Inhalational Anaesthetic Agents
Describe the effects of inhalational agents on the cardiovascular, respiratory and central nervous systems
Describe the toxicity of inhalational agents
Describe the comparative pharmacology of
nitrous oxide, halothane, enflurane, isoflurane, desflurane, sevoflurane, xenon and ether
This section covers features and structures of inhalational anaesthetics. Structure-activity relationships are covered under inhalational anaesthetics.
Common Features of Inhalational Agents
| Property | Action |
|---|---|
| Metabolism | Hepatic CYP450 (CYP2E1) metabolises C-halogen bonds to release halogen ions (F-, Cl-, Br-), which can be nephrotoxic and hepatotoxic. The C-F bond is minimally metabolised compared to the C-Cl, C-Br, and C-I bonds. All agents undergo hepatic oxidation, except for halothane which is reduced. |
| Resp | All halogenated agents ↓ VT and ↑ RR, with an overall ↓ in MV and therefore cause PaCO2 to ↑; and ↓ sensitivity of central respiratory centres to CO2. Impairment of HPV may worsen V/Q matching and ↑ shunt.
|
| CVS | ↓ MAP (predominantly by ↓ in SVR due to NO release and Ca2+ channel blockade), ↓ inotropy due to Ca2+ channel blockade. |
| CNS | Hypnosis. ↓ CMRO2. Above 1 MAC there is uncoupling of the CBF-CMRO2 relationship, and CBF ↑ despite ↓ CMRO2 due to cerebral vasodilation. ICP may mirror CBF changes. All except halothane have some analgesic effect. ↓ EEG frequency such that θ- and δ-wave dominate the EEG as depth ↑. May cause burst suppression.
|
| MSK | Muscle relaxation via blockade of Ca2+ channels. Additional augmentation of the effects of NMBD due to skeletal muscle vasodilation. May precipitate MH. |
| Renal | Dose dependent ↓ in RBF, GFR, and UO secondary to ↓ in MAP and CO. Fluorinated ethers produce F- ions when hepatically metabolised, which may produce high-output renal failure at serum concentrations >50μmol/L. This is probably only a concern with methoxyflurane (as it has significant (>70%) hepatic metabolism) when used at anaesthetic doses. |
| GIT | ↓ Hepatic blood flow. |
| GU | Tocolysis. |
| Toxic Effects | Decreased fertility and increased risk of spontaneous abortion in operating theatre personnel. |
Comparison of Common Inhalational Agents
| Property | Sevoflurane | Isoflurane | Desflurane |
|---|---|---|---|
| Pharmaceutics | Minimally soluble, light stable, not flammable. Formulated with 300ppm of H2O to prevent formation of HF acid by Lewis acids in glass. | Soluble in rubber, light stable, not flammable. | Light sensitive, flammable at 17%. |
| Structure |  |
 |
 |
| Molecular Weight | 200.1 | 184.5 | 168.0 |
| Boiling point | 58.5°C | 48.5°C | 23.5°C |
| SVP (mmHg) at 20°C | 158 | 239 | 669 |
| Blood:gas coefficient | 0.7 | 1.4 | 0.42 |
| Oil:gas coefficient | 50 | 98 | 29 |
| MAC | 2 | 1.15 | 6.6 |
| Metabolism | 3-5% CYP2E1 metabolism to hexafluoroisopropanol and inorganic F- (which may be nephrotoxic) | 0.2% hepatic to nontoxic metabolites | |
| Resp | Bronchodilation, ↓ MV. Smallest ↓ in VT and therefore smallest ↑ in PaCO2 | Bronchodilation, airway irritability. ↓ MV (greater than halothane) with ↑ in RR | Airway irritability manifest as coughing and breath-holding, ↑ secretions |
| CVS | ↑ QT, ↓ SVR causing ↓ MAP without a reflex ↑ HR. Inotropy unchanged. Smallest ↓ in BP of any inhalational agent. | Reflex ↑ HR due to ↓ MAP from ↓ SVR. Small ↓ inotropy and CO, equivalent to sevoflurane but greater than desflurane. May cause coronary steal. | Minimal ↓ inotropy (least of all inhalational agents), but greater ↓ in SVR and BP than sevoflurane. ↑ in HR, with a bigger increase at >1.5 MAC. Large ↑ in SNS tone with rapid ↑ in desflurane concentration. |
| CNS | ↑ Post-operative agitation in children compared to halothane. Smallest ↑ in CBF at > 1.1 MAC, with no increase in ICP up to 1.5 MAC. Cerebral autoregulation intact up to 1.5 MAC. | Best balance of ↓ CMRO2 for ↑ in CBF. | |
| Toxic Effects | Sevoflurane interacts with soda lime to produce Compound A (as well as B through E, which are unimportant), which is nephrotoxic in rats (but not, it seems, in humans). | -CHF2 group may react with dry soda lime to produce CO. | Desflurane has much greater greenhouse gas effects than sevoflurane or isoflurane. |
Comparison of Uncommon Inhalational Agents
| Property | Enflurane | Halothane | Xenon |
|---|---|---|---|
| Pharmaceutics | Structural isomer of isoflurane with different physical properties | Light unstable. Corrodes some metals and dissolves into rubber. | Not flammable. Very expensive to produce. |
| Structure |  |
||
| Molecular Weight | 184.5 | 197 | 131 |
| Boiling point | 56.5°C | 50.2°C | -108°C |
| SVP (mmHg) at 20°C | 175 | 243 | - |
| Blood:gas coefficient | 1.8 | 2.4 | 0.14 |
| Oil:gas coefficient | 98 | 224 | 1.9 |
| MAC | 1.7 | 0.75 | 71 |
| Metabolism | ~25% undergoes oxidative phosphorylation by CYP450 systems, producing trifluoroacetic acid, which binds to protein and can cause a T-cell mediated hepatitis, which can be fatal in ~1/10,000 anaesthetics. | Not metabolised. | |
| Resp | Largest ↓ in VT, therefore largest ↑ in PaCO2 | ↑ In RR, ↓ in VT with overall unchanged PaCO2 | ↓ RR, ↑ in VT such that MV is constant. 3x as dense and 1.5x as viscous as N2O, which increases effective airway resistance. Does not appear to cause diffusion hypoxia. |
| CVS | Greatest ↓ in inotropy, HR, SVR, and MAP. Significant ↑ in catecholamine sensitivity. | More stable MAP, ↓ HR | |
| CNS | Produces 3Hz "spike and wave" EEG pattern at high concentrations, resembling grand mal seizures | Greatest ↑ in CNS blood flow at > 1.1 MAC | Analgesic, ↑ PONV |
| MSK | Muscle relaxation when >60%. Does not trigger MH. | ||
| Renal | Direct nephrotoxicity, potentially related to fluoride (though this association is not present with other anaesthetic agents) | ||
| GU | Least tocolytic effect | ||
| Toxic effects | Produces F- ions | Hepatic damage may be: - Reversible transaminitis - Fulminant hepatic necrosis, with a mortality of 50-75%. |
References
- Khan KS, Hayes I, Buggy DJ. Pharmacology of anaesthetic agents II: inhalation anaesthetic agents. Continuing Education in Anaesthesia Critical Care & Pain, Volume 14, Issue 3, 1 June 2014, Pages 106–111.
- Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
- Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
- Miller RD, Eriksson LI, Fleisher LA, Weiner-Kronish JP, Cohen NH, Young WL. Miller's Anaesthesia. 8th Ed (Revised). Elsevier Health Sciences. Peck and Hill
- Leslie RA, Johnson EK, Goodwin APL. Dr Podcast Scripts for the Primary FRCA. Cambridge University Press. 2011.
- Law LS, Lo EA, Gan TJ. Xenon Anesthesia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Anesth Analg. 2016 Mar;122(3):678-97.