How do volatile anaesthetics work?

[ MAC, Ideal agent, Physical properties, Classical vs Modern, ]

Great review from NEJM in 2003 here. Thanks to frca.co.uk.

MAC - The Minimum Alveolar Concentration (MAC)

Is the concentration of agent in volumes % at equilibrium, which prevents the response to surgical stimulation in 50% of subjects. It acts as a guide to the concentration of volatile required for anaesthesia. It is analogous to ED₅₀ (Effective dose). The AD₉₅ is the anaesthetic dose required to prevent response to surgical stimulus in 95% of subjects.

• MAC-awake. Is MAC to prevent voluntary responses to spoken commands
• MAC-immobility. Is MAC
• MAC-BAR (Blunt Autonomic Responses). Is MAC required to blunt autonomic responses to painful stimuli

What affects the MAC?

To achieve equilibrium the gas must be be at the same concentration in the brain as in the delivered gas flow. The rate at which this occurs depends upon:

1. Delivery
   1. Dilution within existing gases
   2. Uptake by CO2 absorbers
   3. Uptake by rubber and plastic connectors and tubing
2. Pulmonary phase
   1. Inhaled conc.
   2. Alveolar ventilation
   3. Diffusion
   4. Blood/gas partition coefficient. A low b/g partition coefficient indicates low solubility so equilibrium will be reached once a relatively small transfers of gas, and therefore will be rapid.
   5. Partial pressure of the gas in the pulmonary artery. It's the difference in concentration that determines the speed
   6. Pulmonary blood flow
   7. V/Q matching
   8. Concentration effect. More of the gas = greater conc. = quicker
   9. Second gas effect. As nitrous is absorbed it increases the conc of the volatile = speeds absorption
3. Circulatory phase
   1. Cardiac output
   2. Cerebral blood flow. Increasing depth of anaesthesia in SV causes hypoventilation, rise in CO2 and resultant increase in CBF - increasing depth. Hyperventilation decreases CO2 and CBF and slows onset.
   3. Distribution to other tissues. Uptake in tissues is related to their blood flow, solubility and arterio-venous tension difference

Ideal Volatile Agent

List of desirable physical and pharmacological properties:

1. Physical Properties
   1. Non flammable, non-explosive at room temperature.
   2. Vaporizable at room temperature, low specific heat capacity and latent heat of vaporisation, high SVP.
   3. Stable at room temperature, with a long shelf life
   4. Stable with soda lime, as well as plastics and metals
   5. Environmentally friendly - no ozone depletion
   6. Cheap and easy to manufacture
2. Biological properties
   1. Pleasant to inhale, non-irritant, induces bronchodilatation.
   2. Low blood:gas solubility i.e. fast onset.
   3. High oil:gas solubility i.e. high potency.
   4. Minimal effects on other systems, e.g. cardiovascular, respiratory, hepatic, renal or endocrine.
   5. No biotransformation -should be excreted ideally via the lungs, unchanged.
   6. Non-toxic to operating theatre personnel

Explanation of physical properties and their clinical effect

Partition Coefficient

Two definitions:

• Ratio of the amount of substance in one phase to the amount in another substance at stated temperature, with the two phases being of equal volume and equilibrium with each other.
• An expression of the relative solubility of a substance in two immiscible phases. It compares the amount of gas present in the first phase when one part dissolves in the second phase.

Blood / Gas coefficient

Blood/gas coefficient is the ratio of the amount of anaesthetic in blood and gas when the two phases are of equal volume and pressure and in equilibrium at 37oC. In other words it is a reflection of the gas' solubility - a high b/g ratio = highly soluble.

You might think that the more of a substance in the blood - the greater it's effect. Oddly, that is not the case. The greater the partial pressure of a gas in the blood - the greater the effect.

Partial pressure = Total pressure x % by volume.

So a gas with a high solubility will exert a low partial pressure and will be slow to take effect and to offset.

A gas with a low solubility (like Sevoflurane) exerts a high partial pressure and therefore has a rapid onset and offset.

Effect of the B/G partition coefficient and the partial pressure exerted by halothane. 2% Halothane by volume of inspired gas will exert 15.2mmHg (Atmospheric pressure = 760mmHg, 0.02 x 760 = 15.2) Henry's law = the partial pressure will be equal in both But the concentration in the blood will be the product of the concentration in the air and the B/G coefficient. 2 x 2.3 = 4.6%

 

Rate of change of alveolar partial pressure against time. The ratio of alveolar tension (Fa) to Inspired tension (Fi) is plotted against time. The numbers on the right are the B/G coefficients for each agent. It is clear that the lower the B/G coefficient, less gets in the blood, therefore equilibrium is achieved more rapidly. The more soluble the gas is, more molecules have to get into the gas to get to the same partial pressure.

 

 

 

 

It is the partial pressure of the agent in the blood and hence the brain that gives rise to anaesthesia. Therefore, agents with a low b:g coefficient exert a high partial pressure and therefore a more rapid onset/offset of action.

Oil / Gas coefficient

The oil:gas coefficient is an index of potency and is inversely related to MAC. The action of anaesthetic agents is suggested to be related to the lipid solubility (Meyer-Overton theory).

• Potency - A measure of drug activity that is inversely relational to the concentration required to produce a standard effect

 

 

 

	Halothane	Isoflurane	Enflurane	Desflurane	Sevoflurane
Molecular weight	197	184	184	168	200
Boiling point (oC)	50.2	48.5	56.5	22.8	58.5
SVP at 20oC	243	238	175	669	157
MAC in 100% O2	0.75	1.15	1.8	6	2.05
MAC in 70% N2O	0.29	0.56	0.57	2.5	0.66
% Biotrans formation	20	0.2	2	<0.1	3 - 5
Blood / gas	2.2	1.36	1.91	0.45	0.6
Oil / gas	224	98	98.5	28	47

 

 

 

Classical view

Unitary hypothesis = All anaesthetics work via the same mechanism

Meyer-Overton rule = potency of anaesthetics correlates with their solubility in olive oil. Hypothesis: Do they act non specifically on the lipid components of cells.

Why has this been abandoned?

• Anaesthetics only cause slight changes in lipids, which can be reproduced by small changes in temperature that do not cause similar effects
• There are excepts to the correlation that can be explained by variations in size, rigidity, polarity of the anaesthetic
  • "long chain alcohol cutoff" Increasing numbers of methylene groups added to homologous series of anaesthetics increases their potency up to a point
  • There are volatiles with similar structures to known anaesthetic volatiles that either have no anaesthetic effect or induce seizures

 

Modern view

A general anaesthetic usually has many different effects and these are caused in different proportions by different agents. Therefore different agents act to differing degrees on separate sites in the CNS.

Some definitions:

• Amnesia - the partial of complete loss of memory. Anterograde affects are after the agent, Retrograde affects events that preceeded the agent's administration
• Hypnosis - Decreased responsively to environmental stimuli
• Analgesia - loss of sensation of pain
• Sedation - Occasionally synonymous with hypnosis, or hypnosis plus diminished motor activity and decreased arousal

Some effects are spinal and some supra-spinal.

Ablation of movement in response to pain in mediated in the spinal cord.

Hypnosis and amnesia are supraspinal

In the brain there is globally depressed metabolism and blood flow and selective suppression of several centres.

Molecular actions of inhaled anaesthetics:

Ion channels that are sensitive to volatiles - cysteine loop neurotransmitter receptors includes:

• Nicotinic ACh
• 5HT type 3
• GABA type A
• Glycine
• Glutamate receptors type NMDA or AMPA

Working hypothesis is that they

enhance inhibitory postsynaptic channel activity

inhibit excitatory synaptic channel activity