Search our site 
Advanced Search
Home | Exam dates | Contact us | About us | Testimonials |

You are in Home >> Exams >> Mitchell Anaesthetic Notes

Inhalational anaesthetic agents

Created: 24/4/2006
Updated: 28/3/2006
a. Describe the properties of an ideal inhalational anaesthetic agent.

  • Preparation

Easily administered
- Boiling point above ambient temperature
- Low latent heat of vaporization
- Simple apparatus
Chemically stable
- Long shelf-life, compatible with soda-lime, metals and plastics
- Not flammable
- Cheap

  • Pharmacokinetic

Low solubility
Rapid onset, rapid offset, adjustable depth
Minimal metabolism
Predictable in all age groups

  • Pharmacodynamic

High potency
- Allows high FiO2
High therapeutic index

  • Adverse actions

Minimal toxicity
Minimal unwanted effects
- Nausea, vomiting, cardiac arrhythmogenicity
No toxicity with chronic low-level exposure of staff

b. Describe the structure-activity relationships of the volatile agents.

Structure-activity relationships for the volatile anaesthetic agents apply to their physical and chemical properties and to their metabolism.

  • Physical

low molecular weight and non-polar structure produce low boiling point, high vapour pressure

  • Chemical

Large number of hydrogen atoms increases flammability
High fluorine content minimizes flammability
CF2H moiety can liberate CO in reaction with dry soda-lime

  • Pharmacokinetics

Fluorine content reduces solubility in blood and fat
Hydrolysis of ethers is most rapid when the adjacent carbon atoms are not halogenated
Hydrolysis produces a halogenated acetic acid and halogenated methanol, which can release some halides
Fluorine on the 1-carbon of methyl-ethyl-ethers can be liberated as F-

  • Pharmacodynamics
  • Chlorine and hydrogen content increases potency
  • Fluorine content reduces potency
c. Provide a brief overview of the history of nitrous oxide, cyclopropane, ether and chloroform.

1772 N2O first prepared by Priestly
1779 Humphrey Davy suggested N2O had anaesthetic and analgesic properties
1844 N2O demonstrated by Horace Wells for dental extraction
1846 Ether demonstrated by Morton at Massachusetts General
1847 Chloroform introduced, used by Queen Victoria
1880s Ethyl chloride introduced
1930s Cyclopropane and trichloroethylene introduced
Cyclopropane used for single-breath gas inductions (MAC 9%)
Trichloroethylene (Trilene) blue coloured agent with good analgesic properties
1951 Halothane synthesized
Fluroxene enters clinical use
1956 Halothane enters clinical use
1960 Methoxyflurane enters clinical use
1963 Enflurane synthesized
1965 Isoflurane, desflurane synthesized
1966 Enflurane enters clinical use
1968 Sevoflurane synthesized
1971 Isoflurane enters clinical use
1990 Sevoflurane enters clinical use
1992 Desflurane enters clinical use

d. Describe the preparation of nitrous oxide and Entonox and outline their physical properties.

Nitrous oxide

  • Physical properties

- MW 44.02
- BP -88.5°C
- SG 1.53 kg/l

  • Prepared by heating NH4NO3 at 245-270°C

NH4NO3 --> N2O + 2H2O
Small amounts of NH3 and HNO3 produced recombine to NH4NO3 on cooling
Small amounts of NO and NO2 are also produced
- Can cause methaemoglobinaemia, pulmonary oedema if inspired
- N2O must be purified to remove these contaminants


  • 50% O2, 50% N2O supplied in cylinders at 138 bar
  • Maximum pseudo-critical temperature -5.5°C at 117 bar

Separation of constituents occurs below pseudo-critical temperature

  • Analgesic for labour and brief procedures
e. Describe the undesirable effects of nitrous oxide.


  • Contamination in manufacture



  • Cardiovascular
  • Haematological
  • Increase in P50 by 1.6 mmHg

Inhibition of thymidylate synthetase and methionine synthetase by oxidation of cobalt ion on B12
- Megaloblastic anaemia
- Neuropathy
- Teratogenicity

  • CNS

Increase in muscle tone, rigidity especially with opiates


  • Flammability

Not flammable, but will support combustion

  • Gas spaces

Partition into physiological spaces
- Middle ear, gut ? --> nausea
Other spaces
- Expansion of pneumothorax, gas emboli, tube cuffs

  • Hypoxia

Low potency requires high Fi, potential for hypoxic gas mix
Rapid flow of N2O into alveoli on ceasing administration causes diffusional
Hypoxia unless supplemental oxygen is inhaled

f. Describe the comparative pharmacology of halothane, enflurane, isoflurane, methoxyflurane, desflurane and sevoflurane.

BP MW SVP blood: blood: MAC metab. vapor/liquid
(°C) (mmHg) gas brain (%) (%) (v/v)
N2O -88.5 44 4 x 104 0.46 1.0 105 0.004
desflurane 23.5 168 669 0.45 1.3 6.0 0.02 211
sevoflurane 58.5 200 170 0.65 1.7 2.0 3.0 181
isoflurane 48.5 184 240 1.4 1.6 1.15 0.2 196
enflurane 56.5 184 172 1.8 1.5 1.7 2.4 198
halothane 50.2 197 244 2.4 1.9 0.75 20 227
methoxyflurane 105 165 22.5 12 2.0 0.15 50 208
ether 35 74 440 12 1.9 high
trichloroethylene 87 131 59 9.1 0.17
cyclopropane -33 42  6 x 104 0.42 9.2 0

       oil:gas partition approx. = 150 ÷ MAC

g. Describe the physiological effects of the volatile agents.

  • Anaesthesia


  • Anaesthetics act at millimolar concentrations (high)
  • Lipid solubility increases potency for most agents (Meyer-Overton relationship)
  • Some stereospecificity is displayed by chiral agents
  • Lipid fluidity changes induced by agents are very small
  • Inhibition of intracellular Ca2+ release occurs

Several theories

  • Unitary vs degenerate

Agents act at a single site or at multiple sites

  • Lipid vs protein

Agents act by altering lipid fluidity or binding lipophilic regions of proteins

  • Likely explanation

Binding to lipophilic protein regions (differing slightly for different agents) alters ligand-gated ion channel activity, altering some or all of ACh, GABA, NMDA, AMPA and KA transmission

  • Analgesia

Uncertain mechanism of action, probably related to anaesthetic actions

  • EEG decease in frequency increase in voltage from 0.4MAC (asleep)

I, S, D burst suppression at 1.5MAC, silence at 2MAC
H silence at 3.5MAC (impractical)
E seizure activity (increased by low PCO2)

  • Evoked potentials decreased amplitude, increased latency
  • CSF volume E increase, I decrease 
  • CBF loss of autoregulation --> vasodilation
  • H from 0.6MAC
  • E > I from 1.0MAC
  • Decrease in contractility H, E > I, S, D
  • Increase in RAP H, E > I
  • Decrease in SVR I, S, D > E > H (I can cause coronary steal, no tachycardia with S)
  • Catecholamine sensitization H > I, S, D > E
  • Decrease in hypoxic response markedly from 0.1MAC
  • Decrease in hypercapnic response: E, S > I > H
  • Decrease in TV
  • Increase in RR up to 1MAC, then I decreases, H, E increases 
  • Bronchodilation (decease in vagal tone, smooth muscle relaxation)

  • Hepatotoxicity

All decrease portal flow
Hepatic artery flow H decreases, I increases 

  • F- ion toxicity (below)
  • E decreases RBF and GFR
  • I, H, D maintain RBF and GFR
  • Relaxant due to

Decreased central outflow, increased blood flow, decreased post junctional sensitivity, decreased Ca2+ flux
E, I > H

  • Trigger for malignant hyperpyrexia

H > E > I

  • Decreased contractility, vasodilation (increased blood loss), depression in fetus
Immune, haematological
  • H decreased platelet aggregation
  • Impair neutrophil activity
  • N2O > volatiles
  • No proven toxicity from volatiles
h. Describe the metabolism of the volatile agents and the role of their metabolites in toxicity.

  • oxidation (most metabolism if hepatic oxygen delivery is adequate)

--> trifluoroacetic acid, Br-, Cl- ??conjugates of TFA
Inhibited by cimetidine, isoflurane, ischaemia

  • Reduction (0.1-0.5%)

--> Br- + CF3CH2Cl --> HF + F2C=CHCl --> conjugates

  • Toxicity

Alkane volatiles are more arrhythmogenic than ethers
Br- direct sedative
F- nephrotoxicity (but very little liberated)

  • Dose- and hepatic blood flow-related hepatotoxicity
  • Mild increase in ALT, AST
  • Incidence approx. 20%

Associated with increased reductive metabolism
autoimmune fulminant hepatic necrosis

  • 1:30000
  • Accompanied by eosinophilia, rash
  • Associated with oxidative metabolites modifying hepatic proteins
  • May also be associated with other volatiles more rarely 
Fluoride ion liberation
  • Most severe with a-carbon fluorinated ethers
  • M >> S > E >> I > D
  • Systemic [F-] > 50 µmol/l associated with high output renal failure
  • Sevoflurane is metabolized by cytochrome p450 E1 in liver
  • Methoxyflurane and enflurane are metabolized by p450 in kidney, producing higher
  • Local F- concentrations
  • Sevoflurane may also alter renal handling of amino-acids and glucose
i. Describe the interaction of soda-lime with trichloroethylene, halothane and sevoflurane.

  • Sevoflurane

Forms compound A (PIFE) on reaction with warm soda-lime
Sevoflurane ??HF + FH2C-O-C(CF3)=CF2 (a vinyl ether)
Other compounds formed in very small quantities
Compound A causes nephrotoxicity in rats at 150-200 ppm (LD50 1000 ppm)

  • Normal levels in human anaesthesia don't exceed 30 ppm
  • Reduced by gas flow (>2 l/min recommended)
  • Halothane

Forms a vinyl compound in soda-lime
Halothane --> HF + F2C=CBrCl
Greater toxicity in rats than compound A (LD50 250 ppm)
Normal levels in high flow anaesthesia 4-6 ppm

  • Trichloroethylene

Forms toxic compounds with soda-lime
Trichloroethylene ??dichloroacetylene ??phosgene (Cl2C=O) + CO

  • Dichloroacetylene causes neurotoxicity

Esp. cranial nerves V, VII, VIII

  • Phosgene causes pulmonary toxicity

Phosgene + H2O --> 2HCl + CO2

  • (Never to be used with soda-lime; rarely used anyway)

Kindly provided by Dr James Mitchell from his pharmacodynamics series

SiteSection: Article
  Posting rules

     To view or add comments you must be a registered user and login  

Login Status  

You are not currently logged in.
UK/Ireland Registration
Overseas Registration

  Forgot your password?

All rights reserved © 2021. Designed by AnaesthesiaUK.

{Site map} {Site disclaimer} {Privacy Policy} {Terms and conditions}

 Like us on Facebook