Contents:

• How do anaesthetic agents work?
• MAC and oil gas partition coefficient and Meyer-Overton Hypothesis
• Blood gas partition coefficient
• Metabolism
• Comparison tables
• Ideal inhaled anaesthetic agent
• References

How do anaesthetic agents work?

Different theories – none completely explains it.

1. Meyer Overton Hypothesis and membrane expansion theory – Lipid soluble anaesthetic agents enter the cell membranes very easily and alter the molecular arrangement of phospholipids and disruption of the ion channels
2. Perturbation theory – Disruption of annular lipids associated with specific lipid sites and ion channels
3. Specific protein based binding sites – GABA _A and glycine (inhibitory) and neuronal nicotinic and NMDA (excitatory)

Minimum alveolar concentration and oil gas partition coefficient

MAC = minimum alveolar concentration = minimum alveolar concentration at steady-state that prevents reaction to a standard surgical stimulus (skin incision) in 50% of subjects at one atmosphere. A measure of potency.

Potency is an expression of the activity of a drug, in terms of the concentration or amount needed to produce a defined effect.

Higher partial pressure of agent to achieve MAC = less potent agent

MAC is affected by:

	Increases MAC	Decreases MAC
Physiological	Infancy Hyperthermia Hyperthyroidism Stress response Hypernatraemia	Neonatal period Increasing age Pregnancy Hypotension Hypothermia Hypothyroidism
Pharmacological	Catecholamines Sympathomimetics Chronic opioid use Chronic alcohol intake Acute amphetamine intake	Alpha 2 agonists Sedatives Acute opioid use Acute alcohol intake Chronic amphetamine intake Lithium

Meyer-Overton hypothesis

Oil gas partition coefficient = A measure of lipid solubility of an anaesthetic agent. It is inversely related to MAC (as above).

High MAC = low oil:gas partition coefficient = low potency

Kinetics and blood gas partition coefficient

At steady state,

Partial pressure of inhaled anaesthetic within the alveoli (P_A) is in equilibrium with that in the arterial blood (P_a) and subsequently the brain (P_B). Therefore, P_A gives an indirect measure of P_B.

The faster the rise in P_A, the faster the rise in P_B, the faster the onset of anaesthesia.

See this video for a description of partial pressures, Dalton’s law, and how this affects your anaesthetic.

Factors affecting onset of inhalational anaesthesia:

	Faster onset	Slower onset
Agent entering the alveoli	Increased alveolar ventilation Small functional residual capacity High inspired concentration High fresh gas flow Lower circuit volume Little or no circuit absorption of agent Low dead space Second gas effect	Decreased alveolar ventilation Large functional residual capacity Low inspired concentration Low fresh gas flow High circuit volume High absorption of agent from circuit High dead space
Agent entering the capillaries	Low cardiac output (more time for agent to diffuse into blood as the blood passes through the alveoli and achieve equilibrium) Low blood: gas partition coefficient	High cardiac output High blood:gas partition coefficient
Agent reaching the brain from the blood stream	Low blood: gas partition coefficient High oil:gas partition coefficient	High blood: gas partition coefficient Low oil: gas partition coefficient

Blood:gas partition coefficient = 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 37◦C.

High blood:gas partition coefficient = high solubility = low partial pressure in blood = slower onset

Low blood:gas partition coefficient = low solubility = high partial pressure in blood = faster onset

Metabolism

Cytochrome p450 metabolises C-(halogen) bonds to release halogen ions (F-, Cl- or Br-) or trifluoroacetic acid, which may cause hepatic or renal damage.

From the most to least stable (or least to most metabolised):

C-F, C-Cl, C-Br, C-I

Sevoflurane particularly forms Compound A in the presence of soda lime and heat and this has shown to be nephrotoxic in rats.

Any agent that has a CHF2 group (iso, enflurane and des) can produce carbon monoxide in circle systems with dry gas circulating over a weekend.

These are the structures of our commonly used agents:

Top facts about each of the commonly used volatiles:

Isoflurane: Mac 1.17, pungent so rarely used for induction, reduces SVR, may have myocardial protective properties and is used in cardiac anaesthesia for ischaemic preconditioning.

Sevoflurane: Mac 1.8, sweet smelling so often used for induction, can’t be stored in glass bottles in case it is contaminated by Lewis acids in the glass and form hydrofluoric acid, which corrodes the bottle. Forms Compound A (see above)

Desflurane: Mac 6.6, pungent so can’t be used for induction, boiling point of 23.5 degrees which renders it extremely volatile and dangerous to administer via a conventional vaporiser. Previously had a special Tec 6 vaporiser with an inbuilt heater for 39 degrees, now is available with different electronic injection cassettes (Aladdin for GE systems, see below).

General effects of inhalad anaesthetics:

CVS:

• Reduce contractility (Halothane +++, desflurane least)
• Increase heart rate (all except halothane which reduces, sevo no effect)
• Reduce SVR (des and iso the most)
• Coronary steal syndrome (iso only)

Respiratory

• All increase RR
• All reduce tidal volume
• All increase PaCO2 except halothane (no effect)

Physical principles tables:

	Halothane	Isoflurane	Sevoflurane	Desflurane	N2O	Xenon
Molecular weight	197	184.5	200	168	44	131
Boiling point (celcius)	50	48	58	23.5	-88	-108
SVP at 20 degrees C (kPa)	32	33	22	89	5200
MAC (%)	0.75	1.17	1.8	6.6	105	71
Blood:gas partition coefficient (low BGPC = faster onset)	2.4	1.4	0.7	0.42	0.47	0.14
Oil: gas partition coefficient (high OGPC = high potency)	224	98	80	29	1.4	1.9
Odour	Non irritant, sweet	Irritant	Non-irritant	Pungent	Odourless	Odourless

Ideal inhalational agent:

Physical

• Stable to light and heat
• Inert when in contact with metal, rubber and soda lime
• Preservative free
• Not flammable or explosive
• Pleasant odour
• Atmospherically friendly
• Cheap

Biochemical

• High oil:gas partition coefficient; low MAC
• Low blood:gas partition coefficient
• Not metabolized
• Non-toxic
• Only affects the CNS
• Not epileptogenic
• Some analgesic properties

References

1. CEACCP article on inhalational anaesthetics 2014
2. Life in the fast lane article on inhalational anaesthetics
3. Peck and Hill Pharmacology for Anaesthesia and Intensive Care 3rd and 4th Ed
4. FRCA.co.uk