pharmacology of inhalational agents in brief

1. PRESENTED BY –
DR APARNA SAHU
1ST YEAR PG
DEPT OF ANAESTHESIOLOGY & CRITICAL CARE
PHARMACOLOGY & ANAESTHETIC
IMPLICATION OF INHALATIONAL
AGENTS

2. PHARMACOLOGY
• PHARMACOKINETICS – what body does to the drug like
absorption of the drug (uptake), distribution, metabolism,
excretion, etc
• PHARMACODYNAMICS – what drug does to the body like
effect on various organ systems, etc

3. DRUGS
CHEMICAL STRUCTURE

4. THEORIES OF MECHANISMS OF ACTION
 Despite widespread use , current understanding of the molecular basis for
the anesthetic action of inhalational agents is poorly understood.
 This critical gap in the pharmacology not only impedes rational use of
anaesthetics but also hinders development of newer agents to selectively
achieve the desirable endpoints of anaesthseia with fewer adverse
cardiovascular , respiratory & neuropyschological side effects .
 The effects of inhaled anaesthetics cannot be explained by a single
molecular mechanism. Rather, multiple targets contribute to the effects of
each agent
 The IMMOBILIZING EFFECT of inhaled anaesthetics involves a site of
action in the spinal cord
 SEDATION , HYPNOSIS & AMNESIA involve
supraspinal(amydala,hippocampus,cortex) mechanisms.

5. • Since 1842 when Crawford Long for
the first time administered diethyl ether to a patient and performed a painless operation. It has always
been believed that general anaesthetics exert their effects (analgesia, amnesia,
immobility) by modulating the activity of
membrane proteins in the neuronal membrane. However, the exact location and mechanism of this actio
n are still
largely unknown although much research has been done in this area. There are a number of outdated
and modern theories that attempt to explain anaesthetic action.
• Paul Ehrlich [1] states that
drugs act only when they are bound to their targets (receptors). However, this concept is not
working well in case of general anaesthetics because:
– Molecular structures diverse so that there is no obvious structure–activity relationship
– Most general anaesthetics have remarkably weak affinity for their targets acting at much higher
concentrations than most other drugs so that diverse side effects are inevitable
1. Lipid Solubility - Overton & Meyer
2. Alterations to Lipid Bilayers
 lipid perturbation - dimensional change
 lipid phase transition - "lateral phase separation"
 lipid-protein interactions
3. Alteration to Protein Function - luciferase inhibition

6. Lipid solubility-anaesthetic potency correlation
( Meyer-Overton correlation)
• Meyer and Overton had discovered the striking correlation between the physical properties of
general anaestheticmolecules and their potency:the greater is the lipid solubility of the compound
in olive oil the greater is its anaesthetic potency. It was noted also that volatile anaesthetics are
additive in their effects (a mixture of a half dose of two different volatile
anaesthetics gave the same anaesthetic effect as a full dose of either drug alone).
• The LESSER THE MAC THE GREATER THE POTENCY (Halothane has a MAC of slightly less than 1
while Nitrous oxide has a MAC of around 105,halothane is much more potent and it is because
the log of the MAC is plotted on the y axis that halothane has a value of 0.01 and
nitrous oxide has a value of 1.The drug potencyincreases and the dose required to produce
anaesthesia reduces as the oil:gas solubility
increases.
• Exceptions to the Meyer-Overton Rule:-
– Enflurane and Isoflurane are structural isomers and
have similar oil:gas partition coefficients, however
the MAC for Isoflurane is only ~ 70% of that for Enflurane
– thus, it would appear that there are other factors which
influence potency, these include:-
1)convulsant properties
2)the "cutoff effect”- beyond which Anaesthetic potency
sharply decreases
3) specific receptors( activation or enhancement of
GABA-mediated Cl− conductance /decreases cation
conductance in the ion channel controlled by
N-methyl-D-aspartate (NMDA) glutamate receptor

7. LIPID PERTURBATION
• CRITICAL VOLUME HYPOTHESIS -lipid bilayer expansion hypothesis
• Bulky and hydrophobic anaesthetic molecules accumulate inside the hydrophobic (or lipophilic)
regions of neuronal lipid membrane causing its distortion and expansion (thickening) due to volume
displacement. Accumulation of anaesthetic causes volume of the hydrophobic region to expand
beyond some critical volume sufficient to reversibly alter function of membrane ion channels thus
providing anaesthetic effect. Changes in bilayer thickness:-
Actual chemical structure of the anaesthetic agent not important
Molecular volume more important
More space within membrane is occupied by anaesthetic
GREATER ANAESTHETIC EFFECT
• Based on this theory, in 1954 Mullins suggested that the Meyer-Overton correlation with potency
can be improved if molecular volumes of anaesthetic molecules are taken into account. • This
theory was supported by experimental fact that increases in atmospheric pressure reverses
anaesthetic effect (PRESSURE REVERSAL EFFECT)

8. PROTEIN BASED THEORIES OF
ANAESTHESIA
• In the early 1980s, Franks and Lieb demonstrated that the Meyer-Overton correlation can be
reproduced using a soluble protein.
• These are luciferases, and cytochrome P450. Remarkably, inhibition of these proteins by general
anaesthetics was directly correlated with their anaesthetic potencies.
• Demonstrated that general anaesthetics may also interact with hydrophobic protein sites of
certain proteins, rather than affect membrane proteins indirectly through nonspecific interactions
with lipid bilayer as mediator.
• Anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase
C, however, the proteins considered the most likely molecular targets of anaesthetics are ion
channels.
• Bind directly only to small number of targets
in CNS mostly ligand(neurotransmitter)- gated ion
channels in synapse and G-protein coupled receptors
altering their ion flux.
• Cys-loop receptors are plausible targets for
general anaesthetics that bind at the interface
between the subunits. Inhibitory receptors (GABA A, GABA C,
glycine receptors) ,excitatory receptors
(Ach,5HT3 & glutamate NMDA receptor)

9. MACROSCOPIC SITES OF ACTION
• Anesthetic induced ablation of movement in response to pain
is mediated primarily by spinal cord.
• Anesthetic induced amnesia is mediated by higher brain
structures ( hippocampus).
• Anesthetic induced sedation mediated by tuberomammillary
nucleus of hypothalamus.

10. MEASURES OF ANAESTHETIC POTENCY
• MINIMUM ALVEOLAR CONCENTRATION:-
• Best estimate for the potency of inhalational anaesthetics is MAC
• The minimum alveolar concentration of anaesthetic, 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 equivalent of a median effective dose(ED50)
• 1.3 MAC of any of the volatile anesthetics prevent movement in about 95% patients surgical
incision( ED95)
• The MAC values for different anaesthetics are roughly additive. For example, a mixture of 0.5 MAC
of nitrous oxide and 0.5 MAC of halothane approximates the degree of central nervous depression
of 1.0 MAC of isoflurane.
• Common MAC values:-
• Nitrous oxide – 104(Least potent)
• Xenon – 63 - 71
• Desflurane - 6.6
• Ethyl Ether - 3.2
• Sevoflurane - 1.8
• Enflurane - 1.63
• Isoflurane - 1.17
• Halothane - 0.75
• Chloroform - 0.5
• Methoxyflurane - 0.16(Most Potent)

11. MAC VARIANTS
• 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)
• 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.

12. PHYSIOLOGIC & PHARMACOLOGIC
FACTORS AFFECTING MAC
Increase in MAC:-
 Hyperthermia
 Hypernatraemia
 Drug induced elevation of
CNS catecholamine stores
 Chronic alcohol abuse &
chronic opioid abuse
 Increases in ambient pressure
(experimental)
 Cyclosporine
 Excess pheomelanin
production(red hair)
Decrease in MAC:-
 Hypothermia & Hyperthermia (if >42◦ C)
 Hyponatraemia
 Drug induced decrease in CNS
catecholamine level
 Increasing age (6% decrease/decade)
 Preoperative medication
 Hypoxaemia (PaO2< 38mmHg)
 Hypotension(<40 mm hg- MAP)
 Anaemia (Haematocrit<10%)
 Pregnancy ( progesterone)
 Postpartum(returns to normal in 24-72
hrs)
 CNS depressant drugs –
Opioids,Benzodiazepines TCA's etc.
 other drugs–lithium, Lidocaine,Magnesium
 acute alcohol abuse
 Cardiopulmonary bypass

13. • No Change in MAC
 Gender
 Duration of anaesthesia
 Anaesthetic metabolism
 Hypo/ Hyperkalaemia
 Thyroid gland dysfuction
 PaCO2 ~ 15-95 mmHg
 PaO2 > 38 mmHg
 MAP > 40 mmHg

14. PHARMACOKINETICS
• Relationship between a drug‘s dose, tissue concentration, and elapsed time. (i.e-
how a body affects a drug ).
 The absorption phase is usually called -
uptake
 The metabolic phase is usually called - biotransformation
 The excretion phase is usually called –
elimination.
 lowering of drug concentration in one compartment by delivery into another compartment is
called
redistribution
• Inhalational anaesthesia ultimate effect depends on attainment of a therapeutic
tissue concentration in the central nervous system(brain)

15. Basic concepts
• Partial Pressure in gaseous phase - Partial pressure of a gas in a
mixture of gases is the pressure it would have if it alone occupied
the entire volume. This pressure is proportional to its fractional
mass in the mixture of gases
• Partial pressure in Solution -Since pressure of a gas can only be
measured in gaseous phase, while in solution we measure
concentration as an indicator of amount of gas. Partial pressure of a
gas in solution, therefore refers to the pressure of the gas in the gas
phase (if it were present) in equilibrium with the liquid
• Partial pressures assume importance because gases equilibrate
based on partial pressures, not concentrations

16. • Concentration of a gas is directly proportional to its partial pressure.
Pgas = Cgas x Atm

17. BOILING POINT/ VAPOUR
PRESSURE
Boiling Point
(° C )
Vapour
pressure(mm
Hg) at 20°C
HALOTHANE 50.2 243.3
ISOFLURANE 48.5 250
DESFLURANE 22.8 664
SEVOFLURANE 58.5 160

18. Implication
• Desflurane cannot be administered using
standard vapourizer

19. UPTAKE AND DISTRIBUTION OF INHALATIONAL
AGENTS
A series of partial pressure gradients exists from the anaesthetic machine to brain tissue.
Diffusion occurs from a region of higher concentration to a region of lower concentration (down a
concentration gradient).

20. UPTAKE AND DISTRIBUTION
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

21. • Anaesthetic gases administered via the lungs diffuse into blood until
the partial pressures in alveoli and blood are equal
• Transfer of anaesthetic from blood to target tissues also proceeds
toward equalizing partial pressures Because gases equilibrate
throughout a system based on partial pressures .So Monitoring the
alveolar concentration of inhaled anaesthetic provides an index of
their effects in the brain PALVEOLI=PBLOOD=PCNS
• To put it in another way, faster rise in alveolar concentrations of a
given anaesthetic herald a faster induction

22. FACTORS AFFECTING INSPIRATORY
CONCENTRATION (FI)
The patient does not necessarily receive the same concentration set on the vaporizer as
there are numerous intervening factors which vary the concentration.
1) Fresh gas flow rate (FGF rate) = Depend on vaporizer & flowmeter settings
Higher the rate of FGF, closer the inspired gas concentration will be to
fresh gas concentration.(FI =FGC). Induction can be accelerated with the
use of high inflow rates
2) Breathing Circuit Volume: (apparatus dead space) Smaller the volume,
closer the inspired gas concentration will be to the fresh gas concentration.
3) Circuit absorption: Rubber tubing absorbs (plastic & silicon). Lower
the circuit absorption, closer the inspired gas concentration will be to
the fresh gas concentration.
4) The Effect of Rebreathing: Inspired gas is actually fresh gas + exhaled gas .
In rebreathing the inspired gas mixtures may be diluted by residual gases in the
system . Lower the rebreathing, closer the inspired gas concentration will be to the fresh
gas concentration.
Clinically, these attributes translate into faster induction and recovery times.

23. • Concentration in the circuit (FI) will rise according to first-
order kinetics:
• FFGO -is the fraction of inspired
anesthetic in the gas leaving the
fresh gas outlet.
• T - is time.
• τ - is a time constant.
• The time constant is simply the volume or “capacity” of the
circuit (VC) divided by the fresh gas flow (FGF) or τ =
VC/FGF.

24. FACTORS AFFECTING ALVEOLAR
CONCENTRATION (FA)
• 1) Uptake:- Alveolar membrane poses no barrier to the transfer of
anaesthetic gases to pulmonary circulation. The FA / alveolar partial
pressure determines the partial pressure of anaesthetic in the
blood and, ultimately, in the brain which determines clinical effect.
• FA depends on uptake of anaesthetic by pulmonary circulation. If
this uptake is poor, whatever anesthetic is inspired is accumulating
in the alveoli. thus FA increases rapidly towards FI . i.e. FA / FI =1.0
Greater the uptake
Slower the rate of rise FA
Lower the FA:FI ratio
Slower the rate of induction

25. • Concentration of (FA) will rise analogous to
Fi
o methoxyflurane - increases by 75%
o isoflurane - by 18%
o desflurane - by only 6%.
FA -is the alveolar concentration
T - is time.
τ -is a time constant.
The time constant for raise of FA concentration
and equals FRC/VA
FRC-functional residual capacity
VA- minute ventilation
Increase in
Minute alveolar ventilation
Increases FA/FI
The change is greatest for more
soluble anesthetics
negative feedback that results from
respiratory depression
high ventilation → rapid induction →
hypoventilation

26. Time constant
 The time required for flow through a container to equal the capacity of the container.
TC is volume (capacity)/flow.
 The time constant for the lungs is FRC/Valveolar.
 The time constant for the anesthesia circuit is circuit capacity/FGF.
 If 10 liter box is initially filled with oxygen and 5 l/min of nitrogen flow into box then,
 TC is volume (capacity)/flow.
 TC = 10 / 5 = 2 minutes ( 1 Time Constant)
 So, the nitrogen concentration at end of 2 minutes is 63%.

27. Time Constants and Brain Equilibration
Time constant Brain Equilibration time
Isoflurane 3-4 mins 10-15 mins
Sevoflurane 2 mins 6 mins
Desflurane 2 mins 6 mins
Nitrous Oxide 2 mins 6 mins
equilibration with any tissue takes 3 time constants

28. SOLUBILITY OF THE AGENT
• Relative solubility of an anaesthetic in air, blood and tissues are
expressed as partition co-efficients.
• Describes the relative affinity of an anaesthetic for two phases &
each coefficient is the ratio of the concentrations of the anesthetic
gas in each of two phases when equilibrium has been achieved.
• For example, halothane has a blood/gas partition coefficient of 2.4,
indicating that at equilibrium, halothane concentration in blood is
2.4 times its concentration in the gas (alveolar) phase. In another
way , a value of 2.4 means that each ML of blood holds 2.4 times as
much halothane as a ML of alveolar gas.

30. Concentration effect
• Two components:
• 1.the concentrating effect
• 2.an augmented gas inflow effect

31. SECOND GAS EFFECT
The increase in the partial pressures of the other gases(oxygen & inhalational agents) in the
alveolar mixture resulting from the rapid uptake of high concentrations of nitrous oxide during
induction is known as the second gas effect.

32. Concentration and second gas effects
Concentration effect
Administration of 70% nitrous oxide
produces a more rapid rise in the FA/FI
ratio of nitrous oxide than administration
of 10% nitrous oxide
Second gas effect
The FA/FI ratio for 0.5% halothane rises
more rapidly when given with 70%
nitrous oxide than when given with 10%
nitrous oxide.

33. I. Alveolar concentration
(Summary)
Factors raising the alveolar concentration (FA/FI )
a) The inspired concentration (FI)
b) The alveolar ventilation (Valveolar)
c) The time constant
d) Anesthetic uptake by the blood
e) The concentration and second gas effects

34. II. Uptake from lung
Factors determining uptake by blood
A. Solubility in blood
B. Cardiac Output
C. The mixed venous anesthetic concentration
D. Tissue uptake of anesthetic

35. Blood uptake of anesthetic from the lung
Uptake from the lung = Blood solubility x Cardiac Output x [PA-PV]
Barometric pressure
Fick equation
U Lung = λB/G x Q x ((PA-Pvenous)
Barometric pressure
λB/G - blood:gas partition coefficient
Q - cardiac output
PA - alveolar partial pressure of anesthetic
Pv - mixed venous partial pressure of anesthetic
PB is barometric pressure.

36. Solubility/Partition Coefficient
 Solubility is defined in terms of the partition
coefficient
 Partition coefficient is the ratio of the amount of
substance present in one phase compared with
another, the two phases being of equal volume and
in equilibrium [λB/G = CB ]
CG

37. Blood: gas partition coefficien
λB/G
Partition Coefficient = Ratio of Concentration
CG =CB
Equal volume Blood
Gas
PG = PB
Partial pressure Equalize
Partial pressures are equal but concentrations are not !!!
Halothane
λB/G = CB = 2.5 = 2.5
CG 1

39. Higher solubility (λB/G>1)= more agent in the blood and
less in the gas phase.
A lower solubility (λB/G<1)= less agent in the blood and
more in the gas phase.
Other partition coefficients:
-Brain:Blood, Muscle:Blood, Fat:Blood
(describe movement of gas from one
environment to another)

40. PARTITION CO-EFFICIENT
Blood-Gas
Brain-
Blood
Liver-
Blood
Kidney-
Blood
Muscle-
Blood
Fat-
Blood
Desflurane 0.42 1.3 1.4 1.0 2.0 27
Nitrous oxide 0.47 1.1 0.8 — 1.2 2.3
Sevoflurane 0.65 1.7 1.8 1.2 3.1 48
Isoflurane 1.17 1.6 1.8 1.2 2.9 45
Enflurane 1.8 1.4 2.1 — 1.7 36
Halothane 2.4 1.9 2.1 1.2 3.4 51
Diethyl ether 12 2.0 1.9 0.9 1.3 5
Methoxyflurane 15 1.4 2.0 0.9 1.6 38

41. A.Solubility in blood
The more soluble the anesthetic
The more drug will be taken up
by the blood
The slower the rise in alveolar
concentration
Poor solubility Rapid induction
High solubility Slow induction

42. B.Cardiac Output
Greater the cardiac output
The more drug will be taken up
by the blood
The slower the rise in alveolar
concentration
Cardiac output is lowered
cerebral circulation
less maintained (shock)
Induction Induction
slower rapid
An increase in CO
from 2 to 18 L/min
will decrease the
alveolar anesthetic
concentration by
augmenting uptake,
thereby slowing the
rise of the FA/FI ratio.
More soluble anesthetics
(halothane) - effect is more
prominent
Positive feedback - as inspired concentration increases, greater
cardiovascular depression reduces anesthetic uptake and actually
increases the rate of rise of FA/FI.

43. C. The Alveolar-to-Venous
Anesthetic Gradient
The difference between partial pressure in the alveoli and that in venous blood
Partial pressure in venous blood depends on tissue uptake of anesthetic
At equilibrium, (no tissue uptake)
The venous partial pressure = arterial partial pressure = alveolar partial pressure
PA – PV = 0
Rate of rise of the mixed venous concentration depends on the tissue uptake of
the anesthetic

44. D.Tissue uptake of anesthetic
1. The tissue/blood partition coefficient (tissue solubility)
2. The tissue blood flow.
3. The tissue anesthetic concentration
Tissue Uptake = Tissue solubility x Tissue blood flow x [Parterial - PTissue]
Atmospheric pressure

45. Blood: tissue partition coefficient λB/T
Gas
Blood
Tissue
Concentrations Equilibirates
Partial pressure Equalize
CG =CB = CT
PG = PB = PT
Equal volume

47. Blood-Gas
Brain-
Blood
Liver-
Blood
Kidney-
Blood
Muscle-
Blood
Fat-
Blood
Desflurane 0.42 1.3 1.4 1.0 2.0 27
Nitrous oxide 0.47 1.1 0.8 — 1.2 2.3
Sevoflurane 0.65 1.7 1.8 1.2 3.1 48
Isoflurane 1.17 1.6 1.8 1.2 2.9 45
Enflurane 1.8 1.4 2.1 — 1.7 36
Halothane 2.4 1.9 2.1 1.2 3.4 51
Diethyl ether 12 2.0 1.9 0.9 1.3 5
Methoxyflurane 15 1.4 2.0 0.9 1.6 38
PARTITION CO-EFFICIENT

48. Distribution to tissues
The rate of rise in tissue anesthetic concentration is
proportional to tissue blood flow and inversely
proportional to the tissue capacity.
The tissue capacity = tissue solubility х tissue volume
Just as discussed for the lungs, the tissues have a time constant too:
Time Constant = Tissue solubility x Volume
Flow

49. Equilibration of
the VRG complete
in 4 to 8 minutes
After 8 minutes,
the Muscle group
(MG) determines
most of uptake.
Once MG
equilibration is
complete Fat
group (FG)
determines the
uptake
Higher the blood flow to a region, the faster
the delivery of anaesthetic and the more rapid
will be equilibration

50. Two important characteristics of Inhalational
anesthetics which govern the anesthesia are :
Solubility in the blood
(blood : gas partition co-efficient)
Solubility in the fat
(oil : gas partition co-efficient)
Oil : gas partition co-efficient
 It indicates the amount of gas that is soluble in oil phase.
 It is a measure of lipid solubility of anesthetic.
 It is a measure of anesthetic potency
Higher the lipid solubility – potent anesthetic.
(e.g., halothane)

51. Higher the Oil: Gas Partition
Co-efficient lower the MAC .
E.g., Halothane
Inhalation
Anesthetic
MAC value % Oil:Gas
partition Co
Nitrous oxide 104 1.4
Desflurane 6.6 19
Sevoflurane 1.8 47
Isoflurane 1.17 91
Halothane 0.75 220

52. At EQ:Palveoli)= Pblood =PCNS
Rapid transfer of gases:
alveoli > blood > CNS
F is proportional to P, so
1% SEV in the alveoli = 1% SEV in the CNS
At EQ, if you know PA of a gas, then you
know PCNS
Delivery of Inhaled Anesthetics (Summary)

53. Redistribution
 As long as an arterial-to-tissue partial pressure gradient exists,
muscle and fat will absorb anesthetic(especially fat).
 After discontinuation of anesthesia, muscle and fat may continue
to absorb anesthetic, even hours later.
 The redistribution continues until blood/alveolar anesthetic
partial pressure falls below tissue partial pressure.

54. Recovery
Recovery from anesthesia, like induction, depends on:
anesthetic solubility- is the primary determinant of
the rate of fall of FA
 cardiac output
 minute ventilation
Loss of inhaled anesthetics via skin, gastrointestinal viscera
and the pleura are insignificant
The greater the solubility of inhaled anesthetic, the larger the
capacity for absorption in the bloodstream and tissues.

55.  The “reservoir” of anesthetic in the body at the end of
administration depends on:
1. Tissue solubility (which determines the capacity)
2. The dose
3. Duration of anesthetic (which determine how much of that
capacity is filled).
Low solubility→Rapid recovery
Desflurane>Sevoflurane>Isoflurane

56. Recovery from anesthesia, or
“washout,” is usually expressed as
the ratio of expired fractional
concentration of anesthetic (FA) to
the expired concentration at time
zero (FA0) when the anesthetic was
discontinued (or FA/FA0).
During the 120-minute period after ending the anesthetic delivery,
the elimination of sevoflurane and desflurane is 2 to 2.5 times
faster than isoflurane or halothane

57. The longer the duration of a highly soluble anesthetic, the greater the
reservoir of anesthetic in the body, and the higher the curve seen in the right
half( slow recovery)

58. INDUCTION RECOVERY
Induction can be accelerated by Over
Pressure( which offset solubility and
uptake)
The inspired concentration cannot be
reduced below zero
All the tissues initially have the same
anesthetic partial pressure—zero
On recovery, the tissue partial pressures
are variable
100%
60% 10%
0% Recovery

59. Recovery from an inhalational anesthetic
(summary)
1. Increased solubility slows recovery
2. Increasing ventilation may help the recovery from potent
agents
3. Prolonged anesthesia delays recovery
4. There is no concentration effect on emergence

60. Diffusion hypoxia
l At the end of anesthesia after discontinuation of N2O, N2O diffuses from blood into the alveoli much faster than N diffuses
from alveoli into the blood as N2O is 30 times more soluble than N2 in the blood.
↑ Total volume of gas in the alveolus
Dilutes alveolar oxygen and CO2
Directly affect oxygenation by displacing oxygen
Diluting alveolar CO2 decreases respiratory drive & hence ventilation.
HYPOXIA.
This occurs in the first 5-10 mins of recovery. Therefore it is advised to use 100% O2 after discontinuation of N2O.
respiratory drive, which may exacerbate hypoxemia
N2O
N- 79%
O2-21%O2-21%
N- 79%
N2O
O2-16%
N-70%
N2O-14%
PULMONARY
CAPILLARY

61. Classification of
inhalational anaesthetics
Outdated Gases Volatile agents
 Ether
 trilene
Methoxyflurane
Cyclopropane
 chloroform
 Nitrous oxide
 Xenon
 Halothane
 Enflurane
 Isoflurane
 Sevoflurane
 Desflurane

62. Structural activity-relationship
2-chloro,bromo 1-
trifluro ethane.
Methyl –isopropyl
ether.
2-fluro,1-trifluro
methyl ethyl ether.
2-chloro 1-trifluro
methyl-ethyl ether.
1-chloro ,fluro 2-
difluro methyl-ethyl
ether.

63. NEUROLOGIC
 All agents cause CBF, causing ICP(especially Halothane) and
impair autoregulation of vascular tone( least with sevoflurane
at<1MAC)
 Volatile agents cerebral metabolic rate, N2O may
 Desflurane and isoflurane at < 1 MAC can suppress status
epilepticus while sevoflurane concentrations associated whith
epileptiform EEG.
 All agents SEP/MEP signals.(sensory-evoked potentials and
motor-evoked potentials (MEPs).
 All agents decreases CMRO2 :
Desflurane=Isoflurane=Sevoflurane>Halothane

64. Inhaled anesthetics and
Neurophysiology
 Cerebral Metabolic Rate and Electroencephalogram
EEG an isoelectric-no further decreases in CMR are generate,
however:
Desflurane-induced isoelectric EEG reverts to continuous
activity with time, despite an unchanging MAC, a property
unique to Desflurane
All of the potent agents depress CMR to varying
degrees !!!

65. Cerebral Blood Flow
All of the potent agents increase CBF in a time-
dependent as well as dose-dependent manner !!!
Desflurane=Isoflurane=Sevoflurane<Halothane
The increase in CBF with increasing dose caused by the potent
agents occurs despite decreases in CMR - cerebral
uncoupling .
↓CMR→ vasoconstriction (physiologically), with VA vasodilatory
effect

66. Autoregulation
Because the volatile anesthetics are direct vasodilators,
all are considered to diminish autoregulation in a dose-
dependent fashion.
Sevoflurane preserves autoregulation up to approx.1MAC.
At 1.5 MAC sevoflurane preserves better than isoflurane(This may be a
result of less of a direct vasodilator effect of sevoflurane).
0.5 MAC desflurane reduced autoregulation and isoflurane did not.
At 1.5 MAC, both anesthetics substantially reduced autoregulation.

67. Cerebral Blood Flow Response to
Hypercarbia and Hypocarbia
 Significant hypercapnia is associated with dramatic increases in CBF whether or not
volatile anesthetics are administered.
 Hypocapnia can blunt or abolish volatile anesthetic-induced increases in CBF depending
on when the hypocapnia is produced.
Intracerebral Pressure(ICP)
The increase in CBF→ ↑ICP
Isoflurane, sevoflurane and desflurane >1 MAC produce mild increases in ICP,
paralleling their mild increases in CBF.
All three potent agents may be used at appropriate doses, especially with
adjunctive and compensatory therapies, in just about any neurosurgical procedure.

68. Cerebrospinal Fluid(CSF) Production and
Resorption
 Isoflurane does not appear to alter CSF production, but may
increase, decrease, or leave unchanged the resistance to resorption
depending on dose.
 Sevoflurane at 1 MAC depresses CSF production up to 40%.
 Desflurane at 1 MAC leaves CSF production unchanged or
increased.
In general, anesthetic effects on ICP via changes in CSF dynamics are
clinically far less important than anesthetic effects on CBF.

69. Inhaled Anesthetics and the
Circulatory System
A common effect of the potent volatile
anesthetics has been a dose-related
decrease in arterial blood pressure
Primary mechanism to decrease blood
pressure with increasing dose is lowering
regional and systemic vascular resistance.
Sevoflurane up to about 1 MAC results in
minimal, if any, changes in steady-state
heart rate while enflurane, isoflurane, and
desflurane increase it 5 to 10% from
baseline

70. Myocardial Contractility
Isoflurane, desflurane, and sevoflurane resulted in a dose-
dependent depression of myocardial function with no differences
between the three anesthetics.
Despite the small reduction in
baseline contractility, the volatile
anesthetics did not affect the ability
of the myocardium to respond to an
acute increase in cardiac preload.

71. Inhaled Anesthetics and the
Circulatory System(cont.)
 Most of the volatile anesthetics have been studied during both controlled and spontaneous
ventilation.
 Spontaneous ventilation(SV) reduces the high intrathoracic pressures from positive pressure
ventilation.
 The negative intrathoracic pressure during the inspiratory phase of spontaneous ventilation
augments venous return and cardiac filling and improves cardiac output and, hence, blood pressure.
 SV is associated with higher PaCO2, causing cerebral and systemic vascular relaxation. This
contributes to an improved cardiac output via afterload reduction.
 It has been suggested that spontaneous ventilation might improve the safety of inhaled anesthetic
administration because:
Concentration of a VA that produces cardiovascular
collapse > the conc. that results in apnea.

72.  Oxygen consumption is decreased approximately 10 to 15%
during general anesthesia.
 The distribution of cardiac output also is altered by
anesthesia. Blood flow to liver, kidneys, and gut is decreased,
particularly at deep levels of anesthesia.
- In contrast, blood flow to the brain, muscle, and skin is
increased or not changed.
 Sinoatrial node discharge rate is slowed by the volatile
anesthetics. Conduction in the His-Purkinje system also is
prolonged by the volatile anesthetics.

73. Coronary Steal
 Isoflurane (and most other potent volatile anesthetics) increases
coronary blood flow many times beyond that of the myocardial
oxygen demand, thereby creating potential for “steal.”
 Steal is the diversion of blood from a myocardial bed with limited
or inadequate perfusion to a bed with more adequate perfusion.
 Neither isoflurane, sevoflurane, or desflurane at
concentrations up to 1.5 MAC cause steal effect.

74. General Ventilatory Effects of
inhaled anesthetics
There are only minor effects on decreasing
minute ventilation.
The ventilatory effects are dose-dependent.
Their net effect of a gradual decrease in minute
ventilation has been associated with increasing
resting Paco2.
All volatile anesthetics decrease tidal volume ↓(TV)
and increase respiratory rate ↑(RR)

75. TV, RR, MV, PaCO2
Isoflurane does not increase
respiratory rate above 1 MAC.
N2O increases respiratory rate as
much or more than the inhaled
anesthetics.
Desflurane results in the
greatest increase in Paco2 .

76. Response to Carbon Dioxide and
Hypoxemia
 In awake humans, changes in arterial CO2 such that minute
ventilation increases 3 L/min per a 10-mm Hg increase in Paco2.
All inhaled anesthetics produce
a dose-dependent depression of the
ventilatory response to hypercarbia!
The threshold at which breathing
stops, called the apneic threshold.
It is generally 4 to 5 mm Hg below the
prevailing resting Paco2

77. Ventilatory response to hypoxia
Inh.Anesth., including nitrous oxide, produce a dose-dependent
attenuation of the ventilatory response to hypoxia.
Has important clinical implications.
The short-acting sevoflurane and
desflurane may prove advantageous -
more rapid washout and their minimal
effect on hypoxic sensitivity at
subanesthetic concentrations.

78. Bronchiolar Smooth Muscle Tone
Bronchoconstriction under anesthesia occur:
 direct stimulation of the laryngeal and tracheal areas
 administration of adjuvant drugs that cause histamine release
 noxious stimuli activating vagal afferent nerves
The reflex response to these stimuli may be enhanced :
- in lightly anesthetized patients
- in patients with known reactive airway disease including those
requiring bronchodilator therapy
- chronic smoking histories.

79.  Bronchoconstriction - via M2 and M3 muscarinic receptors,
which initiate increases in intracellular cyclic guanosine
monophosphate(cGMP).
 Bronchiolar muscle relaxation – adrenergic β2- receptors →
an increase in intracellular cyclic adenosine
monophosphate(cAMP).
The volatile anesthetics relax airway smooth muscle
primarily by directly depressing smooth muscle contractility
and indirectly inhibiting the reflex neural pathway!
Volatile anesthetics have been used effectively to treat status
asthmaticus when other conventional treatments have failed!
Sevoflurane may be a better choice.

80. Mucociliary Function
Smokers have impaired mucociliary function compared with
nonsmokers.
and the combination of a volatile anesthetic in a smoker who is
mechanically ventilated sets up a scenario for inadequate clearing
of secretions, mucus plugging, atelectasis, and hypoxemia.
Volatile anesthetics and nitrous oxide reduce ciliary
movement and alter the characteristics of mucus.

81. Hepatic Effects
Inadequate hepatocyte oxygenation (oxygen supply relative
to oxygen demand) is the principal mechanism responsible for
hepatic dysfunction following anesthesia and surgery.
The liver has two blood supplies:
1 Hepatic artery(well-oxygenated).
2 Portal vein( poorly oxygenated).
Postoperative liver dysfunction has been associated with most
volatile anesthetics, with halothane receiving the most attention.

82. Hepatic Effects
HBF-Desflurane=Isoflurane=Sevoflurane<Halothane
The ether-based anesthetics (isoflurane,
sevoflurane, desflurane) maintain or
increase hepatic artery blood flow while
decreasing (or not changing) portal vein
blood flow.
Halothane decreases in both portal vein
and hepatic artery blood flow, thereby
significantly compromising total hepatic
artery blood flow.

83.  Altered liver function tests have been used as an index of
hepatic injury during anesthesia.
 ALT, AST, GST
 Increases in the ALT or AST are not uniquely specific to the
liver.
 The centrilobular area of the liver is most susceptible to
hypoxia.
 A more sensitive measure GST(α-glutathione S-
transferase), since it is distributed primarily in the
centrilobular hepatocytes.

84. Neuromuscular System and Malignant
Hyperthermia
The inhaled anesthetics have two important actions on
neuromuscular function:
1. Directly relax skeletal muscle(nitrous oxide does not).
2. Potentiate the action of neuromuscular blocking drugs.
All of the potent volatile anesthetics serve as
triggers for malignant hyperthermia (MH)!!!
While N2O is considered safe in MH-susceptible patients!!!

85. Obstetric use
 Uterine smooth muscle tone is diminished by volatile anesthetics.
 There is a dose-dependent decrease in spontaneous myometrial
contractility.
 Uterine relaxation/atony can become problematic at
concentrations of volatile anesthesia >1 MAC, and might delay the
onset time of newborn respiration.
 Consequently, a common technique used to provide GA for urgent
CS is to administer low concentrations of the VA, such as 0.5 to
0.75 MAC, combined with N20

86. RENAL EFFECTS
Volatile anesthetics produce similar dose-related
decreases in renal blood flow, glomerular filtration rate,
and urine output.
These changes most likely reflect the effects of volatile
anesthetics on systemic blood pressure and cardiac output.
Preoperative hydration attenuates or abolishes many of the
changes in renal function associated with volatile anesthetics.

87. NITROUS OXIDE
Physical properties:
 It is a laughing gas,colorless and odorless
 It is only inorganic anesthetic gas in clinical use.
 Non Explosive and Non Inflammable
 Gas at room temperature and can be kept as a liquid under
pressure.
 It is relatively inexpensive.
 low potency (MAC = 104%) and is relatively insoluble in blood
 Nitrous oxide does not produce significant skeletal muscle
relaxation, but it does have analgesic effects.
 Elimination: almost 100% exhalation.
 It causes post operative Nausea and Vomiting

88. Nitrous Oxide toxicity
• Oxidizes Co atom in vitamin B12, inactivates
methinoine synthetase
 Affects myelin formation →peripheral neuropathies,
neurotoxicity.
 Homocysteine accumulation
 Inhibits thymidylate syntetase(DNA syntesis)→teratogenicity.
 Bone marrow depression-megaloblastic anemia

89. CONTRAINDICATION OF N2O
 Air embolism
 Pneumothorax
 Acute Intestinal Obstruction
 Tension Pneumocephalus
 Tympanic membrane grafting
75% nitrous oxide can expand a pneumo-thorax to
double or triple its size in 10 and 30 minutes!!!

90. Halothane
• Physical Properties:
It is halogenated alkene.
Sweet, non-pungent.
Non Inflammable and Non explosive.
Least expensive .

91. Effects of Halothane
 CV: myocardial depression
- ↓BP and CO by up to 50%
- causes slowing of SA node conduction resulting in bradycardia
 Resp: ↑RR, ↓↓TV, ↓MV, ↓↓hypercapnic drive, potent
bronchodilator.
 CEREBRAL:
It increases cerebral blood flow.
 NEUROMUSCULAR:
Relaxes skelatal muscle and potentiates Non depolarizing
neuro-muscular blocking agents.
 RENAL:
Reduces renal blood flow, glomerular filtration rate and urinary
output.

92.  Hepatic
↓hepatic blood flow: impaired hepatic drug clearance.
-Liver oxidation→trifluoroacetic acid(TFA)
- 20% metabolised
- 1in 5 adults hepatotoxicity(lethargy, nausea,fever)
likely related to changes in HBF.
-”Halothane hepatitis”(rare): massive hepatic necrosis.
likely immune mechanism(eosinophilia, rash, fever)
 Contraindications:
• Unexplained liver dysfunction.
• Intra-cranial mass lesions.
• Hypovolemic patient with severe cardiac diseases

93. Isoflurane
 Isoflurane is a halogenated methyl ethyl ether
 Clear, nonflammable liquid at room temperature.
 Has a high degree of pungency.
 It has become the “gold standard” anesthetic since its
introduction in the 1970s
 Contraindications:
• No such contraindication.
• Patient with severe hypovolemia may not tolorate its vasodilating
effects.
It is the most potent of the volatile
anesthetics in clinical use.

94. Sevoflurane
 Sevoflurane is a sweet-smelling, completely fluorinated methyl
isopropyl ether
 Non-pungent, low solubility- excellent for inhalation
induction
 +muscle relaxation(enough for pediatrics intubation) potentiates
NMBA.
 Elimination:
-5%-liver metabolism
 BaOH, soda lime- Compound A
-nephrotoxic in rats
-but has not been associated with renal injury in human
volunteers or patients, with or without renal impairment, even when
fresh gas flows are 1 L/min or less.

95. Desflurane
 Very similar to Isoflurane in structure but much less soluble,
less potent.
 Very high vapor pressure - requires special vaporizer.
- can boil at normal temperature.
- special vaporizer heats it to a gas and then blends it with the
FGF.
Desflurane is the most pungent of
the VA !!!
and if administered via the face mask results in:
coughing,salivation,breath holding,and laryngospasm.
Desflurane has the lowest blood:gas
solubility of the potent VA

96. Xenon
 Is an inert gas, difficult to obtain, and hence extremely expensive.
 It has many characteristics approaching those of an “ideal” inhaled
anesthetic.
 Nonexplosive, nonpungent, and odorless, and thus can be inhaled
with ease.
 Its blood:gas partition coefficient is 0.14, and unlike the other
potent VA , xenon provides some degree of analgesia.
 Does not produce significant myocardial depression.
 Because of its scarcity and high cost, new anesthetic systems need
to be developed to provide for recycling of xenon.

97. Systemic Effects of Inhaled
Anesthetics
Differential Physiologic Effects of Inhaled Anesthetics
N2O Halothane Isoflurane Sevoflurane Desflurane
HR or or
SVR
CO or or
Contractility
HBF
HBF- hepatic blood flow, HR- heart rate, CO-cardiac output, SVR-systemic vascular resist., and -slight or
mild change, - significant decrease, - no change.

98. Ideal inhalational anaesthetic
• Physical properties
• (1) Stable over a range of temperatures
• (2) Not be degraded by light
• (3) Does not require the presence of a
preservative
• (4) Non-explosive and does not support
combustion
• (5) Odourless or has a pleasant smell
• (6) Environmentally safe
• (7) Does not react with other compounds
(e.g. Soda lime)
• (8) Has a boiling point well above room
temperature
• Pharmacodynamic properties
• (1) Predictable dose-related CNS depression
• (2) Analgesic, anti-emetic and muscle
relaxation properties
• (3) Minimal respiratory depression, does not
cause coughing or bronchospasm
• (4) Minimal cardiovascular effects.
• (5) No increase in cerebral blood flow (and
therefore intracranial pressure).
• (6) Not epileptogenic
• (7) Does not impair renal or hepatic function
• (8) No effect on uterine smooth muscle
• (9) Does not trigger of malignant
hyperthermia
• Pharmacokinetic properties
• (1) Low blood: gas solubility co-efficient
• (2) Low oil: gas solubility co-efficient
• (3) Not metabolised or no active metabolites
• (4) Is excreted completely by the respiratory
system

99. REFERENCES
• 1)MILLER’S ANAESTHESIA
• 2)STOELTING’S PHARMACOLOGY
&PHYSIOLOGY IN ANAESTHETIC PRACTICE
• 3)INTERNET SOURCES

100. THANK YOU