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.

What affects the MAC?

Factors increasing MAC i.e. you need more volatile

Factors decreasing MAC i.e. use less

Infancy Neonatal period
  Increasing age
  Pregnancy
  Hypotension
Hyperthermia / pyrexia Hypothermia
Hyperthyroidism Hypothyroidism
Catecholamines and other sympathomimetics Alpha -2 - agonists (like clonidine)
  Sedatives
Chronic opioid use Acute Opioids
Chronic alcohol use Acute Alcohol
Acute amphetamine use Chronic amphetamine use
Hypernatraemia Lithium

 

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:

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).

 

 

 



 
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?

 

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:

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:

Working hypothesis is that they

enhance inhibitory postsynaptic channel activity

inhibit excitatory synaptic channel activity