inhalational agents (2)

Inhalational Inhalational agentsagents

Dr. Sakunthala PeirisDr. Sakunthala Peiris

Consultant AnaesthetistConsultant Anaesthetist

Nuwara-EliyaNuwara-Eliya

Introduction-HistoryIntroduction-History

1840 - Discovery of anaesthetic properties 1840 - Discovery of anaesthetic properties of Nof N22O , Ether, ChloroformO , Ether, Chloroform

1951 - Halogenated hydrocarbon : 1951 - Halogenated hydrocarbon : decreased flammability by combining decreased flammability by combining carbon with fluorinecarbon with fluorine Alkane derivatives - - ArrhythmogenicAlkane derivatives - - Arrhythmogenic

1960 – Ethers : Methoxyflurane1960 – Ethers : Methoxyflurane 1973 – Enflurane Less Hepato & Renal 1973 – Enflurane Less Hepato & Renal

toxicitytoxicity 1981 - Isoflurane1981 - Isoflurane

Structure activity Structure activity relationshiprelationship

HH EE II C-F Bond decreases flammability C-F Bond decreases flammability SS H atom+C-cl bondH atom+C-cl bondPotencyPotency 3F Carbon -3F Carbon -molecular stabilitymolecular stability

Ether bond – anti arrhythmogenicEther bond – anti arrhythmogenic DD

HalothaneHalothane UsesUses

Induction and maintenance of general anaesthesiaInduction and maintenance of general anaesthesia

ChemicalChemical Halogenated hydrocarbon.Halogenated hydrocarbon.

PresentationPresentation Clear colourless liquid with a sweet smellClear colourless liquid with a sweet smell should be protected from light.should be protected from light. The commercial preparation contains 0.01% thymol which prevents The commercial preparation contains 0.01% thymol which prevents

decomposition on exposure to lightdecomposition on exposure to light Thymol can cause vaporizer malfunction. Thymol can cause vaporizer malfunction.

Mode of actionMode of action Mechanism of general anaesthesia remains unclear.Mechanism of general anaesthesia remains unclear.

Routes:Routes: Inhalation, via a calibrated vaporiser. Induction dose 2-4%, Inhalation, via a calibrated vaporiser. Induction dose 2-4%,

maintenance 0.5-2%.maintenance 0.5-2%.

EnfluraneEnflurane UsesUses::

Induction and maintenance of general anaesthesia.Induction and maintenance of general anaesthesia.

ChemicalChemical:: Halogenated methyl ethyl ether. Structural isomer of isoflurane.Halogenated methyl ethyl ether. Structural isomer of isoflurane.

PresentationPresentation

Clear colourless liquid with a sweet smell Clear colourless liquid with a sweet smell should be protected from light.should be protected from light.

Mode of actionMode of action:: Mechanism of general anaesthesia remains unclear.Mechanism of general anaesthesia remains unclear.

RoutesRoutes:: Inhalation, via a calibrated vaporiser. Induction dose 1-10%, Inhalation, via a calibrated vaporiser. Induction dose 1-10%,


IsofluraneIsoflurane

UsesUses Induction and maintenance of general anaesthesia.Induction and maintenance of general anaesthesia.

ChemicalChemical:: Halogenated methyl ether. Structural isomer of Enflurane.Halogenated methyl ether. Structural isomer of Enflurane.

PresentationPresentation Clear colourless liquid, with a pungent smell.Clear colourless liquid, with a pungent smell.

Mode of actionMode of action Mechanism of general anaesthesia remains unclear.Mechanism of general anaesthesia remains unclear.

RoutesRoutes:: Inhalation, via a calibrated vaporiser. Induction dose 1-4%, Inhalation, via a calibrated vaporiser. Induction dose 1-4%,


SevofluraneSevoflurane

UsesUses:: Induction and maintenance of general anaesthesiaInduction and maintenance of general anaesthesia

ChemicalChemical Halogenated etherHalogenated ether

PresentationPresentation Clear colourless liquid, non-flammableClear colourless liquid, non-flammable

Mode of actionMode of action Mechanism of general anaesthesia remains Mechanism of general anaesthesia remains

unclearunclear

RoutesRoutes: : Inhalation, via a calibrated vaporiser. Induction Inhalation, via a calibrated vaporiser. Induction

dose 5-8%, maintenance 0.5-3%dose 5-8%, maintenance 0.5-3%

DesfluraneDesflurane UsesUses

Induction and maintenance of general anaesthesia.Induction and maintenance of general anaesthesia.

ChemicalChemical: : Halogenated ether. Halogenated ether.

PresentationPresentation:: Clear colourless liquid that should be protected from light.Clear colourless liquid that should be protected from light.

Mode of actionMode of action mechanism of general anaesthesia remains unclear.mechanism of general anaesthesia remains unclear.

RoutesRoutes Administered by inhalation. Because of the high saturated Administered by inhalation. Because of the high saturated

vapour pressure, Desflurane is administered by a specific vapour pressure, Desflurane is administered by a specific pressurised and heated vaporiser. Induction dose, 4-11%; pressurised and heated vaporiser. Induction dose, 4-11%; maintenance, 2-6%.maintenance, 2-6%.

Tec 6 Desflurane vaporiserTec 6 Desflurane vaporiser:: volatility of this agent,, requires a different vaporiser to contain, transfer and volatility of this agent,, requires a different vaporiser to contain, transfer and

vaporise it. vaporise it. The SVP at room temperature (20 degrees C) is 88.5 kPa -The SVP at room temperature (20 degrees C) is 88.5 kPa - desflurane is nearly boiling at room temperature. desflurane is nearly boiling at room temperature. The vaporiser is a gas/vapour blender, not a variable bypass type. The vaporiser is a gas/vapour blender, not a variable bypass type.

Electrically heated, dual circuit gas/vapour blender, constant- temperature, Electrically heated, dual circuit gas/vapour blender, constant- temperature, agent specific and out-of-circuit. agent specific and out-of-circuit.

FunctionFunction:: Heats the agent to 39 degrees C, which produces a vapour pressure of around 1550 Heats the agent to 39 degrees C, which produces a vapour pressure of around 1550

mmHg.mmHg. Electronic controls inject pure vapour into the fresh gas flow stream from the Electronic controls inject pure vapour into the fresh gas flow stream from the

flowmeters, controlled by the concentration control dial, and a transducer (which flowmeters, controlled by the concentration control dial, and a transducer (which senses the fresh gas flow rate and adjusts the vapour output accordingly)senses the fresh gas flow rate and adjusts the vapour output accordingly)

Requires electrical power and has alarms.Requires electrical power and has alarms. It has interlocks, and is mounted on the back bar .It has interlocks, and is mounted on the back bar . It is accurate at low flows.It is accurate at low flows. It may be filled during use.It may be filled during use. A mark on a liquid crystal display indicates when the liquid level is one bottle low A mark on a liquid crystal display indicates when the liquid level is one bottle low

(250 ml). There is an alarm for low liquid level. (250 ml). There is an alarm for low liquid level. The unit requires a warm-up period. Internal switches cut out the system if The unit requires a warm-up period. Internal switches cut out the system if

temperature increases above 57 degrees C or if the vaporiser is tilted or becomes temperature increases above 57 degrees C or if the vaporiser is tilted or becomes empty.empty.

Physical propertiesPhysical properties

Halothane Isoflurane Enflurane Desflurane Sevoflura

Molecular weight 197 184 184 168 200

Boiling point (oC) 50.2 48.5 56.5 22.8 58.5

Saturated vapour pressure at 20 degrees C 243 238 175 669 157

Minimum alveolar concentration (MAC) in 100% O2 0.75 1.15 1.8 6 2.05

MAC in 70% N2O 0.29 0.56 0.57 2.5 0.66

% Biotransformation 20 0.2 2 <0.1 3-5

Blood / gas 2.2 1.36 1.91 0.45 0.6

Oil / gas 224 98 98.5 28 47

PharmacokineticsPharmacokinetics

1.1. The concentration effectThe concentration effect

2.2. The second gas effectThe second gas effect

3.3. Diffusion HypoxiaDiffusion Hypoxia

4.4. Blood:gas coefficientBlood:gas coefficient

5.5. Effect of cardiac outputEffect of cardiac output


The concentration effectThe concentration effect higher inspired concentrations of an anaesthetichigher inspired concentrations of an anaesthetic

rate of rise in arterial tension is greater.rate of rise in arterial tension is greater. NN22O has a low blood :gas partition coefficient and O has a low blood :gas partition coefficient and

therefore a rapid onset and offset of actiontherefore a rapid onset and offset of action N2O is about 20 times more soluble than O2 and N2O is about 20 times more soluble than O2 and

N2. N2. During induction the volume of N2O entering the During induction the volume of N2O entering the

pulmonary capillaries is greater than the N2 pulmonary capillaries is greater than the N2 leaving the blood and entering the alveolus.leaving the blood and entering the alveolus.

volume of the alveolus decreases,volume of the alveolus decreases, increasing the fractional concentration of the remaining increasing the fractional concentration of the remaining

gases.gases. augments ventilation as bronchial and tracheal gas is augments ventilation as bronchial and tracheal gas is

drawn into the alveolus to make good the diminished drawn into the alveolus to make good the diminished alveolar volumealveolar volume


The second gas effectThe second gas effect usually refers to nitrous oxide usually refers to nitrous oxide

combined with an inhalational agentcombined with an inhalational agent NN22O is not soluble in blood, O is not soluble in blood, rapid absorption from alveoli causes an rapid absorption from alveoli causes an

abrupt rise in the alveolar abrupt rise in the alveolar concentration of the other inhalational concentration of the other inhalational anaesthetic agentanaesthetic agent

Diffusion HypoxiaDiffusion Hypoxia First described by Fink in 1955, First described by Fink in 1955, Elimination of a poorly soluble gas Elimination of a poorly soluble gas

from the alveoli may proceed at as from the alveoli may proceed at as greater rate as its uptake, greater rate as its uptake, thereby adding to alveolar airthereby adding to alveolar air dilutes alveolar air, and available oxygendilutes alveolar air, and available oxygen when room air is inspired hypoxia may when room air is inspired hypoxia may

resultresult

Blood:gas coefficientBlood:gas coefficient The solubility of a gas in liquid is given by its Ostwald The solubility of a gas in liquid is given by its Ostwald

solubility coefficient. solubility coefficient. the ratio of the concentration in blood to the concentration in the ratio of the concentration in blood to the concentration in

the gas phase the gas phase This is independent of pressure, obeying Henry's lawThis is independent of pressure, obeying Henry's law serum proteins and RBC's are the major determinants of serum proteins and RBC's are the major determinants of

solubility.solubility.

higher blood gas partition coefficient means a higher uptake of higher blood gas partition coefficient means a higher uptake of the gas into the blood and therefore a slower induction timethe gas into the blood and therefore a slower induction time

Lower B:G coefficients are seen withLower B:G coefficients are seen with Haemodilution Haemodilution ObesityObesity Hypoalbuminaemia and starvationHypoalbuminaemia and starvation

Higher coefficients are seen in:Higher coefficients are seen in:

Adults versus childrenAdults versus children HypothermiaHypothermia PostprandiallyPostprandially

Effect of cardiac outputEffect of cardiac output A higher cardiac output removes more volatile A higher cardiac output removes more volatile

anaesthetic from the alveoli anaesthetic from the alveoli lowers the alveolar partial pressure of the gaslowers the alveolar partial pressure of the gas take longer for the gas to reach equilibrium between take longer for the gas to reach equilibrium between

the alveoli and the brain. the alveoli and the brain. Therefore, a high cardiac output prolongs induction Therefore, a high cardiac output prolongs induction

time.time.

The alveolar to venous partial pressure difference The alveolar to venous partial pressure difference reflects tissue uptake of the inhaled anaesthetic agent. reflects tissue uptake of the inhaled anaesthetic agent.

All inhalational anaesthetics have high fat/blood All inhalational anaesthetics have high fat/blood partition coefficientspartition coefficients

This means that most of the gas will bind to fatty tissue This means that most of the gas will bind to fatty tissue as times goes byas times goes by

inhalational anaesthetics stored in such tissue in obese inhalational anaesthetics stored in such tissue in obese patients may delay awakening at the end of patients may delay awakening at the end of anaesthesia. anaesthesia.

PharmacokineticsPharmacokineticsHalothane Halothane Isoflurane Isoflurane EnfluraEnflura DesfluranDesfluran SevoflurSevoflur

absorption B/G coefficientabsorption B/G coefficient 2.42.4 1.41.4 1.91.9 0.420.42 0.60.6

absorption O/G coefficientabsorption O/G coefficient 225225 9898 9898 1919 4747

absorption MACabsorption MAC 0.750.75 1.151.15 1.81.8 66 2.052.05

DistributionDistribution

MetabolismMetabolism 20%20% 0.20%0.20% 2.40%2.40% 0.02%0.02% 3.00%3.00%

ExcretionExcretion 60-80%60-80%90%90%0.2%0.2%

80%80%2.4%2.4% lungslungs lungslungs

MetabolismMetabolism HalothaneHalothane

20% of dose is metabolised in the liver 20% of dose is metabolised in the liver oxidation/dehalogenation to yield oxidation/dehalogenation to yield

trifluoroacetic acidtrifluoroacetic acid TrifluoroacetylethanolamideTrifluoroacetylethanolamide ChlorobromidifluorethyleneChlorobromidifluorethylene chloride and bromide radicals.chloride and bromide radicals.

EnfluoraneEnfluorane 2.4% of dose is slowly metabolised in the liver 2.4% of dose is slowly metabolised in the liver

(oxidation/dehalogenation)(oxidation/dehalogenation) Organic Fluoride Organic Fluoride Plasma fluoride ion concentrations may reach 10 Plasma fluoride ion concentrations may reach 10

times those observed with halothane or times those observed with halothane or isoflurane-> Nephrotoxicityisoflurane-> Nephrotoxicity

MetabolismMetabolism IsofluraneIsoflurane

0.2% of dose is slowly metabolised in the liver 0.2% of dose is slowly metabolised in the liver (oxidation/dehalogenation)(oxidation/dehalogenation)

Methanol and trifluoro-acetic acidMethanol and trifluoro-acetic acid

DesfluraneDesflurane 0.02% is metabolised, predominantly to 0.02% is metabolised, predominantly to

trifluoroacetic acid.trifluoroacetic acid.

SevofluraneSevoflurane By hepatic cytochrome P450IIEI to By hepatic cytochrome P450IIEI to

hexafluoroisopropanolhexafluoroisopropanol further conjugated to its glucoronidefurther conjugated to its glucoronide 3% of the absorbed dose is metabolised3% of the absorbed dose is metabolised

PharmacodynamicsPharmacodynamics

Minimum alveolar concentration Minimum alveolar concentration Concentration which is delivered at Concentration which is delivered at 1 1

atmosphereatmosphere That prevents That prevents skeletal muscleskeletal muscle

movement in response to a movement in response to a supramaximalsupramaximal painful stimulus in painful stimulus in 50%50%

Reflects the partial pressure at site of Reflects the partial pressure at site of anaesthetic actionanaesthetic action

Most useful index of anaesthetic potencyMost useful index of anaesthetic potency

MAC: minimum alveolar MAC: minimum alveolar concentrationconcentration

The rationale for this measure of anaesthetic The rationale for this measure of anaesthetic potency is:potency is:

Alveolar concentration can be easily measuredAlveolar concentration can be easily measured

Near equilibrium, alveolar and brain tensions are Near equilibrium, alveolar and brain tensions are virtually equalvirtually equal

High cerebral blood flow produces rapid High cerebral blood flow produces rapid equilibrationequilibration

Impact of physiological and Impact of physiological and pharmacological factors on pharmacological factors on

MACMAC

Increase in MACIncrease in MAC

Decrease in MACDecrease in MAC

No change in MACNo change in MAC

Mechanism of action of Mechanism of action of inhaled anaesthetic agentsinhaled anaesthetic agents

Meyer Overton theory (Critical volume Meyer Overton theory (Critical volume hypothesis)hypothesis) Inhaled anaesthetic agents act in different ways at the level of Inhaled anaesthetic agents act in different ways at the level of

the central nervous system. the central nervous system. Direct interaction with the neuronal plasma membrane is very Direct interaction with the neuronal plasma membrane is very

likelylikely High correlation between lipid solubility and anaesthetic High correlation between lipid solubility and anaesthetic

potency potency suggests that inhalational anaesthetic agents have a hydrophobic suggests that inhalational anaesthetic agents have a hydrophobic

site of action.site of action. The Meyer-Overton theoryThe Meyer-Overton theory describes the correlation describes the correlation

between lipid solubility of inhaled anaesthetics and between lipid solubility of inhaled anaesthetics and MAC .MAC .

a sufficient number of inhalational anaesthetic molecules a sufficient number of inhalational anaesthetic molecules dissolve in the lipid cell membranedissolve in the lipid cell membrane anaesthesia. anaesthesia.

The Meyer-Overton theory postulates that it is the number of The Meyer-Overton theory postulates that it is the number of molecules dissolved in the lipid cell membrane, and not the molecules dissolved in the lipid cell membrane, and not the type of inhalational agent, that causes anaesthesia. type of inhalational agent, that causes anaesthesia.

Combinations of different inhaled anesthetics may have Combinations of different inhaled anesthetics may have additive effects at the level of the cell membrane additive effects at the level of the cell membrane

Protein Receptor HypothesisProtein Receptor Hypothesis Site of action as protein receptors –Site of action as protein receptors –

suggested by steep dose response curve of suggested by steep dose response curve of MAC.MAC.

Alterations in neurotransmitter Alterations in neurotransmitter AvailabilityAvailability Interference with the formation, release, Interference with the formation, release,

break-down of neurotransmitters in CNSbreak-down of neurotransmitters in CNS

Effects on organ systemsEffects on organ systemsHaloHalo EnEn IsoIso DesDes SevoSevo

CVS CVS HRHR

Reflex Reflex tachytachy Little Little

effecteffectLittle Little effecteffect

CO/SVCO/SV

MaintainMaintaineded

MaintainMaintaineded

--

SVRSVR //unchangeunchangedd

BPBP Adrenaline/Adrenaline/NANA

Sensi. +++Sensi. +++ ++++ nono no no

nono

OtherOther Coronary Coronary steelsteel

HaloHalo EnEn IsoIso DesDes SevoSevo

ResRes DepressaDepressantnt

Powerful Powerful depressadepressantnt

DepressaDepressantnt

DepressaDepressantnt

? ? No No effecteffect

TVTV

RRRR ++ ++ Little Little effecteffect

+ + ++++

MVMV unchangunchangeded

ResponseResponse

OtherOther Non Non irritantirritant

Non Non irritantirritant

Very Very irritantirritant Very Very

irritantirritantPleasantPleasant


CNSCNS

CBFCBF ++++VasodilatatVasodilatationion

++++ ++ ++ ++++ ++++

ICPICP ++++ ++++++ ++++ ++++ ++

EEGEEG nono ++ nono nono nono

OtherOther Decrease Decrease muscle muscle tonetone

No effectNo effect no effectno effectDecrease Decrease muscle muscle tonetone

No effectNo effect

AnalgeAnalgesiasia

nono nono nono nono nono


AbdoAbdo Hepatic Hepatic bd. flowbd. flow

MaintainMaintainss

MaintainMaintainss

??

SplancniSplancnicc

MM MM MM

LFTLFT Inc.Inc. Mild Mild IncInc

NoNo NoNo NoNo

GUGU

RBFRBF??

GFRGFR ?? ?? ??Uterine Uterine tonetone

?? ??

ToxicityToxicityHalothaneHalothane ToxicityToxicity: :

trigger agent for malignant hyperthermiatrigger agent for malignant hyperthermia myocardial dysrhythmias with hypoxia, myocardial dysrhythmias with hypoxia,

hypercapnia or excessive catecholamine hypercapnia or excessive catecholamine

Halothane hepatitisHalothane hepatitis Type I hepatotoxicity Type I hepatotoxicity

benign, self-limiting, and relatively common (up to benign, self-limiting, and relatively common (up to 25-30% incidence). 25-30% incidence).

mild, transient increases in serum transaminase and mild, transient increases in serum transaminase and glutathione S-transferase concentrations glutathione S-transferase concentrations

probably results from probably results from reductivereductive (anaerobic) (anaerobic) biotransformation of halothane rather than the biotransformation of halothane rather than the normal oxidative pathwaynormal oxidative pathway

does not occur with otherdoes not occur with other

Type II hepatotoxicityType II hepatotoxicity massive centrilobular liver cell necrosis that leads to fulminant massive centrilobular liver cell necrosis that leads to fulminant

liver failureliver failure . No histopathologic findings are specific . No histopathologic findings are specific characterised by fever, jaundice and grossly elevated serum characterised by fever, jaundice and grossly elevated serum

transaminase transaminase immune mediated and is initiated by immune mediated and is initiated by oxidative oxidative halothane halothane

metabolism to an intermediate compoundmetabolism to an intermediate compound binds to trifluoroacetylate proteins in the hepatic endoplasmic binds to trifluoroacetylate proteins in the hepatic endoplasmic

reticulumreticulum occur in genetically predisposed individualsoccur in genetically predisposed individuals type II hepatotoxicity after enflurane or isoflurane type II hepatotoxicity after enflurane or isoflurane

administration is extremely rare.administration is extremely rare.

The Committe on Safety of Medicines in 1986 The Committe on Safety of Medicines in 1986 recommended the avoidance of halothane following:recommended the avoidance of halothane following: history of previous adverse reactionshistory of previous adverse reactions previous exposure within 3 months unless the indications are previous exposure within 3 months unless the indications are

clinically overriding (the safe time interval is clinically overriding (the safe time interval is notnot known) known) history of unexplained jaundice/pyrexia after previous history of unexplained jaundice/pyrexia after previous

exposure to halothane.exposure to halothane.

ToxicityToxicity

EnfluraneEnflurane Trigger agent for malignant hyperthermiaTrigger agent for malignant hyperthermia Isolated reports of hepatotoxicity.Isolated reports of hepatotoxicity. Theoretical risk of fluoride ion toxicity in Theoretical risk of fluoride ion toxicity in

renal failurerenal failure May cause myocardial dysrhythmias May cause myocardial dysrhythmias

IsofluraneIsoflurane Trigger agent for malignant hyperthermiaTrigger agent for malignant hyperthermia Isolated reports of hepatotoxicity Isolated reports of hepatotoxicity

ToxicityToxicity

DesfluraneDesflurane Trigger agent for malignant hyperthermia. Trigger agent for malignant hyperthermia. Unsuitable for use during gaseous Unsuitable for use during gaseous

inductioninduction

SevofluraneSevoflurane Trigger agent for malignant hyperthermia Trigger agent for malignant hyperthermia

The ideal anaesthetic agentThe ideal anaesthetic agent

Physical propertiesPhysical properties

1. Non-flammable, non-explosive at room temperature1. Non-flammable, non-explosive at room temperature

2. Stable in light.2. Stable in light.

3. Liquid and vaporisable at room temperature i.e. low 3. Liquid and vaporisable at room temperature i.e. low latent heat of vaporisation.latent heat of vaporisation.

4. Stable at room temperature, with a long shelf life 4. Stable at room temperature, with a long shelf life

5. Stable with soda lime, as well as plastics and metals5. Stable with soda lime, as well as plastics and metals

6. Environmentally friendly - no ozone depletion 6. Environmentally friendly - no ozone depletion

7. Cheap and easy to manufacture 7. Cheap and easy to manufacture

The ideal anaesthetic The ideal anaesthetic agentagent

Biological properties Biological properties

1. Pleasant to inhale, non-irritant, induces 1. Pleasant to inhale, non-irritant, induces bronchodilatationbronchodilatation

2. Low blood:gas solubility - i.e. fast onset2. Low blood:gas solubility - i.e. fast onset

3. High oil : water solubility - i.e. high potency3. High oil : water solubility - i.e. high potency

4. Minimal effects on other systems - e.g. 4. Minimal effects on other systems - e.g. cardiovascular, respiratory, cardiovascular, respiratory, hepatic, renal or endocrinehepatic, renal or endocrine

5. No biotransformation - should be excreted ideally 5. No biotransformation - should be excreted ideally via the lungs, unchangedvia the lungs, unchanged

6. Non-toxic to operating theatre personnel6. Non-toxic to operating theatre personnel

inhalational agents (2)

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