INHALATIONAL ANAESTHETICS

PRESENTER: Dr. Karthick. DMODERATOR: Dr Anand H.Kulkarni

Topics Covered

Comparison of commonly used inhalational anaesthetics,

- physical/chemical properties

- various organ system effects

- metabolism and toxicityNitrous oxide

ISOFLURANE

SEVOFLURANE

HALOTHANE

PHYSICAL AND CHEMICAL PROPERTIES OF INHALED

ANAESTHETICS

BOILING POINT/ VAPOUR PRESSURE

Boiling Point (° C )

Vapour pressure(mmHg) at 20°C

HALOTHANE 50.2 243.3

ISOFLURANE 48.5 250

DESFLURANE 22.8 664

SEVOFLURANE 58.5 160

Implication

Desflurane cannot be administered using standard vapourizer

Physical properties (cont..)HALOTHANE Clear, non-explosive, non-

inflammable liquid at room temperature, non-pungent odor

ISOFLURANE Clear, non-inflammable liquid at room temperature, pungent ethereal odor.

SEVOFLURANE Non pungent minimal odor

DESFLURANE Pungent odor , irritating and unpleasant to inhale.

Implication

In regard to negligible airway irritant activity sevoflurane followed by halothane are very suitable for inhalational induction

STRUCTURE

Halothane: Halogenated alkane derivative

2 chloro, 2 bromo 1,1,1 trifluoroethane Other halogenated agents: Halogenated

ether derivatives

STRUCTURE

Isoflurane

Sevoflurane

ii H

Implication

Effect on ozone layerSensitization of heart to epinephrineToxicity

BLOOD GAS PARTITION COEFFICIENT

HALOTHANE 2.5

ISOFLURANE 1.4

SEVOFLURANE 0.69

DESFLURANE 0.42

Implication

Lower the blood gas partition coefficient ……….. Rapid is the induction and recovery from anaesthesia

STABILITY

HALOTHANE ISOFLURANE

SEVOFLURANE

ALKALI Some decomposition

Stable Stable

UV LIGHT Decomposes Stable Stable

METAL May react Stable Stable

STABILITY

Halothane - - - susceptible to decomposition to hydrochloric acid, chlorine, bromide and phosgene.

Stored in amber coloured bottlesPreservative - - - Thymol (0.01%)

METABOLISM

Oxidative and Reductive metabolism

HALOTHANE 20%

ISOFLURANE 0.2%

DESFLURANE 0.02%

SEVOFLURANE 4%

MINIMUM ALVEOLAR CONCENTRATION

MAC in oxygen(%)

Halothane 0.75

Enflurane 1.68

Isofurane 1.15

Sevoflurane 2

Desflurane 6

Nitrous oxide 105

Xenon 71

EFFECTS ON VARIOUS ORGAN SYSTEM

CARDIOVASCULAR SYSTEM

MEAN ARTERIAL PRESSURE

Halothane, Isoflurane, Desflurane, Sevoflurane ……… dose dependant decrease in MAP.

Halothane/ Enflurane ….. Decreases cardiac contractility

Isoflurane/Desflurane/Sevoflurane

……….. principally decreases systemic vascular resistance

HEART RATE

INHALATIONAL ANAESTHETIC

HEART RATE

HALOTHANE DECREASES

ISOFLURANE/ENFLURANE/DESFLURANE/SEVOFLURANE

INCREASES

CARDIAC OUTPUT AND STROKE VOLUME

Halothane ……. Dose dependent decrease in cardiac output

Isofurane/Sevoflurane ….. Very minimal decrease

Nitrous oxide ……. Moderate increase

SYSTEMIC VASCULAR RESISTANCE

ISOFLURANE/DESFLURANE/SEVOFLURANE

Decrease

HALOTHANE No net effect

NITROUS OXIDE No effect

PULMONARY VASCULAR RESISTANCE

Halogenated volatile anaesthetics ……. No predictable effect

Nitrous oxide …. Increases

CORONARY BLOOD FLOW

Isoflurane ….. Most potent coronary vasodilator

….. Small coronary vessels

….. Coronary steal phenomenon halothane/ Sevoflurane

….. Cause coronary vasodilatation

EPINEPHRINE INDUCED ARRYTHMIAS

Halothane precipitates arrhythmias in combination with epinephrine.

Epinephrine tolerated: micrograms/kg

Halothane: 1.5

Isoflurane, sevoflurane,desflurane: 4.5

When used at MAC levels.

RESPIRATORY SYSTEM

PATTERN OF BREATHINGHalothane/ Desflurane/ Sevoflurane … dose

dependant increase in the frequency of breathing

Isoflurane

…. Upto 1 MAC – dose dependant increase

> 1 MAC – no further increase

TIDAL VOLUME ..

all inhalational anaesthetics --- decrease

PATTERN OF BREATHING

Net effect :

Rapid/ shallow pattern of breathing

Minute ventilation … ?

Decreases

MINUTE VENTILATION

VENTILATORY RESPONSE TO CO2

All inhalational anaesthetics… decrease in ventilatory response to CO2

Mediated principally at the level of medulla.

N2O ----- doesn't increase PaCO2

VENTILATORY RESPONSE TO O2

Volatile anaesthetics and N2O ….. Attenuate ventilatory response to hypoxemia in dose- dependant manner.

Peripheral chemoreceptors appear to be the major site of this inhibitory response.

AIRWAY RESISTANCE

All volatile anaesthetics ---- potent bronchodilators

Halothane ….. Most potent

followed by isoflurane and sevoflurane.

AIRWAY RESISTANCE

AIRWAY IRRITABILITY

Desflurane ----- most irritantEnflurane/ Isoflurane ------ irritantHalothane/ Sevoflurane ------ non – irritant

thus preferred for inhalational induction.

What if irritant agents are used for inhalational induction?

MUCOCILIARY FUNCTION

Postoperative hypoxemia and atelectasis – common causes of postoperative morbidity

Halothane ---- dose dependant decrease in mucociliary function.

CENTRAL NERVOUS SYSTEM

CEREBRAL BLOOD FLOWVolatile anaesthetics administered during

normocapnia in conc > 0.6 MAC

…. Cerebral vasodilatation

…. Decreased cerebral vascular resistance

…. Dose dependant increase in CBFGreatest increase in CBF---- Halothane (200%)Least increase ----- Isoflurane( minimal/no

increase)

CEREBRAL BLOOD FLOW

AUTOREGULATION:

HALOTHANE ABOLISHED

ISOFLURANE IMPAIRED

SEVOFLURANE INTACT

CEREBRAL BLOOD FLOW

CEREBRAL METABOLIC OXYGEN REQUIREMENT

All volatile anaesthetics …. Dose dependent decrease in CMRO2

Isoflurane = Desflurane = Sevoflurane > Halothane

CBF / CMR

CEREBROSPINAL FLUID

CSF PRODUCTION ABSORPTION

HALOTHANE ↓(30%) ↓

ISOFLURANE -- ↑

ENFLURANE ↑ ↓

Increase in ICP parallels increase in CBF.Enflurane …… increased incidence of

epilepsy Iso/Des/ Sevoflurane …. No evidence of

convulsive activity on EEG.N2O administration …. Increases motor

activity with clonus and opisthotonus even in clinically used concentrations.

HEPATIC SYSTEM

HEPATIC BLOOD FLOW

BLOOD FLOW HALOTHANE ISOFLURANE

PORTAL VEIN ↓ ↓

HEPATIC ARTERY

↓ ↑

NET FLOW ↓ Maintained

Desflurane/ Sevoflurane ……. Similar to isoflurane

HEPATIC BLOOD FLOW

DRUG EFFECTS

Interference of drug clearance by volatile anaesthetics is due to,

1, decrease in hepatic blood flow

2, inhibition of drug metabolizing enzymes

Halothane … inhibits oxidative metabolism of drugs

HEPATOTOXICITY

TFA (Trifluoro acetic acid)

HALOTHANE Large amounts

ISOFLURANE/ ENFLURANE/ DESFLURANE

Minute quantities

SEVOFLURANE Nil

-- depends on the quantity of drug getting metabolised

RENAL SYSTEM

All volatile anaesthetics : dose related decrease in renal blood flow, glomerular filtration rate and urine output.

Reflects the effect of volatile anaesthetic on systolic B.P and cardiac output.

NEPHROTOXICITY

Flouride induced nephrotoxicity

Methoxyflurane, Enflurane, Sevoflurane

Vinyl halide induced nephrotoxicity

Sevoflurane

FLOURIDE INDUCED NEPHROTOXICITY

High output renal failure

Manifestations : polyuria, hypernatremia, hyperosmolarity, inability to conc. urine.

First observed after methoxyflurane administration

FLOURIDE INDUCED NEPHROTOXICITY

Renal threshold limit of plasma flouride(toxicity)

…… 50μm/litSource of fluoride :

intrarenal production …. Methoxyflurane/ enflurane

hepatic metabolism …. sevoflurane

FLOURIDE INDUCED NEPHROTOXICITY

VINYL HALIDE NEPHROTOXICITY

Reaction of CO2 absorbents with sevoflurane.Degradation products : Compound A – ECompound A …. Fluromethyl 2,2 difluoro 1 trifluro methyl

vinyl ether. …. Proximal renal tubular injury.Precipitating factorsDegradation of compound A to reactive thiol.

SKELETAL MUSCLE EFFECTS

SKELETAL MUSCLE RELAXATION

Sevoflurane/ Desflurane/ Isoflurane …. Two fold greater skeletal muscle relaxation than halothane.

N20 …. No relaxation

> 1 MAC …. Skeletal muscle rigidity

INTERACTION WITH NEUROMUSCULAR BLOCKING AGENTS

Dose dependant enhancement …. All volatile anaesthetics

Isoflurane / Desflurane/ Sevoflurane >= Halothane

N2O …. No significant potentiation

CARBONMONOXIDE TOXICITY

Reflects degradation of volatile anaesthetics that contain a CHF2 moiety ( desflurane, enflurane, isoflurane) by the strong bases present in carbondioxide absorbents.

Desflurane > Enflurane / IsofluraneHalothane/ Sevoflurane…. No CO

formation

NITROUS OXIDE

INTRODUCTION OF NITROUS OXIDE

Humpry Davy …. 1800 first observed its analgesic effect …. Laughing gas

HORACE WELLS …. 1844

Used N2O to facilitate

the extraction of a toothUnfortunately, his first

public demonstration

was a failure.

N2O USAGE IN THE INITIAL DAYS

PHYSICAL PROPERTIES

Molecular weight : 44Boiling point : - 88°CColourless, sweet smelling, non-

inflammable and non – irritant gas.MAC …. 105 %

PHYSICAL PROPERTIES

Blood gas partition coefficient … 0.42Metabolism … nilExcretion … lungsSupply :

…. Pure nitrous oxide( 5000 kPa at 20°C)

…. Entonox (15000 kPa at 20°C)

NITROUS OXIDE CYLINDERS

Full cylinder at room temperature contains liquid

The pressure in these cylinders will not reflect how much N2O it contains as long as there is liquid N2O in the cylinder.

Critical temperature …. 36.5 °C

ENTONOX

Mixture of equal parts of N2O and O2.

Supplied in cylinders pressurized to 15000 kPa at 20°C.

Pseudocritical temperatureManufactured utilizing Poynting effect Labour analgesia

PHARMACOKINETICS

Low blood gas solubility … rapid equilibration of Fa/Fi ratio.

Second gas effectConcentration effectDiffusion hypoxia or Fink effectN2O …. Enclosed gas – filled cavity within

the body.

CONCENTRATION CONCENTRATION EFFECTEFFECT

Inspired anaesthetic concentration influences Inspired anaesthetic concentration influences alveolar concentration that may be achieved alveolar concentration that may be achieved and the rate at which that concentration may and the rate at which that concentration may be attainedbe attained

Concentration effect states that with higher Concentration effect states that with higher inspired concentrations of an anesthetic, the inspired concentrations of an anesthetic, the rate of rise in arterial tension is greaterrate of rise in arterial tension is greater

CONCENTRATION CONCENTRATION EFFECTEFFECT

The The FFA A / / FFII ratio indicates the percent of ratio indicates the percent of

anesthetic removed by uptake.anesthetic removed by uptake. At 100% inspired concentration, uptake no At 100% inspired concentration, uptake no

longer limits the rise in longer limits the rise in FFA A / / FFII

19% oxygen

80% nitrous oxide

19% oxygen

40% nitrous oxide

32% nitrous oxide

1% second gas

7.6% oxygen

0.4% second gas

1% second gas

Uptake of half of nitrous oxide

Absorbed gases replaced by added ventilation

SECOND GAS EFFECT

SECOND GAS EFFECTSECOND GAS EFFECT

Factors that govern concentration effect also Factors that govern concentration effect also influence the concentration of any gas given influence the concentration of any gas given concomitantly with concomitantly with NN22OO

Loss of volume associated with the uptake of Loss of volume associated with the uptake of NN22O O concentrates the second gasconcentrates the second gas

Replacement of the gas taken up by an increase in Replacement of the gas taken up by an increase in inspired ventilation augments the amount of inspired ventilation augments the amount of second gas in the lungsecond gas in the lung

DIFFUSION HYPOXIA

The uptake of large volumes of N2O into the alveoli during recovery.

Occurance of hypoxia … 2 means

- directly affects oxygenation by displacing oxygen

- by diluting alveolar CO2 , they may decrease respiratory drive and ventilation.

PHARMACODYNAMICS

VARIOUS ORGAN SYSTEM EFFECTS

CENTRAL NERVOUS SYSTEM

Significantly increases CBF and ICP.Minimally increases cerebral metabolismWhen used in neurosurgery … diffuses into

air pockets left within the skull following closure of wound

Thus not recommended for neurosurgical cases.

RESPIRATORY SYSTEM

Pleasant to inhale and not irritating to the airway

Increases the uptake of the accompanying agent in addition to reducing the MAC

Minimal effect on ventilation

RESPIRATORY SYSTEM

Ventilatory response to CO2 … no alteration

Ventilatory response to hypoxia … significantly reduces

Risk of diffusion hypoxia

CARDIOVASCULAR EFFECTS

Direct effect …. Myocardial depressantThis is offset by its stimulation of the

sympathetic nervous system.

TOXICITY

N2O interacts with Vit B12

…. Monovalent cobalt to bivalent cobalt which is no longer methyl group carrier.

Methionine synthesis / THFA synthesis affected.

TOXICITY

Exposure time :

< 30 min – no measurable change in methionine synthase activity.

> 2 hrs – probably interferes with methionine synthase activity.

CLINICAL USES

Good analgesicLabour analgesiaFor anaesthesia used in combination with a

second agent.

-- reduces MAC of second agent.

-- increases rate of induction and recovery

REFERENCES

Miller‘s Anesthesia – sixth editionStoelting‘s Pharmacology and physiology

in anasthetic practicePrys – Roberts – International practice of

anaesthesia 1st editionWylie – text book of anaesthesia 7th editionGoogle images.