Inhalational Anaesthetic Agents

Dr. Nigel Harper

2011

Physicochemical Properties

•halogenated hydrocarbons•more dense than water•structural isomerism

Physicochemical Properties

• halogenated hydrocarbons• more dense than water• structural isomerism• similar molecular weights (168-220)• 1cc produces approx 200 cc saturated

vapour

Obsolete theories of anaesthesia

Meyer Overton (potency lipid solubility) – BUT!– anaesthetics work in the absence of lipid (firefly

luciferase)– many long chain molecules do not fit the relationship

Mechanisms of Anaesthesia

• facilitation at inhibitory (chloride) GABAa channels

• facilitation at inhibitory glycine (chloride) channels

• inhibition of excitatory NMDA (cation) channels - nitrous oxide and xenon

MAC

• The concentration in volumes percent of an agent in oxygen that will prevent movement in response to a standard surgical incision in 50% of the population

MAC skin incision

MAC awake

Halothane 0.74 0.38 Enflurane 1.7 0.5 Isoflurane 1.2 0.36 Sevoflurane 2.0 0.36 Desflurane 6.0 2.6

MAC awake

MAC skin incision

MAC awake

Halothane 0.74 0.38 Enflurane 1.7 0.5 Isoflurane 1.2 0.36 Sevoflurane 2.0 0.36 Desflurane 6.0 2.6

(s-a)/s

0.490.70.70.820.56

Margin of anaesthetic depth

MAC – MAC awakeMAC

Factors affecting MAC

• age: MAC maximum at 1 year. Compared with MAC at 20yrs, MAC reduced 20% at 40yrs and by 40% at 80 years

• 60% Nitrous oxide reduces MAC isoflurane by 40% and MAC sevoflurane by 24%

• opioids and other sedatives

Uptake and Distribution

• depth of anaesthesia depends on the partial pressure of the agent at the effect site

• a poorly soluble agent needs fewer molecules of drug per volume blood to achieve a given partial pressure

• transport depends on (blood solubility x blood flow)

Blood flow as a percentage of Cardiac Output

• vessel rich group (brain & viscera) 75%• muscle (23%)• fat (2%)

Mapleson water analogue• diameter of the cylinders

capacity of the tissue for the agent

• height of water partial pressure of the agent in that tissue

• pipe diameter (blood flow x blood gas partition coefficient)

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

Why is a low cardiac output associated with rapid

induction of anaesthesia?

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

lungs

viscera inc brain

muscle

fat

fresh gas flow

ventilation

Concentration Effect1. uptake of agent › uptake of O2 and nitrogen2. PAagent falls progressively until a new

breath arrives bringing more agent3. effect is more marked if the Cinsp is small

because the PAagent is reduced to a greater extent before the next inspiration

“the higher the inspired concentration the faster the rise in alveolar (end-tidal) concentration”

Second Gas Effect• rate of uptake of volatiles depends on alveolar

ventilation• N2O taken up in large quantities because lack of

solubility more than outweighed by high alveolar concentration

• high N2O uptake effectively increases alveolar ventilation

• effect more marked with more soluble agents

“The addition of nitrous oxide increases the rate of uptake of the volatile agents”

Sodalime constituents

• Calcium Hydroxide 70% to 80 %• Sodium Hydroxide and/or Potassium

Hydroxide. 1.5% - 5 %• Indicator dye < 0.05 %• Zeolite (Spherasorb only) 5 %• Water 14 to 16 % • Barium Hydroxide ( Baralyme only) 11 %

Carbon Dioxide absorption

1) H2O + CO2 ====> H2CO3

high pH

2) H2CO3 + 2 NaOH ====> Na2CO3 + 2H2Ohigh pH

3) Na2CO3 + Ca(OH)2====> CaCO3 + 2 NaOHhigh pH

•Carbon Dioxide is ultimately converted to Calcium Carbonate (CaCO3).•Carbon Dioxide absorption will cease when reaction 3 stops (Calcium Hydroxide levels are too low).

Sevoflurane Metabolism & Toxicity

1) Biotransformation to fluoride

– 3% of sevoflurane biotransformed by Cp450 (2E1) to hexafluoroisopropanol + fluoride

– 7 MAC hours sevoflurane 40 M fluoride but no proven renal toxicity

2) Reaction with sodalime Compound A

Sevoflurane & Compound A

sevofluraneheat

sodalimeCompound A

Compound A conjugate

cysteine

beta lyasetoxic metabolite

Renal toxicity

Sevoflurane & Compound A

• Greater in sodalimes which contain KOH• Less in KOH and NaOH – free sodalimes

Low-alkali sodalimes

• Spherasorb: no KOH & very little NaOH• LoFloSorb and Amsorb: no KOH or NaOH

Carbon Monoxide and

Monday morning

Carbon monoxide 1

• Physiological 0.4 – 0.8%• Headache, nausea & vomiting• Smokers up to 10%• Closed breathing system

0.5 – 1.5% non-smokers3% smokers

• Minimal flow circuit1 – 1.5%

Carbon monoxide 2

• Desflurane > isoflurane > sevoflurane• Greater with dry sodalime

CNS effects of inhalational agents• all impair autoregulation of CBF (halothane

(4x) > enflurane (2x) > isoflurane/sevoflurane/desflurane)

• effect on CBF attenuated by prior hyperventilation

• enflurane > 1.5 MAC excitatory spikes (avoid in epileptics) ? sevoflurane

• Neuro-protection

Neuroprotection

• Modulation of intracellular Ca++ homeostasis

• Inhibition of the apoptosis initiator caspase-9

• MCA occlusion studies in rats– Histological & functional protection– Persists up to 8 weeks

Cardiovascular effects

• depression of vasomotor centre• depression of cardiac contractility• peripheral dilatation• autonomic effects (desflurane –

airway receptors?)• sensitization to catecholamines• cardioprotection

Anaesthetic pre-conditioning

• Seen with ALL inhalational agents• Except nitrous oxide• Not seen with propofol• Demonstrable with morphine and ? remifentanil

(animal studies) – possibly δ receptor-mediated• Blocked by ketamine

• 20 CABG patients• Either TIVA or sevoflurane• LA and LV pressure catheters• Changes in dP/dtmax with leg elevation• Load dependence of myocardial relaxation

R=slope (time constant of isovolumetric relaxation / end-systolic pressure)

• Post-CABG troponins for 36h

sevoflurane pre-conditioning

De Hert SG et al. Anesthesiology 2002; 97: 42-49

sevoflurane v propofol and CABG (deHert 2002)

Median, 95%CI

Individualpatients

sevoflurane pre-conditioning

• ↑preload resulted in a decrease in dP/dtmax in propofol group but not in sevoflurane group

• Load dependence ↑ in propofol group but not in the sevoflurane group

• Fewer patients needed inotropic support in sevoflurane group

• Lower troponin T post-op, persisting for 36 hours

Priming of mitochondrial and sarcolemmal ATP -sensitive K channels

• ↑ Probability of ATP-induced channel opening• Shortening of cardiac action potential• Decreased energy consumption• Reduced cytosolic Ca load• Blunting of mitochondrial K overload• Restoration of membrane function• Restoration of normal ATP consumption

Effects of inhalational agents on respiration

• 1 MAC isoflurane completely abolishes response to hypoxia and depresses response to hypercarbia by 50%

• enflurane most depressant and halothane least

• desflurane most irritant and sevoflurane least• Halothane most bronchodilating

General hepatic effects• cardiac output reduced• hepatic portal flow reduced• increased dependence on hepatic arterial

flow• hepatic arterial bed autoregulation impaired

by halothane > enflurane> sevoflurane > isoflurane

Anaesthesia Induced Hepatitis• Oxidative metabolism trifluoroacetyl halide

(TFA)• TFA changes structure of CP450 & other

proteins to become haptens• dramatic immune response in susceptible

individuals• TFA antibodies common in halothane

hepatitis

• Halothane most common• Cross-sensitivity between inhalational agents

(except sevoflurane which is not metabolised to TFA)

• 70% have a history of atopy• More common in obese women• Predisposed by chronic ethanol or isoniazid

Anaesthesia Induced Hepatitis

Halothane hepatitis: non immume-mediated

• transient, minor rise in transaminases more common than fulminant hepatitis

• may be associated with a direct hepatotoxic effect of reductive metabolites

Neuromuscular effects• all inhalational agents potentiate the

effects of neuromuscular blocking drugs

• reduce contractility• reduce acetylcholine release• sevoflurane> isoflurane/desflurane>

halothane

Environmental exposure

• UK occupational exposure standards (1996)• 8 hour time-weighted average• 20% of the exposure producing no effect in

rats• nitrous oxide 100 ppm• enflurane 50 ppm• isoflurane 50 ppm• halothane 10 ppm

Xenon• Very low blood/gas solubility (0.2)• MAC 63-71% Inhibits NMDA channel opening• Very dense• No odour, non-irritant, analgesic• Almost complete cardiorespiratory stability• Cardioprotective• Neuroprotective• CBF • Some nausea• Can be recycled

Effects of barometric pressure: plenum vaporizers

• Depth of anaesthesia depends on partial pressure, not concentration

• Partial pressure depends only on temperature

• Plenum vaporizers add a fixed mass of saturated vapour to a stream of carrier gas that depends only on the splitting ratio (not the atmospheric pressure)

• The splitting ratio will not change with altitude

• At altitude the fixed mass of agent will have the same partial pressure as at sea level but the barometric pressure is lower

• The concentration of the agent will increase

Concentration =Partial pressure of agent

Barometric pressure

example

• If the dial setting of a vaporizer is set to "1%" at sea level, it will deliver 1.013 kPa and the concentration will be 1.0%

• If the atmospheric pressure is reduced to 80 kPa the vaporizer will continue to deliver 1.013 kPa of vapour and the volume percent will increase to 1.01/80 = 1.26%

• The partial pressure of the vapour will be unchanged

Altitude: summary

• The delivered concentration is reduced but not the partial pressure

• It is not necessary to change the (plenum) vaporizer setting at altitude (except for desflurane)

FormulaBP (oC)

SVP (kPa at 20oC)

Blood gas partition

coefficient

Oil gas partition

coefficient

Halothane C2HBrCl3F 50.2 32.4 2.3 224

Enflurane C3H2CF5O 56.5 22.9 1.9 96

Isoflurane C3H2CF5O 48.5 31.9 1.4 91

Sevoflurane C4H3F7O 58.5 21.3 0.6 53

Desflurane C3H2F6O 23.5 88.3 0.42 19

Desflurane vaporizer

• Heated vaporization chamber:– Capacity 450ml– Temperature 39o

– Pressure 1550 mmHg (206 kPa, 30 psi)• No carrier gas enters the vaporization chamber• Dial controls the flow of saturated vapour into the

carrier gas flow (no carrier gas enters the vaporization chamber)

Desflurane vaporizer & altitude

• Vaporizer uses a pressure transducer to measure atmospheric pressure

• Transducer signal influences the valve which the controls output from the vaporization chamber to maintain the (volume %) concentration of agent constant

• The dial setting has to be increased at high altitude to maintain the desired partial pressure of agent

Desflurane vaporizer & altitude

• If the vaporizer dial is set to "6%" at sea level it will deliver 6% by volume and the partial pressure of desflurane will be 0.06 x 101.3 = 6.078 kPa

• If the atmospheric pressure is reduced to 80 kPa then the vaporizer will continue to deliver 6% desflurane by volume-percent but the partial pressure will be 0.06 x 80 = 4.8 kPa

Formula Boiling point(oC)

SVP at 20oC(kPa)

Blood gaspartition

coefficient

Oil gaspartition

coefficientHalothane C2HBrClF3 50.2 32.4 2.3 224Enflurane C3H2CF5O 56.5 22.9 1.9 96Isoflurane C3H2CF5O 48.5 31.9 1.4 91Sevoflurane C4H3F7O 58.5 21.3 0.6 53Desflurane C3H2F6O 23.5 88.3 0.42 19

Ischaemia Receptor activation:α adrenergicopioidbradykinin

Activation of:

G-proteins

protein kinase C (PKC)

Ischaemic pre-conditioning

Cardio-protectionIncreased KATP

channel opening

Post-conditioning

ReperfusionIschaemia

Pre-conditioning

Early (begins Immediately& lasts 2-3h)

Late (begins at 12-24h& lasts 24-72h)