Volatile Anaesthetics: Physical Properties

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Volatile anaesthetics

Ether anaesthesia was successfully demonstrated by William Morton in October 1846. Ether, nitrous oxide and chloroform were introduced in 1847 rapidly became common surgery. Of these, only nitrous oxide remains in use today. Methyl ethyl ethers are more potent, stable and better anaesthetics than diethyl ethers. They all cause myocardial depression, most markedly halothane, while isoflurane and sevoflurane cause minimal cardiovascular depression. Other adverse effects include hepatic and renal damage. Liver damage is not caused by the anaesthetics themselves, but by reactive metabolites. Type I hepatitis occurs fairly commonly with minor disturbance of liver enzymes. Chloroform was introduced as an anaesthetic almost simultaneously with ether (1847) and for a time largely replaced it in popularity.

Physical properties

Anaesthetic and Solubility Properties

The blood/gas solubility values for modern anaesthetic drugs vary from the least soluble (N 2 O, 0.47) to the most soluble (halothane, 2.4). Solubility in blood and brain is important if anaesthetics are to cross the alveolar– capillary membrane and the blood–brain barrier. Solubility is quantified by the partition coefficient, the ratio of the concentration of dissolved gas/vapour in the blood or tissue to the concentration in the gaseous phase at equilibrium. There is a good correlation between the oil/gas partition coefficient of an anaesthetic and its potency.

The most soluble drugs have the slowest induction and recovery characteristics. This is because the speed of induction and recovery are not related to the mass of drug absorbed by or removed from the blood but to its relative partial pressure (tension) in the alveoli and the brain. The anaesthetic delivered to the lungs diffuses into the blood until its partial pressure in the alveoli and blood are in equilibrium. For agents with high blood/ gas solubility, the blood has a tremendous capacity for absorbing the agent so that it is constantly being removed from the alveoli. As alveolar tension is virtually synonymous with brain tension, both induction of and recovery from anaesthesia with these drugs will be slow. Because the partial pressures of inhaled anaesthetics equilibrate throughout the body, monitoring their alveolar concentration provides a reliable way of monitoring their effect on the brain.

Vapour Pressure

Inhalational anaesthetics are either gases or the vapours of volatile liquids A substance is a gas when above its critical temperature (the temperature above which it cannot be liquefied irrespective of how much pressure is applied), and a vapour when below the critical temperature. Thus nitrous oxide (N2O), which has a critical temperature of +36.4°C, is a vapour when inhaled at 20°C, but a gas when exhaled at 37°C.

In the gaseous phase, vapours exert a measurable pressure, the vapour pressure. When a vapour is in equilibrium with the liquid agent, the vapour pressure is referred to as the saturated vapour pressure or SVP. The lower the SVP the more volatile is the anaesthetic. SVP decreases with temperature, with time the concentration of anaesthetic being delivered decreased, necessitating frequent adjustments to the vaporiser to maintain a constant inspired concentration. Modern vaporisers are designed to compensate for changes in the temperature of the liquid, so that for any setting of the device the concentration delivered to the patient remains constant

Correlation between the potencies of wide variety of inhalational anaesthetics and their oil/gas solubility

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Physical properties of inhalational anaesthetics

Agent M.W SVP (kPa)  at 20°C Boiling point (°C) MAC in O2 Air irritability
Nitrous oxide 44.02  2500 -88.5 105%  No
Chloroform  113.4  21.15 62  0.5%  No
Diethyl ether  74.1  58.6 34.6 12%  Very marked
Xenon  131.3 -108.1  6-70%  No
Halothane  197.4  32.3 50.2 0.8%  Minimal
Isoflurane  184.5  33.23 48.5  1.2%  Marked
Desflurane  168  88.3 23.5 6.5%  Marked
Enflurane  184.5  22.9 56.5  2-8%  Some
Sevoflurane  200.5  21.3 58.5 1.8%  Minimal
Trichloroethylene  57 mmHg 87.5  0.17%   No
Cyclopropane 10%   No
Fluroxene  286 mmHg  3.4%   No

Graph showing how the ratio between the inspired ( FI ) and alveolar ( FA ) concentrations of inhalational anaesthetics changes with time of administration. The least soluble drugs approach equilibrium ( FA/FI ) the fastest

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The higher the inspired concentration, the more rapid the rise in alveolar concentration and hence the more quickly equilibrium is attained between tensions in the alveoli and the brain. A decrease in cardiac output, by slowing the transit time through the pulmonary circulation, will allow the tension of the inhaled agent in the blood to increase more rapidly, and consequently induction of anaesthesia will be faster. An increase in cardiac output will slow induction, as in patients who are anxious.

Potency: Minimum Alveolar Concentration

MAC is defined as the minimum alveolar concentration of an anaesthetic at one atmosphere ambient pressure that suppresses gross movement in response to a defined painful stimulus in 50% of subjects. It is thus the equivalent of the EC 50 for intravenous drugs. The ‘minimum alveolar concentration’ (MAC) has become accepted as the standard measure of clinical potency of the inhaled anaesthetics. It is noteworthy that MAC only measures the potency of an anaesthetic to suppress the motor response to a noxious stimulus, which is mediated by the spinal cord, not the brain.

There was no correlation between immobility during noxious stimulation and electroencephalographic (EEG) activity, suggesting that the cortex is not the site at which anaesthetics act to block motor responses to noxious stimulation

 Structure–Activity Relationships
All modern volatile anaesthetics, with the exception of halothane (a fluorinated alkane), are halogenated methyl ethyl ethers. No alkanes after halothane were developed because they predispose the heart to ventricular arrhythmias.

Methyl ethyl ethers are more potent, stable and better anaesthetics than diethyl ethers. Fluorine or other halogen substitution on the ether molecule lowers the boiling point, increases chemical stability and generally decreases toxicity and flammability. the presence of at least one hydrogen atom is necessary for anaesthetic potency. Fluorine atoms form a strong chemical bond with carbon atoms, which contributes to the stability of fluorinated anaesthetics. However, among structurally similar compounds, an increase in molecular weight is associated with an increase in anaesthetic potency. The potency of isoflurane is four times that of desflurane as a result of replacing one fluoride atom in desflurane by a chloride atom.

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