Inhalation anaesthetics

1. SPEAKER - DR. SRINIVAS
INHALATIONAL AGENTS

2. WHAT ARE INHALATIONALAGENTS ??
• Inhalational anaesthetics are volatile agents administered in vapour
form through a vaporizer to the patient via pulmonary route.

3. HISTORY
• Experimentation with inhalation of gases and vapors for the purpose of
obtunding the distress associated with surgery began in the 19th century.
• Discovery of anesthetic properties of N2O, diethyl ether & chloroform took place
in 1840’s.
• William.T.G.Morton – October 16 1846.
• 1951 – Fluroxene
• 1956 – Halothane
• 1960 – Methoxyflurane
• 1973 – Enflurane
• 1981 – Isoflurane
• 1992 – Desflurane
• 1994 - Sevoflurane

4. PROPERTIES OF
INHALATIONAL AGENTS
• Inhaled anaesthetics are both taken up and eliminated
through alveolar blood–gas exchange.
• Tissue-dependent metabolism is unnecessary for drug
clearance.

5. PARTIAL PRESSURE !!
• Partial pressure is the portion of total pressure contributed
by one component of a gas mixture.
• Usually expressed as a % of the delivered gas mixture.
• Gas moves from regions of high partial pressures to low
partial pressures until a state of Equilibrium is achieved.
• Maximum partial pressure of a volatile agent is called its
VAPOR PRESSURE.

7. PARTITION COEFFICIENT :
• Ratio of concentrations of drug in one compartment versus
other intercommunicating compartment at equilibrium.

8. BLOOD GAS PARTITITON
COEFFICIENT : ( OSTWALD )
• Ratio of con. of an agent in the blood phase to that in the gas
phase.
• Tells about solubility of the agent.
• The lower the solubility coefficient, the less soluble the
vapour, and the faster its onset of action or change in depth of
anaesthesia.
• The anaesthetic effect is only achieved when the
concentration in the blood is the same as that in the gas in the
alveoli.

9. • For eg: blood/gas coefficient of isoflurane is 1.4 at 37ºc. It
implies that after attaining equilibrium blood contains more
isoflurane than alveolar gas.
affinity of agent for blood (λb )
Blood gas coefficient = ____________________
affinity of agent for gas ( λg )

11. OIL GAS PARTITION COEFFICIENT :
• Concentration of the agent in the olive oil divided by its
concentration in gas at equilibrium.
• Tells about the POTENCY of the agent.

13. • The lower the oil : gas solubility coefficient, the less lipid
soluble the drug and the faster it’s offset.

14. PHARMACODYNAMICS

15. MECHANISM OF ACTION:
• By the 1870s, a wide range of structurally unrelated
compounds were known to have anaesthetic properties
leading Claude Bernard to postulate a common
mechanism of action, the ‘unitary theory of narcosis’.
• Meyer and Overton observed a strong correlation
between anaesthetic potency and solubility in olive oil,
theorizing that anaesthetic agents act non-specifically on
the hydrophobic, lipid components of cells.

16. MEYER OVERTON RULE :
• First experimental evidence on the mechanism of action.
(1899)
• Linear relationship.
• The greater the lipid solubility of the agent greater is its
potency.

18. SHORTCOMING’S !!
• Stereo-isomers of a drug have different anesthetic potency
but their oil – gas partition coefficients are same.
• Certain lipid soluble agents are convulsants rather than
anesthetics.
• Increased temperature.
• Non-immobilizers : Halogenated alkanes

19. CRITICAL VOLUME HYPOTHESIS
• Mullins.
• States that the absorption of anesthetic molecules could
expand the bilayer beyond a critical volume, altering
membrane function.
• Distort channels necessary for sodium ion flux and the
development of action potentials necessary for synaptic
transmission.

20. • Change in Membrane Physical State:
Fluidization Theory: Anesthetics increase the general
fluidity of plasma membranes
Lateral Phase Separation Theory: Anesthetics inhibit
the formation of an ordered, low volume gel phase
around ion channels, normally required for channel
opening.

21. A change in the membrane lateral pressure shifts conformational
equilibrium of certain membrane proteins

22. • Protein Interaction Theory:
Anaesthetics bind to specific proteins that affect ion flux,
resulting in either potentiation of inhibitory
neurotransmitters (e.g., GABA, glycine) or inhibition of
excitatory neurotransmitters (e.g. glutamate NMDA
receptors)

23. • The mechanisms of action of inhalation anaesthetics
may be subclassified as
 Macroscopic (brain and spinal cord),
 Microscopic (synapses and axons), and
 Molecular (pre- and post-synaptic membranes)

24. MACROSCOPIC
• At the spinal cord level:
decrease transmission of noxious afferent information
ascending from the spinal cord to the cerebral cortex.
There is also inhibition of spinal efferent neuronal activity
reducing movement response to pain.
• Hypnosis and amnesia, on the other hand, are mediated at
the supraspinal level.
• Inhalation agents globally depress cerebral blood flow and
glucose metabolism.

25. MICROSCOPIC(SYNAPSES AND AXONS)
• Inhaled anaesthetics are believed to
inhibit excitatory presynaptic channel activity mediated
by neuronal nicotinic, serotonergic and glutaminergic
receptors, while also augmenting the inhibitory post-
synaptic channel activity mediated by GABAA and
glycine receptors. The combined effect is to reduce
neuronal and synaptic transmission

26. MOLECULAR(PRE AND POST SYNAPTIC MEMBRANES)
• Inhalation anaesthetics prolong the GABA receptor-
mediated inhibitory Cl¯ current, thereby inhibiting post-
synaptic neuronal excitability.
• Two-pore domain potassium channels
Voltage independence coupled with absent activation
and inactivation kinetics are characteristics of these
channels. Most recently their role has been described.

27. MINIMUM ALVEOLAR CONCENTRATION
:
• The alveolar concentration of an anaesthetic at 1 atmosphere
that prevents movement in 50% of patients in response to a
noxious stimulus.
• It is a population average not an individual’s response.
• MAC values are additive.
• Analgesia begins at about 0.3 MAC; Amnesia at about 0.5
MAC.
• It’s an indicator of POTENCY

32. MAC VARIANTS :
• MAC AWAKE : defined as the anaesthetic concentration needed to
suppress a voluntary response to verbal command. ( emergence concept )
• MAC UNAWAKE : concentration at which patient remain responsive to
verbal commands when anaesthetic concentration is increased ( induction
concept )

33. • MAC BAR : defined as concentration that blocks
autonomic responses to surgical incision
• MAC CLASSIC/ MAC SKIN INCISION : MAC that
allows for surgical procedure.
• MAC INTUBAION : MAC allows for intubation without
movement or coughing.
• MAC BAR>MAC intubation>MAC incision>MAC awake

34. • Blood gas partition coefficient – solubility
• Oil gas partition coefficient – potency
• MAC – potency

35. PHARMACOKINETICS

36. FACTORS AFFECTING UPTAKE &
REDISTRIBUTION :
• Transfer from inspired air to alveoli .
• Transfer from alveoli to arterial blood .
• Transfer from arterial blood to tissues .
PA Pa Pbrain

37. • INSPIRED CONCENTRATION ( Fi ) :
Pi = Fi x Atm
Greater the inspired concentration greater is the partial pressure.
1. Breathing circuit volumes
2. Fresh gas flow rate
3. Absorption of the agent in the rubber or plastic components of the
breathing system.

38. • Wash in of the circuit - PRIMING
• Breathing circuit components, such as CO2 adsorbents and the plastic or
rubber of the circuit tubing and connectors, influence the rate of
equilibration.
• Because such materials can absorb volatile anaesthetics, increasing the
effective circuit volume.

39. FACTORS THAT SPEED INDUCTION
• High fresh gas flows
• Low circuit volume
• Low circuit absorption

40. • ALVEOLAR VENTILATION :
 Rate of rise in FA is dependent upon minute ventilation and FRC.
 A larger FRC dilutes the inspired concentration of gas resulting initially in a
lower alveolar partial pressure and therefore slower onset of anaesthesia
 If minute ventilation is increased, the tension in alveolar air and arterial
blood will rise more quickly - Lung washin.

41. ALVEOLI BLOOD
• Anaesthetic uptake into blood depends on -
 Pulmonary blood flow (which is typically close to cardiac
output, Q )
Blood’s capacity to solvate anaesthetic from the gas state
(the blood/gas partition coefficient, λb/g)
Alveolar–venous partial pressure gradient and tissue
uptake
Uptake= Q × λb/g × (PA −PMV)

42. - THESE EFFECTS ARE GREATER FOR HIGHLY SOLUBLE AGENTS
Increased cardiac output
Increased pulmonary blood flow
Increased anaesthetic uptake
Rapid delivery to the tissues including the CNS
Accelerates the equilibration of tissue anaesthetic partial pressures with
that of arterial blood
However, this does not hasten induction, as the alveolar concentration is
lowered by the high uptake of anaesthetic
Decrease in alveolar concentration
Delayed induction

44. • key factor determining the speed of onset and recovery
alveolar partial pressure of the agent,
• A higher blood–gas partition coefficient (higher solubility)
Greater uptake by the pulmonary circulation, but
slower increase in alveolar partial pressure of the agent
(FA/Fi ratio) and
therefore more prolonged induction and recovery from
anaesthesia.

46. Alveolar–venous partial pressure gradient and
tissue uptake:
• The difference between alveolar and venous partial
pressures is due to tissue uptake of inhalation agents.
• Tissue uptake is dependent on
- tissue blood flow,
-the blood to tissue partial pressure difference, and
-the blood tissue solubility coefficient.

47. • Brain tissue equilibrates quickly because it is highly
perfused with blood.
• Lean tissue (muscle) has roughly the same affinity for
anaesthetic agents as blood (blood tissue coefficient
1:1), but perfusion is much lower than brain tissue;
therefore, equilibration is slower.
• Fat–blood coefficients are significantly >1. Such high
affinity of fat tissue for anaesthetic and its low perfusion
levels result in a very long equilibration time

49. OTHER FACTORS
• Dead space .
• Shunts : right – left & left – right .

51. CONCENTRATION EFFECT & SECOND
GAS EFFECT :
• The higher the inspired concentration the more rapid is the
rise in alveolar concentration
• Includes two factors
 Concentrating effect
 Augmentation inflow effect.
Concentrating effect is more significant with nitrous oxide than volatile
agents.

52. • As alveolar gas volume diminishes, the concentration of N2O
is maintained (the concentration effect), and the
concentrations of other gases increase (the second gas
effect).

53. • AUGUMENTATION INFLOW EFFECT :
When appreciable volumes of anaesthetic is taken rapidly
the lungs do not collapse, instead sub atmospheric pressure
created by anaesthetic uptake which causes passive drive in
of additional volume of gas to replace that lost by uptake.

55. Nitrous oxide
Augments its own alveolar conc.
augments alveolar conc of
volatile agent simultaneously used
Concentrating effect
second gas effect

56. • DIFFUSION HYPOXIA :
Described by Fink . ( FINK EFFECT )
Opposite of above effects .
The elimination of a poorly soluble gas, such as N2O, from the
alveoli may proceed at as greater rate as its uptake, thereby adding
as much as 1 l/min to alveolar air.
This gas effectively dilutes alveolar air, and available oxygen, so that
when room air is inspired hypoxia may result this is usually only mild
and rarely clinically significant.

57. BLOOD TISSUES :
• Depends on :
Tissue:blood partition coefficient
 Tissue blood flow
 Arterial to tissue pressure difference

58. • The time required for anaesthetic partial pressure equilibration
between arterial blood (Part = PA) and a specified tissue is
shorter if its blood flow is high, and longer if that tissue has a
large effective volume.
• The rate of rise of tension in different regions is proportional to
the arterial-tissue tension difference.
• At equilibrium the concentration in lipid tissues will be far
greater than that in blood.

62. ELIMINATION OF INHALATIONAL
AGENTS :
• The factors affecting the elimination of an anaesthetic agent are identical
to those for uptake and distribution.
• Removal of anaesthetic agent from the body is via
1. Exhalation
2. Biotransformation&
3. Transcutaneous loss
Biotransformation is more important for halothane and methoxyflurane.
Both undergo extensive metabolism in liver via 450(cyp).
Fat and muscle act as reservoirs for anaesthetic agent and more time will be
required for elimination.

64. IDEAL ANAESTHETIC AGENT :
• PHYSICAL PROPERTIES
o Stable over a range of temperatures
o Not be degraded by light
o Does not require the presence of a preservative
o Non-explosive and does not support combustion
o Odourless or has a pleasant smell
o Environmentally safe
o Does not react with other compounds (e.g. Soda lime)
o Has a boiling point well above room temperature

65. 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 malignant hyperpyrexia

66. 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

67. • AN IDEAL ANAESTHETIC AGENT IS YET TO BE
DISCOVERED!!

73. HALOTHANE :
• Amber colored bottle.
• Color code – red.
• Thymol preservative.
• Pleasant smell- pediatrics group.
• Agent of choice for asthmatics.
• Most arrhythmogenic agent .
• Atony of uterus.
• Halothane shakes – postop shivering.
• Malignant hyperthermia.

74. HALOTHANE HEPATOTOXICITY :
• Associated with two distinct types of hepatic injury.
• Subclinical hepatotoxicity :
- halothane reduction to a 2-chloro-1,1,1-trifluoroethyl radical
- seen in 20% of cases
- elevation of hepatic enzymes postoperatively
- reversible
• Fulminant hepatitis :
- elevated AST, ALT, ALP, bilirubin
- massive hepatitis
- very rare

75. ENFLURANE :
• Orange color coded.
• Epileptogenic.
• Potent cardiovascular depressant.

76. ISOFLURANE :
• Isomer of enflurane.
• Volatile & pungent.
• Only agent that preserves baro-receptor reflex best.
• Agent that causes coronary steal .
• Agent of choice for neuro-anaesthesia.
• Agent of choice for controlled hypotension.

77. DESFLURANE :
• Agent that boils at room temp.
• Agent of choice for geriatric patients.
• Agent of choice for hepatic failure pt’s.
• Agent of choice for renal failure pt’s.

78. SEVOFLURANE :
• Pleasant smell.
• Agent of choice for pediatric populations.
• 2nd agent of choice for
- neuro anesthesia
- cardiac anesthesia
- asthmatics

79. FLUORIDE ASSOCIATED
NEPHROTOXICITY :
• Methoxyflurane causes polyuric renal insufficiency.
• Attributed to inorganic fluoride (F) released during its metabolism.
• The nephrotoxic threshold for plasma F− is approximately 50 μM.
• Typical peak fluoride concentrations after 2 to 3 MAC-hours of
sevoflurane anaesthesia are 20 to 30 μM, and less than 5 μM after
isoflurane and desflurane.

80. • Absence of renal toxicity with current volatile
anaesthetics likely derives from a combination of factors:
their lower tissue solubility's, particularly in kidney
resulting in lower intrarenal fluoride production
lower rates of biotransformation
 more rapid respiratory clearance from the body

81. SEVOFLURANE & COMPOUND A
• Halogenated anaesthetics can undergo chemical breakdown while interacting
with CO2 absorbents.
• Strong bases extract a proton from the isopropyl group of sevoflurane
resulting in haloalkene (fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl
ether), known as compound A.
• Compound A is volatile.
• Inhaled concentration is dependent on the FGF rate and the type of CO2
absorbent present.
• Higher FGF rates result in a smaller accumulation of compound A .
• However, compound A exposure is not associated with clinically significant
nephrotoxicity in humans

82. • PTN in rats .
• Compound A exposure can be limited by careful
selection of fresh gas flows, vaporizer output, and CO2
absorbent materials.
• The use of 2 L/min fresh gas flows ensures that for the
vast majority of patients, exposure to compound A will be
below the most conservative threshold for nephrotoxicity.

83. N2O & VITAMIN B12 :
• N2O is unique among anaesthetics in irreversibly inhibiting
cobalamins (vitamin B12) by oxidizing the Co ligand.
• Long-term N2O exposure, can cause megaloblastic anemia,
myelopathy, neuropathy, and encephalopathy, sometimes
presenting as psychosis.

84. ENVIRONMENTAL EFFECTS :
• GLOBAL WARMING :
Inhaled anaesthetics are recognized greenhouse gases
The global warming potential of volatile anaesthetics ranges from
1230-fold (isoflurane) to 3714-fold (desflurane) that of an equal
mass of CO2.
The global warming potential of N2O is approximately 300-fold
greater than that of an equal mass of CO2 .
• OZONE DEPLETION :
Halogenated volatile anesthetics are similar to chlorofluorocarbons
(CFCs), which are major ozone depleting pollutants.