimes desirable
f. uterine relaxation sometimes desirable
Disadvantages
a. only sleep is completely obtained: require additional analgesia, muscle
relaxation, etc.
b. hypoxia/hypercapnia - respiratory depression
c. hypotension

33. ENFLURANE

34. Advantages
a. moderately high potency
b. low blood: gas partition coefficient rapid induction of and recovery from
anaesthesia
rapid changes in depth of anesthesia
c. relatively non-irritant and bronchodilator laryngospasm and bronchospasm
uncommon
d. nonflammable & nonexplosive in combination with O2
e. muscle relaxation is often adequate for surgery
f. incidence of arrhythmias is less than halothane
g. uterine relaxation sometimes desirable
Disadvantages
a. deep anesthesia with enflurane respiratory & circulatory depression,
hypoxia/hypercapnia/hypotension
b. seizure activity may occur with high concentrations, or hypocarbia
c. uterine relaxation contraindicated at parturition

35. METHOXYFLURANE

36. Advantages
a. provides profound analgesia
b. nonflammable & nonexplosive in combination with O2
c. enhancement of muscle relaxation
d. doesn't relax uterine smooth muscle: analgesia in labor
Disadvantages
a. deep anesthesia with MF profound respiratory & circulatory depression
hypoxia/hypercapnia/hypotension
b. renal toxicity has effectively removed it from general use
c. slow induction, changes of depth, and emergence from anaesthesia

37. ISOFLURANE

38. Advantages
a. moderately high potency
b. low blood:gas partition coefficient ® rapid induction of and recovery from anaesthesia
rapid changes in depth of anaesthesia
c. nonflammable & nonexplosive in combination with O2
d. enhancement of muscle relaxation
e. incidence of arrhythmias is less than halothane
f. maintenance of CO and lack of myocardial depression
g. minimal biotransformation
h. ICP controllable via PaCO2
Disadvantages
a. deep anaesthesia with isoflurane ® respiratory & circulatory depression
hypoxia/hypercapnia/hypotension
b. more pungent odour and initial respiratory irritation
c. possible subendocardial steal syndrome with hypotension in IHD
d. uterine relaxation contraindicated at parturition
e. more expensive

39. DESFLURANE

40. SEVOFLURANE

41. NITROUS OXIDE

42. • N2O is a colourless gas, without appreciable odour or taste
• first synthesised by Priestly in 1772
• first used in anaesthetic practice by Cotton & Wells in 1844
• the gas is neither flammable, nor explosive, but will support
combustion of flammable agents

43. Advantages
a. nonflammable & nonexplosive
b. non-irritant
c. potent analgesic
d. very rapid onset, changes in depth and recovery
e. little or no toxicity during normal applications
Disadvantages
a. weak anaesthetic agent
b. no augmentation of muscle relaxation
c. diffusion hypoxia on recovery
d. expansion of closed internal air-spaces
e. depressed methionine synthase activity: megaloblastic marrow changes
demyelination of the cord in long term abusers