Pharmacology: Volatile agents

Contents:

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)
This table is from Peck and Hill’s Pharmacology for Anaesthesia and intensive care 3rd ed

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 MACDecreases MAC
PhysiologicalInfancy
Hyperthermia
Hyperthyroidism
Stress response
Hypernatraemia
Neonatal period
Increasing age
Pregnancy
Hypotension
Hypothermia
Hypothyroidism
PharmacologicalCatecholamines
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
The Meyer-Overton theory describes the correlation between lipid solubility of inhaled anaesthetics and MAC and suggests that anaesthesia occurs when a sufficient number of inhalational anaesthetic molecules dissolve in the lipid cell membrane. The Meyer-Overton theory postulates that it is the number of molecules dissolved in the lipid cell membrane, and not the type of inhalational agent, that causes anaesthesia. Combinations of different inhaled anesthetics may have additive effects at the level of the cell membrane. (FRCA.co.uk) Graph from Peck and Hill 3rd Ed.

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 (PA) is in equilibrium with that in the arterial blood (Pa) and subsequently the brain (PB). Therefore, PA gives an indirect measure of PB.

The faster the rise in PA, the faster the rise in PB, 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 onsetSlower onset
Agent entering the alveoliIncreased 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 capillariesLow 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 streamLow 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:

Figure 1 from Sevoflurane--a long-awaited volatile anaesthetic. | Semantic  Scholar
% metabolised: N2O <0.01, Halothane 20%, Sevoflurane 3.5%, enflurane 2%, isoflurane 0.2%, desflurane 0.02%

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).

aladin inside
Aladdin cassettes by GE – commonly used in the Aisys GE machines.
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:

HalothaneIsofluraneSevofluraneDesfluraneN2OXenon
Molecular weight197184.520016844131
Boiling point (celcius)50485823.5-88-108
SVP at 20 degrees C (kPa)323322895200
MAC (%)0.751.171.86.610571
Blood:gas partition coefficient (low BGPC = faster onset)2.41.40.70.420.470.14
Oil: gas partition coefficient (high OGPC = high potency)2249880291.41.9
OdourNon irritant, sweetIrritantNon-irritantPungentOdourlessOdourless
Boiling point important to note Desflurane below room temperature. Note high MAC and low potency of N2O and xenon, low BG partition coefficients of N2O, Des and Xenon compared to halothane, and high OGPC of halothane compared to N2O/xenon

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

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