Department of Anesthesia

INHALATONAL ANESTHEIC AGENTS(IAA):Part I

Kumlachew G: (BSc, MSc in Anaesthesia)

 outline
• History and introduction
• Ideal properties of IAA
• Pharmacokinetics of IAA
 Introduction

• Maintenance of general anesthesia is primarily carried out using inhalation

anesthetics, although intravenous anesthetics may be used for short procedures.
• Inhalation anesthetics provide quicker changes of anesthetic depth than injectable
anesthetics, and reversal of central nervous depression is more readily achieved,
explaining for its popularity in prolonged anesthesia (less risk of overdosing, less
accumulation and quicker recovery)
Inhalant Technique Injectable Technique

Expensive Equipment Cheap (needles, syringes)

Patent Airway and high O2 Not necessarily

Better control of anesthetic depth and

easy of administration and monitoring Once given, suffer the consequences
of their effect

Ease of elimination (ventilation) Only through metabolism & Excretion

Pollution No
Inhalational anesthesia agents

• History
• Physical characteristics of volatile anesthetics govern their clinical effects and
practicality associated with their use
• The volatile anesthetics are administered as vapors after their evaporation in
devices known as vaporizers
History
• Nitrous oxide, chloroform, and ether were the first universally accepted general
anesthetics.

• Inhalation agents currently in widespread use in clinical anesthesiology include

nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane

• IAA used in clinical practice can be either in liquid (VIAA)form or gaseous

form(N2o and cyclopropane)

• Most older agents are not used in the current practice due to flammability or toxic
to the liver and kidney
• Methoxyflurane and enflurane, two potent halogenated agents, were used for many years in North
American anesthesia practice.

• Methoxyflurane was the most potent inhalation agent, but its high solubility and low vapor
pressure yielded longer inductions and emergences.

• Up to 50% of it was metabolized by cytochrome P-450 (CYP) enzymes to free fluoride (F-),
oxalic acid, and other nephrotoxic compounds .
• Prolonged anesthesia with methoxyflurane was associated with a vasopressin-
resistant, high-output, renal failure that was most commonly seen when F- levels
increased to greater than 50 µmol/
• Enflurane
• has a non-pungent odor and is nonflammable at clinical concentrations.
• It depresses myocardial contractility.
• It also increases the secretion of cerebrospinal fluid (CSF) and the resistance to
CSF outflow.
• During deep anesthesia with hypocarbia electroencephalographic changes can
progress to a spike-and-wave pattern producing tonic–clonic seizures.
• Because of these concerns, methoxyflurane and enflurane are no longer used
How they administered?

• N2o delivery is controlled by a flowmeter from the anesthesia machine.

• VIAAs are delivered through vaporizers

• Modern IAA are halogenated either partially or fully with fluorine

• This fluorination makes them more stable and less toxic

 cont’d..
• The course of a general anesthetic can be divided into three phases: (1) induction,
(2) maintenance, and (3) emergence

• Adding only a fraction of a volatile anesthetic to the inspired oxygen results in a

state of unconsciousness and amnesia.

• When combined with intravenous adjuvants, such as opioids and

benzodiazepines, a balanced technique is achieved that results in analgesia
 cont’d…
• N20 used for intraoperative and labor analgesia and speed up inhalational
induction(2nd gas effect)

• Inhalation anesthetics, such as halothane and sevoflurane, are particularly useful in

the induction of pediatric patients in whom it may be difficult to start an intravenous
line

• And majorly they are used for the maintenance phase of GA

Ideal properties of IAA
o 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

Pharmacodynamic properties
o Predictable dose-related CNS depression

o Analgesic, anti-emetic and muscle relaxation properties

o Minimal respiratory depression, does not cause coughing or bronchospasm

o Minimal cardiovascular effects.

o No increase in cerebral blood flow (and therefore intracranial pressure).

o Not epileptogenic

o Does not impair renal or hepatic function

o No effect on uterine smooth muscle

o Does not trigger of malignant hyperpyrexia

Pharmacokinetic properties

• Low blood: gas solubility co-efficient

• Low oil: gas solubility co-efficient

• Not metabolised or no active metabolites

• Is excreted completely by the respiratory system

Mechanisms of action of inhalation agents
• The precise mechanisms whereby inhalation agents induce general anesthesia are
not known

• no single proposed mechanism of action fully explains their clinical effects

• The mechanisms of action of inhalation anesthetics may be subclassified as

1.macroscopic (brain and spinal cord),

2.microscopic (synapses and axons), and

3.molecular (pre-and post-synaptic membranes )

Macroscopic
At the spinal cord level, inhalation anesthetics decrease transmission of noxious afferent
information ascending from the spinal cord to the cerebral cortex via the thalamus,
thereby decreasing supraspinal arousal.

• 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
Synaptic

• Can affect the release of neurotransmitters pre-synaptically or change the response of

postsynaptic threshold to NT.

• Inhaled anaesthetics are believed to inhibit excitatory presynaptic channel activity mediated
by neuronal nicotinic, serotonergic and glutaminergic receptors,

• And also augmenting the inhibitory post-synaptic channel activity mediated by GABAA
and glycine receptors. The combined effect is to reduce neuronal and synaptic transmission
Molecular
• Effects of inhalation agents on a-subunits of the GABAA transmembrane
receptor complex are likely to be important.
• GABA binding to its receptor leads to opening of a chloride channel leading to
increased Cl2 ion conductance and hyperpolarization of the cell membrane
increasing the depolarization threshold.
• Inhalation anaesthetics prolong the GABAA receptor-mediated inhibitory Cl2
current, inhibiting post-synaptic neuronal excitability
• Inhaled anesthetics act through multiple complex mechanisms and pathways within the central
nervous system (CNS).

• The agents act by binding to target sites in proteins to enhance inhibitory receptors (gamma-amino
butyric acid, glycine) and suppress excitatory transmission (block the action of glutamate at N-
methyl D-aspartate (NMDA) receptors).

• Hypnosis/sedation and amnesia are produced through effect sites in the brain. Immobility is
produced by actions within the spinal cord.

• Lipid solubility correlates to anesthetic potency (Meyer-Overton correlation).

• Nitrous oxide is an inhaled anesthetic that works primarily by NMDA receptor antagonism
POTENCY

• The potency of an inhalational anaesthetic agent can be measured by its MAC.

• It is defined as the minimum alveolar concentration at steady-state that prevents

reaction to a standard surgical stimulus (skin incision) in 50% of subjects at 1
atmosphere.

• MAC is affected by a wide range of physiological and pharmacological factors

Unique Features of Inhaled Anaesthetics

Speed, Gas State, and Route of Administration

o The inhaled anaesthetics are among the most rapidly acting drugs in existence

o The ability to quickly increase or decrease anaesthetic levels as necessary

o Among inhaled anaesthetics only nitrous oxide(N2O) and xenon are true gases, while the

so-called potent agents are the vapours of volatile liquids.

These agents are all nonionized and have low molecular weights.
 This allows them to diffuse rapidly without the need for facilitated diffusion or
active transport from bloodstream to tissues.

The other advantage of gases is that they can be delivered to the

bloodstream via the lungs.

Speed, gaseous state, and route of administration combine to form the

major beneficial feature of the inhaled anaesthetics.
Physical Characteristics of Inhaled Anaesthetics

o Most potent volatile anaesthetics are liquids.

o If the system in which the volatile liquid resides is a closed container, molecules of the
substance will equilibrate between the liquid and gas phases -the vapor pressure.

o One important property of vapor pressure is that as long as any liquid remains in the
container, the vapor pressure is independent of the volume of that liquid.

o For all of the potent agents, at 20°C the vapor pressure is below atmospheric pressure.

o If the temperature is raised, the vapor pressure increases.

o The boiling point of a liquid is the temperature at which its vapor pressure exceeds
atmospheric pressure in an open container.
For any mixture of gases in a closed container, each gas exerts a pressure
proportional to its fractional mass.
o This is its partial pressure
Gases in solution
 The goal of delivering inhaled anaesthetics is to produce the anaesthetic state by

establishing a specific concentration of anaesthetic molecules in the CNS.

 This is done by establishing the specific partial pressure of the agent in the lungs, which

ultimately equilibrates with the brain.

 At equilibrium, CNS partial pressure equals blood partial pressure, which in turn equals

alveolar partial pressure

 Solubility is the term used to describe the tendency of a gas to equilibrate with a solution,

hence determining its concentration in solution.

The principles of partial pressures and solubility apply in mixtures of gases in
solution.

That is, the concentration of any gas in a mixture of gases in solution depends on
two factors:
 Its partial pressure in the gas phase in equilibrium with the solution

 Its solubility within that solution

The implications of these properties are that anesthetic gases administered via the
lungs diffuse into blood until the partial pressures in alveoli and blood are equal.
Pharmacokinetics of inhalation agents
• The clinical effect of inhalation anesthetics is dependent on reaching therapeutic tissue
concentrations in the CNS.

• Effect-site concentrations are related to the partial pressure of these agents in the CNS and are
represented at equilibrium by the alveolar concentration.

• Kety in 1950 was the first to examine the pharmacokinetics of inhaled agents in a systematic fashion

Pharmacokinetics-The study of:

 Absorption/uptake

 Distribution

 Metabolism…biotransformation

 Excretion/elimination
Inhalation agents should transfer from:

• Inspired air to alveoli

• Alveoli to arterial blood

• Arterial blood to tissues

Uptake of inhaled anaesthetic agents
• Inhalation agents must pass from inspired gas into the blood of the alveolar-
capillary network (ie, uptake), then from circulating blood into the central nervous
system (CNS; ie, redistribution) in order to exert anesthetic effects

• At equilibrium, the partial pressures of the agents will be identical throughout the
body,

• When a difference in partial pressure exists between two compartments there will
be a pressure gradient that favors the mov’t of gases until the equilibrium reaches.
Speed of uptake and of onset of anesthetic effect depends

• on the inspired concentration of the inhalation agent

• Blood–gas partition coefficient

• minute ventilation

• patient's pulmonary blood flow

• Achievement of satisfactory brain levels of anaesthetic agent occurs in three
stages:
1.Delivery phase
2. Pulmonary phase
3.Circulatory phase
Delivery phase
• Is the introduction of the anaesthetic agents into the gas to be inspired.

• The fresh gas mixture produced by the anaesthetic machine is passed into the
anaesthetic breathing system

• Dialed up on the anaesthetic machine does not guarantee the same levels in the
inspired gas, because the anaesthetic agent is lost in several ways:

• Dilution with existing gas in the breathing system

• Uptake by CO2 absorbers

• Uptake by rubber and plastic components of the circuit

Pulmonary phase
o The following factors influence the uptake of anesthetic agents from inhaled gas to the blood:
Inhaled concentration
Alveolar ventilation
Diffusion
Blood/gas partition coefficient
Partial pressure of agent in the pulmonary artery
Pulmonary blood flow
Ventilation/perfusion distribution
Concentration effect
Second gas effect
 Inhaled concentration
The inhaled concentration directly affects the inhaled partial pressure or tension. The higher the
tension the higher the levels achieved in the blood
Alveolar ventilation

• Increasing alveolar minute volume speeds up the approximation of alveolar to inspired levels

• Induction is slowed by hypoventilation ,in res depression and airway obstruction

 Diffusion
The small molecules of volatile agents pass easily through the pulmonary membrane
and in health diffusion is not a limiting factor.

• disease processes may reduce the surface area and increase the thickness of the alveolar
membrane.

• emphysema reduces the available area and pulmonary fibrosis increases the thickness
of the membrane, so transfer of inhaled agents into the capillary blood may be delayed.
 The blood: gas partition coefficient is defined as the ratio of the amount of

anaesthetic in blood and gas when the two phases are of equal volume and pressure

in equilibrium at 37ºC e.g. halothane has high B:G coefficient : onset slow.

 If the agent is more soluble in blood, more inhaled agent will be removed from

lungs to blood slow increase in partial pressure of agent in alveoli and slow

onset

 Desflurane has low B:G coefficient : fast onset

 Blood/gas partition coefficient
o The rate of increase of the PA towards the PI is inversely related to the
solubility of the anesthetic in blood(B/G partition coefficient)

o When blood solubility is low, minimal amounts of the anesthetic have to be

dissolved in the blood before equilibrium is reached such that the rate of increase
of the PA and that of the Pa and Pbr are rapid
 Based on blood:gas partition coefficients, inhaled
anesthetics are categorized as
Soluble
 Intermediately soluble, and
Poorly soluble
• Partial pressure of volatile agent in the pulmonary artery
• The rate of uptake of volatile agent from each alveolus is dependent on the tension
difference between the alveolus and the capillary blood.
• As the concentration and tension in the blood rises the rate of uptake is reduced
and so the rate of tension rise decreases.
• Pulmonary blood flow
As blood passes through the pulmonary capillaries the tension of volatile agent in
the capillary will increase and so reduce the rate of transfer in the latter part of the
capillary.
• Therefore, increasing the blood flow will increase uptake

• Ventilation/perfusion distribution
• Ventilation/perfusion mismatch will reduce perfusion of well-ventilated areas of
lung and increase perfusion of alveoli poorly supplied with volatile agent
The overall effect is an increase in the alveolar partial pressure
(particularly for highly soluble agents) and a decrease in the arterial
partial pressure (particularly for poorly soluble agents).

Thus, a bronchial intubation or a right-to left intracardiac shunt will

slow the rate of induction
Second gas / concentration effect
o The higher the PI, the more rapidly the PA approaches the PI
concentration effect’  fast onset
o When two inhalational anesthetics are given simultaneously, the uptake of
large volumes of one agent may increase the alveolar tension of the other, thus
accelerating the induction of anesthesia - 2nd gas effect
o  concentration of agent at the alveoli draws more agent into alveoli to
replace N20 (‘2nd gas effect’)  fast onset. E.g if you are using halothane in
combination with nitrous oxide more halothane will be available at the alveoli
Circulatory phase

 The following factors influence the transport of the volatile agent dissolved to the brain:

• Cardiac output
• Cerebral blood flow
• Distribution to other tissues

• The uptake of agent by the tissues is proportional to tissue perfusion, solubility and arteriovenous tension
differences
• Cardiac output

• Of cardiac output, 70–80% is distributed to the vessel-rich organs (brain, heart, liver,
kidney) that constitute about 9% of body mass.

• Of the total, 14% goes to the brain (2.2% of body mass).

• A large proportion of the absorbed anesthetic is thus directed to the brain.

• by their high lipid solubility, the brain has a relatively high affinity for anesthetic agents
 Redistribution
Depends on

• the tissue: blood partition coefficient (ie, the ratio of the agent's solubility in
tissue to its solubility in blood) for each perfused tissue bed

• also depends on the blood flow to these tissue compartments

• Blood flow to the brain

Metabolism

• Sevoflurane, desflurane, isoflurane, and N2O undergo negligible

biotransformation and metabolism, thus these agents are primarily exhaled
unchanged.

• Halothane – Up to 50 percent of halothane is metabolized in the liver, while 50

percent or more is exhaled unchanged. Hepatic metabolism of halothane to
hepatotoxic intermediates, particularly trifluoroacetic acid, is thought to be largely
responsible for the transient,

• usually mild hepatic injury seen in approximately 25 percent of patients after

halothane administration (halothane hepatotoxicity)
Clearance
• Clearance of inhalation agents with termination of anesthetic and other effects
depends on the same factors that influence uptake.
• Specifically, redistribution out of the CNS depends on the presence of a
concentration gradient favoring clearance from the brain to blood, then from
blood to alveoli (from which the agent is exhaled from the body)
It depends on
• Brain: blood partition coefficient
• blood: gas partition coefficient
• patient's minute ventilation
• and on pulmonary blood flow
Minimum alveolar concentration

• The minimum alveolar concentration at steady state of inhaled anaesthetic at 1 atm pressure
that prevents movement (e.g. withdrawal) in response to a standard surgical midline
incision in 50% of a test population.

• It reflects the actions of an inhalation agent on spinal cord-mediated reflexes by measuring

somatic responses

• It measures the potency of IAA

• An estimated MAC can be calculated as 150 divided by the oil:gas partition coefficient
 MAC values for inhaled anesthetics
are additive.
For example, 0.5 MAC of nitrous
oxide plus 0.5 MAC isoflurane
has the same effect at the brain as
does a 1-MAC concentration of
either anesthetic alone

 A 1-MAC dose prevents skeletal

muscle movement in response to a
painful stimulus in 50% of patients,
whereas a modest increase to about
1.3 MAC prevents movement in at
least 95% of patients
Factors to decrease MAC

o hypotension(MAP < 40mmmhg)

o anemia (PCV<13%)
o hypothermia
o metabolic acidosis
o hypoxia(Pao2< 40mmhg)
o premedicants
o pregnancy
o aging
o hypothyroidism
o concurrent use of analgesics
Factors to increase MAC
o increased body temperature
o hyperthyroidism
o hypernatremia
o concurrent use of central nervous stimulant (e.g., doxapram).
o Chronic alcohol use
o Young age
• Factors known not to affect MAC
o duration of anesthesia
o sex
o PaCO2
o hypertension (between 15-95 mmHg)
o potassium
Blood : gas partition co-efficient:

 It is a measure of solubility in the blood.

 major determinant of speed of anesthetic onset

 It determines the rate of induction and recovery of Inhalational anesthetics.

 Lower the blood : gas co-efficient – faster the induction and recovery – e.g. Desflurane,Nitrous oxide.

 Higher the blood : gas co-efficient – slower induction and recovery – Halothane

 Nitrous oxide (N2O) = desflurane < sevoflurane < isoflurane < halothane
Oil: gas partition co-efficient:

o It is a measure of lipid solubility.

o Lipid solubility - correlates strongly with the potency of the anesthetic.

o Higher the lipid solubility – potent anesthetic. e.g., halothane

o Lower lipid solubility: fast recovery

• Oil:gas partition coefficients from highest to lowest (ie, most to least potent) are :
• halothane > isoflurane > sevoflurane > desflurane > N2O
Tissue: blood partition coefficient

• Tissue: blood partition coefficients (i.e, the ratio of agent solubility in tissue to its
solubility in the blood)

• is a primary determinant of the speed of redistribution of each inhalation agent

• The speed with which tissue: blood equilibrium is reached in the brain and other
tissues also depends in large part on blood flow to each perfused tissue compartment

• redistribution of an agent out of the tissues into the blood is faster if it has a low
tissue: blood partition coefficient
THANK YOU