1. Dr. Milan Kharel presented on inhalational anesthetic agents and provided a history of anesthesia including the first use of diethyl ether and chloroform. 2. Key concepts around MAC, vapor pressure, blood solubility, and the three stages of gas transfer from inspired air to tissues were discussed. 3. Ideal properties of anesthetic agents include rapid induction and recovery, precise control of anesthetic depth, and an absence of toxic effects. Nitrous oxide, halothane, isoflurane, sevoflurane, and desflurane were compared based on their solubility and other characteristics.

1. Presentator – Dr.Milan Kharel
Moderator - Dr. Madhu Gyawali

2. INHALATIONAL ANAESTHETIC AGENT
Introduction
▶ IV anesthesia : induce anesthesia
Inhalation anesthesia : maintain anesthesia
▶ IV anesthesia : mg/KG or microgram/Kg
Inhalation anesthesia : Percentage of the volume
%
EXAMPLE:
2 L/min. O2 + 4 L/min N2O
Conc. Of N2O = 4/(2+4) = 66%

3. HISTORY OF ANESTHESIA

4. Diethyl ether first used by William T.G. Morton in the USA
in 1846
Chloroform was the next agent to receive attention, by James
Simpson in 1847 it was discontinued due to:-
a. severe cardiovascular depression (sudden death ? VF)
b. dose dependent hepatotoxicity
Cyclopropane was discovered accidentally in 1929 and was
very popular for almost 30 yrs
the increasing use of electronic equipment necessitated the
discontinuation of this inflammable agent.

5. Halothane, synthesized in 1951 by prominent
British chemist, Charles Walter Suckling,
while working at the Imperial Chemical
Industries (ICI). Later in 1956, M. Johnstone
used it clinically first time
Enflurane has been in use since 1970
Isoflurane- (1981), Desflurane-1996

6. 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

7. THE BASIC CONCEPTS…
7

8. MAC Definition
▶ Minimal alveolar concentration (MAC):
Is defined as the conc. At 1 atmosphere of
anesthetic in the alveoli that is required to
produce immobility in 50% of adults patient
subjected to a surgical incision
▶ MAC is important to compare the potencies
of various inhalational anesthetic agents
▶ 1.2 -1.3 MAC prevent movement in 95% of
patients
8

9. MAC Value
▶ N2O = 105%
▶ Halothane = 0.75%
▶ Isoflurane = 1.16%
▶ Euflurane = 1.68%
▶ Sevoflurane = 2%
▶ Deslurane = 6%
▶ N2O alone is unable to produce adequate
anesthesia ( require high conc. )
9

10. 10

11. No Effect on MAC
▶ Gender
▶ Duration of anesthesia
▶ Carbon dioxide tension (21-95 mmHg)
▶ Metabolic Acid base status
▶ Hypertension
▶ Hyperkalemia
11

12. Pressure exerted bythe molecules of the vapor phase at
equilibrium of molecules moving in and out of liquid phase
Vapor Pressure dependent on temperature and physical
characteristics of liquid, independent of atmospheric
pressure
↑ Temperature→↑ Vapor Pressure
Vapor pressure is a measure of the agent’s abilityto
evaporate (volatility) .The greater is the vapor pressure,
the greater the concentration of inhalant deliverable to
the patient (and environment).
Boiling Point: Temperature at which vapor pressure
equals atmospheric pressure
Vapour Pressure & BP

13. Vapour Pressure & BP
Agent BP (0C) VP (20 0C)
Halothane 50 243
Enflurane 56 175
Isoflurane 48 238
Sevoflurane 58 160
Desflurane 23 664
Nitrous Oxide -89
Xenon -107

15. 15

16. 1. Transfer from Inspired Air to Alveoli
i. the inspired gas concentration FI
ii. alveolar ventilation VA
iii. characteristics of the anaesthetic circuit
2. Transfer from Alveoli to Arterial Blood
i. blood:gas partition coefficient τB:G
ii. cardiac output CO
iii. alveoli to venous pressure difference dPA-vGas
3. Transfer from Arterial Blood to Tissues
i. tissue:blood partition coefficient τT:B
ii. tissue blood flow
iii. arterial to tissue pressure difference dPa-tGas

19. A)Inspired Gas Concentration FI:-
▶ according to Dalton's law of partial pressures, the
tension of an individual gas in inspired air is equal to,
▶ PIgas = FIgas x Atm
▶ the greater the inspired pressure the greater the
approach of FA to FI = the concentration effect
▶ this is only significant where FI is very high, as is
the case for N2O (or cyclopropane)
▶ when another gas is used in the presence of such an
agent, there is increased uptake of the second gas, the
Second gas effect

20. ▶ each inspiration delivers some anaesthetic to the
lung and, if unopposed by uptake into the blood,
normal ventilation would increase FA/FI to 95-98%
in 2 minutes
▶ this rate of rise is dependent upon minute
ventilation and FRC
▶ the greater the FRC, the slower the rise in FA
▶ hyperventilation will decrease CBF, and this tends
to offset the increased rise of FA/FI

21. ▶ A) Blood:Gas Partition Coefficient
▶ the solubility of a gas in liquid is given by its
Ostwald solubility coefficient, τ
▶ this represents the ratio of the concentration in blood
to the concentration in the gas phase
▶ lower B:G coefficients are seen with,
haemodilution ,obesity , hypoalbuminaemia and
starvation
▶ higher coefficients are seen in, adults versus
children, hypothermia & postprandially

22. Solubility of Inhaled Drugs
solubility (partition) coefficient - the extent to
which a gas will dissolve in a given solvent
Predicts the speed of induction, recovery
, and change in
anesthetic depth for an inhalant.
Ideal inhaled anesthetics should have low blood/gas and
low tissue/ blood solubilityand low solubilityin plastic
and rubber.
Low solubilitymeans rapid induction and emergence and
more precise control

23. Solubility of Inhaled Drugs
Halo Enflur Isoflur Sevofl Desfl N2O
Blood/G
as
2.54 1.8 1.4 0.69 0.42 0.47
Brain/Bl
ood
1.9 - 1.6 1.7 1.3 0.5
Fat/ 51 - 45 48 27 2.3
Blood

24. Solubility of Inhaled Drugs

25. ▶ Effective pulmonary blood flow determines the
rate at which agents pass from gas to blood
▶ an increase in flow will slow the initial portion of
the arterial tension/time curve by delaying the
approach of FA to FI
▶ a low CO state, conversely, will speed the rise of
FA/FI
▶ these effects are greater for highly soluble
agents

26. ▶ this represents tissue uptake of the inhaled
agent
▶ blood cannot approach equilibrium with alveolar air
until the distribution of anaesthetic from the blood
to the tissues is nearly complete
▶ with equilibration, the alveolar/mixed venous
tension difference progressively falls as tissue
tensions rises
▶ since diffusion is directly proportional to the tension
difference, the rate of diffusion into the blood
progressively slows

27. ▶ A) Tissue:Blood Partition Coefficient:-
▶ the rate of rise of tension in these regions is
proportional to the arterial-tissue tension difference
conversely, their solubility in lipid tissues is far
greater than that for blood
▶ at equilibrium the concentration in lipid tissues will be
far greater than that in blood
▶ the tissue concentration will rise above that of blood
well before pressure equilibrium, even though the
tissue tension is lower

28. ▶ Methoxyflurane- 61
▶ Halothane- 62
▶ Enflurane -36
▶ Isoflurane- 52
▶ Sevoflurane -55
▶ Desflurane - 30
▶ Nitrous Oxide- 2.3

29. ▶ the higher the blood flow to a region, the faster the
delivery of anaesthetic and the more rapid will be
equilibration
▶ the body tissues have been divided into groups
according to their level of perfusion and tissue
blood flow,

30. ▶ a. vessel rich group VRG - brain, heart,
kidney & liver
▶ b. the muscle group MG - muscle & skin
▶ c. the fat group FG - large capacity/minimal
flow
▶ d. vessel poor group VPG - bone, cartilage,
CT

31. ▶ with equilibration tissue tension rises and the rate
of diffusion slows, as does uptake in the lung
▶ the rate is determined by the tissue time constant,
which in turn depends upon both the tissue
capacity (τT:B) and the tissue blood flow
▶ TC(τ)= Tissue Capacity / 100g
Blood Flow/ 100g

32. ▶ Concentration and Second Gas Effects
▶ - increasing the inspired concentration not only
increases the alveolar conc but also increases the
rate of rise of volatile anaesthetic agents in the
alveoli
▶ eg., during the inhalation of 75% N2O/O2, initially
as much as 1 l/min may diffuse into the
bloodstream across the lungs ,this effectively draws
more gas into the lungs from the anaesthetic circuit,
thereby increasing the effective minute
ventilation

33. ▶ this effect is also important where there is a
second gas, such as 1% halothane, in the
inspired mixture
▶ the removal of a large volume of N2O from the
alveolar air increases the delivery of the second
gas, effectively increasing its delivery to the alveoli
and increasing its diffusion into arterial blood K/A
Second Gas Effect

34. 1. Rapid and pleasant induction
2. Rapid changes in the depth of anesthesia
3. Adequate muscle relaxation
4. Wide margin of safety
5. Absence of toxic/adverse effects
CHARACTERISTICS OF AN
IDEAL ANESTHETIC
No single agent yet identified is an ideal anesthetic

35. INHALATIONAL ANAESTHETIC
AGENTS
35
CLASSIFICATION
1.Gas :
• Nitrous Oxide
2. Volatile Liquids :
• Ether
• Halothane
• Enflurane
• Isoflurane
• Desflurane
• Sevoflurane

36. Nitrous Oxide (N2O)
36

37. ▶ Physical property:
-
-
-
-
-
laughing
Not flammable
Odorless
Colorless
Tasteless
37

38. ▶ PHARMACOLOGY:
- Good Analgesic
- Weak anesthetic
- Excreted via lungs
- MAC = 105%
- Lower water solubility
- Not Metabolized in the body
38

39. ▶ SIDE EFFECTS:
-
-
Diffusion Hypoxia.
Effects on closed gas spaces.(nitrous oxide can
diffuse 20 times faster into closed spaces than it can be
removed, resulting in expansion of pneumothorax, bowel
gas, or air embolism or in an increase in pressure within
noncompliant cavities such as the cranium or middle ear.
CVS depression
Toxicity
Teratogenic
-
-
-
39

40. What is diffusion hypoxia?
Diffusion hypoxia is a decrease in PO2usually
observed as the patient is emerging from an
inhalational anesthetic where nitrous oxide (N2O)
was a component. The rapid outpouring of
insoluble N2O can displace alveolar oxygen,
resulting in hypoxia. All patients should receive
supplemental O2at the end of an anesthetic and
during the immediate recovery period.
40

41. Second gas effect: The ability of the large
volume uptake of one gas (first gas) to
accelerate the rate of rise of the alveolar
partial pressure of a concurrently
administered companion gas (second
gas) is known as the second gas effect.
41

42. EFFECT IN CLOSED GAS SPACE

43. ETHER

44. •Properties:
•Colorless, highly volatile, pungent odor,
flammable, explosive, stored in cool area.
Solubility 12;
MAC 2-3%

45. •Pharmacodynamics:
▶Lungs: Stimulates resp, increases secretion, not
good in respiratory diseases
▶Kidney: decreases urine output
▶Liver: Minimum effect, decreases liver glycogen
▶Heart: Initially increases cardiac output, then
decreases card. output, suppresses
vasomotor center.

46. Ether as an anesthetic
•Advantage: CNS depression, excellent muscle
relaxant, causes surgical anesthesia
•Disadvantage: Flammable, irritates mucus
membrane, breath holding, induces nausea &
vomiting
•Contraindications: Resp., kidney and liver
diseases
•Better agents are available now, so not used now.

47. Halothane

48. Synthesized in 1951.
* Most potent inhalational anesthetic
•MAC of 0.75%
It has low blood/gas solubility coeffient of 2.5 and
thus induction of anasthesia is relatively rapid.

49. ▶ Chemical and Physical Properties
▶ Halogenated compound chemically:
2-bromo-2-chloro-1,1,1-tri fluoro
ethane
▶ Volatile, so kept in sealed bottles
▶ Colorless, Pleasant odor, Non-irritant
▶ Non-explosive, Non-inflammable
▶ Light-sensitive
▶ Corrosive, Interaction – rubber and plastic tubing

51. ▶Potency is
defined(determined)
quantitatively as the minimum
alveolar concentration (MAC),
▶Numerically, MAC is small for
potent anesthetics such as
Halothane and large for less
potent agents such as nitrous
oxide.

52. ▶ Halothane is a potent anesthetic but a relatively
weak analgesic. Thus, it is usually coadministered
with nitrous oxide, opioids, or local anesthetics.
▶ It is a potent bronchodilator.
▶ Halothane relaxes both skeletal and uterine muscles
and can be used in obstetrics when uterine relaxation
is indicated.
▶ Halothane is not hepatotoxic in children (unlike its
potential effect on adults).
▶ Combined with its pleasant odor, it is suitable in
pediatrics for inhalation induction, although
sevoflurane is now the agent of choice.

53. ▶ No specific receptor has been identified as the locus of
general anesthetic action –generally-.
It appears that a variety of molecular mechanisms may
contribute to the activity of general anesthetics.
Halothane activates GABAA , glycine receptors, 5-HT3and
twin-pore K+c
h
a
n
n
e
l
s.
It antagonizes NMDA receptor.
It inhibits nACh(block excitatory postsynaptic currents of
nicotinic receptors) and voltage-gated sodium channels.
▶
▶
▶
▶
--
At clinically effective concentrations, general anesthetics
increase the sensitivity of the γ-aminobutyric acid (GABA-A)
receptors to the inhibitory neurotransmitter GABA. This
increases chloride ion influx and cause
➢
Hyperpolarization Decrease Excitability CNS Depression

55. ▶ 20% metabolized in liver by oxidative
pathways.
▶ Major metabolites : bromin, chlorine,
Trifloroacetic acid, Trifloroacetylethanl
amide.

56. ▶ The induction dose varies from patient to patient.
The maintenance dose varies from 0.5 to 1.5%.
▶ Halothane may be administered with either
oxygen or a mixture of oxygen and nitrous oxide.

57. ▶ Indications
▶ Halothane is indicated for the induction and
maintenance of general anesthesia.
▶ Contraindications
▶ Halothane is not recommended for obstetrical
anesthesia except when uterine relaxation is
required.

58. Respiratory system:
▶ Halothane anesthesia progressively depresses
respiration.
▶ Its cause inhibition of salivary & bronchial secretion.
▶ Its may cause tachypnea & reduce in tidal volume and
alveolar ventilation .
▶ Its cause decrease in mucocillary function which lead
to sputum retention.
▶ It causes bronchodilation. Hypoxia, acidosis, or apnea
may develop during deep anesthesia.

59. Cardiovascular system:
▶ Halothane anesthesia reduces the blood pressure, and cause
bradycardia.(atropin may reverse bradycardia.).
▶ It cause myocardial relaxation & Hypotention.
▶ Its also causes dilation of the vessels of the skin and skeletal
muscles
▶ Halothane maybe advantages In pts with CAD , bcz of
decrease of oxygen demand.
▶ Arrhythemias are very common .(especially with
epinephrine).
◦ To minimize effects :
Avoid hypoxemia and hypercapnia
Avoid conc. Of adrenaline higher than 1 in 10000

60. Gastro intestinal tract:
Inhibition of gastrointestinal motility.
▶ Cause sever post. Operative nausea & vomiting
Uterus:
▶ Halothane relaxes uterine muscle, may cause postpartum
hemorrhage .
▶ Concentration of less than 0.5 % associated with increase
blood loss during therapeutic abortion.
Skeletal muscle:
▶ Its cause skeletal muscle relaxation .
▶ Postoperatively , shivering is common , this increase oxygen
requirement>>> which cause hypoxemia

61. Hepatic dysfunction:
▶ Two type of dysfunction:
▶ 1- Type I hepatotoxicity ,mild, associated with derangement
in liver function test , this result from metabolic of Halothane
in liver. results from reductive (anaerobic) biotransformation
of halothane rather than the normal oxidative pathway.
▶ 2- Type II hepatotoxicity: fulminate (uncommon); sever
jaundice ,fever,progressing to fulminating hepatic necrosis,
Its increased by repeated exposure of the drugs.
high mortality 30-70%

62. ▶ 1- A careful anasthetic history .
▶ 2- repeated exposure of halothane within
3 months should be avoided.
▶ 3- History of unexplained jaundice or
pyrexia after previous exposure of
halothane.

63. ▶ Rapid smooth induction .
▶ Minimal stimulation of salivary & bronchial
secretion.
▶ Brochiodilatation.
▶ Muscle relaxant .
▶ Relatively rapid recovery.

64. ▶ Poor analgesia.
▶ Arrhythmias.
▶ Post operatively shivering.
▶ Possibility of liver toxicity.

65. Enflurane
•MAC =1.68%
•Potent cardiovascular depressant
Sweet and ethereal odor.
Generally do not sensitizes the heart to
catecholamines.
Seizures occurs at deeper levels –
contraindicated in epileptics.
Caution in renal failure due to fluoride.

66. Isoflurane
Properties
- isomer of enflurane.
- Carcinogenic (not approved)
- colorless, volatile, liquid, pungent odor.
- stable.
- No preservative .
- Non-flammable.

67. Isoflurane
Properties
- Least soluble of the modern inhalational agent
equilibrate more rapidly
- Induction rapid theoretically (pungency??)
- pungency cough, breath holding.

68. Isoflurane
effects on systems:-
Respiratory:
dose dependent depression of vetilation.
CVS:
- myocardial depressant (vitro Vs Clinical),
coronary vasodilatation (coronary steal
syndrome).
uterus: relaxation of uterine muscles (same).

69. Isoflurane
effects on systems:-
CNS:
low concentration Vs High concentration.
▪ Low : no change on the flow.
▪High : increase blood flow by
vasodilatation of the cerebral arteries.
-Muscles: relaxation (dose-dependent).

70. Isoflurane
Advantages and Disadvantages
Advantages
-Rapid induction and recovery.
-Little risk of hepatic or renal toxicity.
-Cardiovascular stability.
-Muscle relaxation.
Disadvantages
-Pungent odor.
-Coronary vasodilatation.

71. Sevoflurane
Properties
-New drug.
-Non flammable.
-Pleasant smell.
-MAC 2%.
-Stable.
-Low blood/gas partition coefficient faster
equilibrium.
- non irritant so the fastest for induction.

72. Sevoflurane
effects on systems
- Respiratory:
-non-irritant, depression.
-CVS: same as isoflurane (slightly lower
effect)
-CNS: same as halothane and isoflurane.
-Muscle relaxation: same as isoflurane.

73. Sevoflurane
Advantages and Disadvantages
Advantages
Well tolerated (non-irritant, sweet odor), even at high. 1
concentrations, making this the agent of choice for
. inhalational induction
) Rapid induction and recovery (low blood:gas coefficient. 2
Does not sensitize the myocardium to catecholamines as. 3
.much as halothane
Does not result in carbon monoxide production with dry. 4
. soda lime

74. Sevoflurane
Disadvantages
.Less potent than similar halogenated agents. 1
Interacts with CO2 absorbers. In the presence of soda lime. 2
(and more with barium lime) compound A (a vinyl ether) is
. produced which is toxic to the brain, liver, and kidneys
About 5% is metabolized and elevation of serum fluoride. 3
. levels has led to concerns about the risk of renal toxicity
Postoperative agitation may be more common in children. 4
. then seen with halothane

75. Desflurane
MAC =6 %
It is delivered through special vaporizer.
It is a popular anesthetic for day care surgery.
Induction and recovery is fast, cognitive and
motor impairment are short lived
It irritates the air passages producing cough and
laryngospasm.

76. Anesthetic Blood: Gas
Partition
Coefficients
Oil: Gas
Partition
Coefficients
Features Notes
PLEASANT Arrhythmia
PUNGENT
PUNGENT
Hepatitis
Hyperthermia
Seizures
Hyperthermia
Widely used
PLEASANT Ideal
IRRITANT Cough
Halothane 2.3 220
Enflurane 1.9 98
Isoflurane 1.4 91
Sevoflurane 0.62 53
Desflurane 0.42 23
Nitrous oxide 0.47 1.4 PLEASANT Anemia

77. Miller’s Anesthesia 7th Edition
Pharmacology – K.D. Tripathi Clinical Pharmacology – Bennett & Brown

78. 78