Volatile Anaesthetics

Inhaled agents

Mechanism of A ction - Uncertain

Anatomy Site Comment
Macroscopic CNS Transmission disrupted throughout CNS
  Brain vs Spinal cord Decerebration does not alter anaesthetic requirements
Microscopic Axon vs Synapse Axonal disruption needs higher concentration than synaptic disruption
  Excitatory vs Inhibitory Blockage and enhancement of excitatory transmission occurs
  Pre vs Post synaptic Intracellular [Ca 2+] alters pre and other ions alter post
Molecule Membrane The Meyer-Overton rule states that the potency of an anaesthetic is proportional to its lipid solubility.  This suggests a lipophilic site of action.
  Lipid vs protein Both involved

The most likely site of action are proteins, specifically ion channels, membrane receptors and intracellular enzyme systems. The idea of a unitary theory of anaesthesia must be considered obsolete.  It is clear that drugs that act at multiple sites to produce anaesthesia.
  1. The GABA A receptor-chloride channel is a ligand-gated inhibitory complex that contains modulatory sites for benzodiazepines, barbiturates, etomidate, propofol, steroid anaesthetics and volatile anaesthetics.   Intravenous and inhalational anaesthetis also modulate the presynaptic release or uptake of GABA
  2. There are at least six different classes of voltage-sensitive calcium channels , at least three have been linked to the action of volatile and intravenous anaesthetics
  3. Nitrous oxide, Xenon and ketamine preferentially act on the N-methyl-D-aspartate (NMDA ) receptor
  4. The Muscarinic complex is important in memory and consciousness.
  5. The neuronal nicotinic acetylcholine receptors (nACh) have their slow desensitised conformational state stabilised by all general anaesthetics.
  6. Halothane, enflurane, isoflurane, desflurane and sevoflurane, at clinical concentrations, significantly suppress voltage-gated sodium channels.

B iokinetics








A bsorption

D istribution

  1. Factors affecting the rate of delivery of an anaesthetic to the lungs
    1. The inspired partial pressure of volatile agent
    2. The "second gas effect"
      • The concentrating effect
      • The passive increase in alveolar ventilation
    3. Alveolar ventilation
  2. Factors affecting the uptake of anaesthetic from the lungs
    1. The blood gas solubility coefficient (Blood/Gas)
    2. The cardiac output
    3. The difference between mixed venous and alveolar volatile partial pressure
  3. Factors affecting uptake of anaesthetic by the tissue (mixed venous partial pressure)
    1. Blood tissue solubility coefficient
    2. Tissue blood flow (vessel rich vs muscle group vs fat group)
    3. The difference between tissue and arterial volatile partial pressure (oil/water)


2.5 1.91 1.4 0.42 0.6 0.47 0.115


220 120 170 18.7 55 3 20


1.9 1.4 1.9 1.3 1.7 1.1  


1.8 ? 1.6 1.3 1.8 1.1  


51 36 45 27 48 2.3  


2.1 2.1 1.8 1.3 1.8 0.8  


1.2 1 1.1 1 1.2 0.85  


3.4 1.7 2.9 2 3.1 1.2  
M etabolism Oxidation in the liver to T ri F luoro A cetic acid and free fluoride ions   Hexa-fluoro- isopropyl Nil Nil


20-50% 2% 0.2% 0.02% 2% - -

E xcretion

Breath and urine Breath Breath

C hemistry







Halogenated Alkane Halogenated Methyl ethyl ethers Methyl- Isopropyl -ether Gas Nobel Gas



CH(CF 3 )2 0CH 2 F





D ose - Given via a calibrated vaporiser

A standard measure of potency is the Minimal Alveolar Concentration. This is the alveolar concentration of an agent, at one atmosphere required to produce immobility in 50% of patients when exposed to a noxious stimulus (defined as skin incision in humans).

Note no mention of the times involved are mentioned and one presumes steady state.

MAC is "Decreased" by

MAC is "Increased" by















E ffects









Cardiovasc Dose dependant depression

No effect


-- --- - - - - No effect


- (SAnode) + ++ ++++ ++ ~ No effect


- (AV node)           No effect


            No effect
Arrhythmia +++ + + ~ ~ ~  
SVR ~ --- ---- --- -- ~ No effect
MAP ~ -- --- -- -- ~ No effect
Coronary ~ ~ Dilatation     ~ No effect
Cerebral Anaesthesia and analgesia, decreasing metabolic rate and oxygen requirements

Blood flow

++++ +++ ++ ++ ++ + Nil


++++ +++ ++ ++ ++ + Nil


+++ ++ + + + + Nil


  Bursts- EEG Flat EEG        
Respiration Dose dependant depression Xe > E > I > S > D > H > N 2 O


+ + ~ + + ~ Dec

Tidal Volume

-- -- --- -- -- ~ Inc


Dose dependant dilatation, abolish hypoxic pulmonary vasoconstriction    
GUT Uterine Relaxation        

Bowel distension

bowel distension

  Hepatic buffer lost            
  Muscle relaxation, potentiation of muscle relaxation.

F ormulation









Container 0.01 thymol

no preserv

no preserv

no preserv

no preserv


Mol Weight 197 184.5 184.5 168 198 44 54
SVP KPa 32.3 23.3 33.2 88.5 23.5 5,500  
Boiling point

50 o C

56 o C

49 o C

23.5 o C

58.5 o C

-88 o C

-108.1 o C


6 %

6 %

0 %

0 %

0 %


I ndications

Contra indications


Halothane Hepatitis

Epidemiology: ~1/35 000 patients on exposure to halothane will develop hepatic necrosis.

Risk factors that increase the chances are:- late middle age (50), obesity and being female.

Diagnosis: All other causes of jaundice must be considered and excluded before a diagnosis of halothane related hepatitis can be made. The most important is to rule out the various types of viral hepatitis, which may not be serologically positive in the early postoperative period. Other causes include

  1. Surgical complications, especially bile duct surgery,
  2. Peri-operative hypotension;
  3. Intra-abdominal sepsis and / or septicaemia;
  4. Infections with CMV, EBV and toxoplasmosis;
  5. Reactions to other drugs used before or during surgery;
  6. Sickle-cell crisis

Mechanism of toxicity:

Type I halothane hepatitis : This is an asymptomatic rise in serum transaminases 1-2 weeks after exposure, that resolves without treatment. Histologically there is an acute hepatitis like picture. There have been many theories about the causation of type I hepatitis.

Direct allergic reaction to the intact halothane molecule. This is not the case as a protein complex is needed to trigger an immunological event. Unfortunately this simplistic theory gave rise to the erroneous impression that halothane is safe to use again after 3 months, in spite of an earlier reaction.

Direct biochemical destruction of the liver by reductive metabolic intermediates analogous to the liver damage caused by the free radical species formed during the metabolism of carbon tetrachloride and chloroform.

Hepatic hypoxia can easily be precipitated by a minor degree of hypotension because of the loss of the hepatic artery buffer reserve. The first step in the reductive pathway is believed to be an insertion of a single electron into the halothane molecule to produce a highly reactive metabolite which then undergoes debromination to another free radical intermediate. The simplistic approach is that liver macromolecules interact with metabolic intermediates or free radicals. Free radicals are moieties capable of independent existence that contain one or more unpaired electrons. These free radicals capture electrons from adjacent molecules and produce a chain reaction in which free radicals beget other free radicals which, in effect go on a destructive rampage. This may cause an autocatalytic peroxidative chain reaction in the liver, leading to breakdown and necrosis of essential fatty acids, lipoproteins and cell membranes.

Type II halothane hepatitis :

This reaction is uncommon and unpredictable, there is clinical and laboratory evidence of severe hepatic necrosis. There is no relationship between the amount of halothane used and the likelihood of this reaction, but there does seem to be a correlation between the amount of halothane used and the severity of the liver failure. Onset may be by the 7 th day after administration or relatively delayed compared to direct hepatotoxic drugs e. g. paracetamol, for up to 28 days. It is accompanied by the rapid development of jaundice, raised liver enzymes, pyrexia, arthralgia, rash, and direct evidence of immune sensitisation - eosinophilia, circulating immune complexes and a variety of autoantibodies to normal tissue components. There is characteristically a very high mortality rate. There are several case reports of halothane hepatitis in children and in anaesthetic personnel.

There is now strong evidence that this is due to an immune response directed against hepatocytes. The most convincing evidence for this theory is that serum from patients with type II halothane hepatitis contains antibodies that react with an acyl halide that is covalently bounded to liver cell membranes (N-e-Lysine). This acyl halide (CF 3 COCl) acts as an epitope or hapten that is presented to the immunocompetant cells, setting up and antibody reaction. The acyl halide is a mandatory precursor to the production of Trifluoroacetic acid (TFA), the major oxidative metabolic breakdown product of halothane, enflurane, isoflurane and desflurane. Why only a small percentage of patients amount an immune response appears to be related to a variety of susceptibility factors

  1. Variability in the levels of expression of cytochrome P450 isoenzyme
  2. Abnormal expression of the protein bound epitope from the endoplasmic reticulum to the cell surface.
  3. Variability of lymphocyte damage by electrophilic metabolites
  4. Variability of immunological factors
  5. Variability of the natural tolerance to the protein bound epitope.

This has now given rise to the theory that if no reaction to halothane has occurred within 28 days after exposure it is probably safe to give halothane again, but that if there was any form of reaction to an halothane exposure it is never again safe to give halothane. This leads to a practical difficulty, which is that Boyle’s machines that have been used for halothane anaesthesia continue to emit halothane for some time after the agent has been removed. This is due to absorption of halothane into the plastic components of the system providing a reservoir. The anaesthetic machine should be flushed free of halothane with 100% oxygen at a flow rate of 8L/Hr for 8 hours

Sevoflurane toxicity

Renal toxicity

Fluoride induced

Inorganic fluoride nephrotoxicity was first recognised in 1960 with the introduction of methoxyflurane. A serum level > 50mmol/L over a prolonged period of time i. e. the area under the graph, was associated with polyuria, proteinuria, glycosuria, impaired renal concentrating ability with a lack of response to vasopressin and an increased serum sodium, urea, creatinine and osmolarity. Sevoflurane metabolism readily releases inorganic fluoride with concentrations exceeding 50mmol/L after 2 MAC hours. However after extensive use for prolonged periods of time in Japan there have been no reports of renal dysfunction - Why?

The peak fluoride level is short lived in sevoflurane anaesthesia because the low blood/gas solubility coefficient allows rapid removal of the agent via the breath. This decreases the area under the curve considerably.

The fluoride liberated during methoxyflurane anaesthesia appeared to be produced in the kidney and was able to cause the damage directly. Sevoflurane is metabolised four times less readily in the kidney with lower fluoride levels within the kidney.

Compound A induced

Sevoflurane undergoes spontaneous degradation, to compound A-E, when exposed to high temperatures (>50 o C) that occur in sodalyme and baralyme. Compound A has been found to be nephrotoxic in rats but never in humans - Why?

The amount of compound A is dependant on the temperature of the absorber, Sodasor is the most commercially used product and produces the lowest temperature 40 o C because of the lack of KOH.

The fresh gas flow used is very seldom minimal today and so helps wash out compound A

The nephrotoxicity in rats is because of b lyase metabolism, in the rat kidney, to a reactive thiadacyl intermediate that does the damage. Human kidney renal b lyase activity is much lower than the rat’s.


Oxidative metabolism of sevoflurane produces no reactive intermediaries and so is incredibly unlikely to ever be associated with an immune linked hepatotoxicity. This makes sevoflurane the agent of choice in a patient who has documented sensitivity to the reactive intermediary produced during trifluoroacetic acid production.

Guedals stages of anaesthesia





One- Analgesia

regular small volume

Central small


Two - Excitement


Divergent large

eyelash absent

Three- Anaesthesia
Plane I

Regular  Large volume

Central small

eyelid absent and conjunctival depressed

Plane II

Regular Large volume

Central medium

corneal depressed

Plane III

Regular becoming diaphragmatic small volume

Central medium

Laryngeal depressed

Plane IV

Irregular diaphragmatic small volume

Central large

Carinal depressed

Four - Overdose


Central full dilatation

Cardiac depressed

Desflurane vaporiser

Desflurane with its boiling point of 22.8 o C if administered in a conventional plenum vaporiser could produce disastrous changes in output with small increases in temperature. If the vaporiser temperature rose above the boiling point a continuous flow of gaseous agent would be produced until all the liquid evaporated, or until the latent heat of vaporisation resulted in the temperature being lowered below the boiling point. The boiling point is so close to that of room temperature, that so called "temperature compensators" would be inadequate. The alternative approach, used with nitrous oxide, to contain the liquid in a cylinder and draw off the gas is also impractical because at room temperature the saturated vapour pressure is too low. These are overcome using a vaporiser with a sump heater so that vapour pressure is raised to around two atmospheres absolute pressure (37 o C) internally and then dispensed using a system of differential pressure transducers and variable resistance. The vapour can be mixed with fresh gas using a metering valve. The entire vapour pathway is heated to prevent the high partial pressure of the agent (potentially above the saturated vapour pressure at room temperature) from "raining out".


Xenon: A little more detail on the drug, just to tempt us!

Despite the high cost of xenon, xenon anaesthesia will become possible at a reasonable cost.  The hourly uptake of xenon decreases rapidly and with full recycling of the gas during closed circuit anaesthesia, xenon anaesthesia will be economically viable.

Physical properties

Anaesthetic agent

      1. Whole body paraesthesia & hypo-algesia.
      2. Euphoria & increased psychomotor activity.
      3. Analgesia with partial amnesia (after 3-4min).
      4. Surgical anaesthesia with a degree of muscle relaxation.

Specific effects on the body

Why Xenon is going to become a potential volatile anaesthetic.

Practical usage

  1. Nitrogen must be washed out by giving a high flow of pure oxygen for at least 5 minutes
  2. Normal induction and muscle relaxation
  3. After intubation connect the patient to an appropriate anaesthesia delivery system
  4. The hypnotic concentration of 40-45%  is achieved after 1.5min
  5. The anaesthetic concentration of 60-70% takes approximately 8 minutes.


Owing to environmental concerns there may be no alternative but to use xenon even if it incurs an increase in cost.