Sevoflurane

1. Basic Properties

2. Mechanism of Action

• Potentiating GABA-A receptors (hyperpolarization via increased Cl- influx)
• Inhibiting NMDA receptors and neuronal Na+/K+ channels
• Modulating two-pore domain K+ channels (K2P), increasing background leak conductance to hyperpolarize neurons

3. Clinical Pharmacology / ADME

• Induction: Rapidly achieved using 2-4% inhaled concentration. The preferred volatile agent for inhalational (mask) induction in both children and adults due to its pleasant odour and lack of airway irritation - has largely replaced halothane for this purpose.
• Rapid onset and offset: Due to low blood:gas solubility, induction and recovery are quick; anesthetic depth can be changed rapidly.
• Maintenance: Widely used post-IV induction; also used as the sole agent via VIMA (Volatile Induction and Maintenance of Anaesthesia).
• Metabolism: ~5% metabolized by hepatic CYP2E1 to hexafluoroisopropanol + inorganic fluoride. NOT metabolized to trifluoroacetate (unlike halothane), so it does not cause halothane-type immune hepatitis.

4. Organ System Effects (Side Effects)

Cardiovascular

• Concentration-dependent decrease in arterial blood pressure (due to systemic vasodilation) and decrease in cardiac output
• Does NOT cause tachycardia - preferable in patients prone to myocardial ischaemia
• Half as potent a coronary vasodilator as isoflurane

Respiratory

• Concentration-dependent reduction in tidal volume + increase in respiratory rate
• Net effect: reduced minute ventilation and increased PaCO2
• NOT irritating to airway - most potent clinical bronchodilator among inhalational anaesthetics (useful in asthma)
• Respiratory reflexes are inhibited (unlike isoflurane/desflurane which initially stimulate)

Central Nervous System

• Increases cerebral blood flow (CBF) and ICP (similar to isoflurane/desflurane), but the response to hypocapnia is preserved - ICP increases can be prevented by hyperventilation
• Reduces CMRO2 (cerebral metabolic rate of O2)
• Emergence delirium in children - short-lived, no long-term sequelae; managed with fentanyl, propofol, ketamine, or alpha-2 agonists (midazolam premedication is ineffective)

Neuromuscular

• Produces skeletal muscle relaxation and enhances the effects of non-depolarizing neuromuscular blocking agents

Hepatic

• Low hepatotoxic potential - not metabolized to trifluoroacetate, so antibody-mediated hepatitis does not occur

5. Toxicity - Compound A and Renal Concerns

• Sevoflurane reacts with CO2 absorbents (soda lime/Baralyme) containing strong bases (NaOH, KOH) to form Compound A (fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether - a vinyl halide/haloalkene)
• Compound A is a dose-dependent nephrotoxin in rats (proximal tubular necrosis at >150 ppm-hours)
• In humans: No clinically significant nephrotoxicity has been demonstrated, even with >200 ppm-hour exposures. This is because human kidneys have far lower beta-lyase activity than rat kidneys (the enzyme that converts the cysteine conjugate of Compound A to a toxic reactive intermediate)
• Practical precaution: Maintain fresh gas flows above 2 L/min when using soda lime to minimize Compound A accumulation
• Sevoflurane also produces inorganic fluoride on metabolism (as does methoxyflurane at toxic levels), but renal-concentrating defects have NOT been associated with sevoflurane at clinical doses
• Malignant hyperthermia trigger - like all halogenated volatile agents, sevoflurane is a trigger for MH in susceptible individuals (must avoid in MH-susceptible patients)

Figure: Comparison of inhalational anaesthetic effects - Sevoflurane notably inhibits respiratory reflexes (vs stimulation by isoflurane/desflurane) and carries some renal risk via Compound A

Key Advantages (Summary)

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Miller's Anesthesia 10e; Barash Clinical Anesthesia 9e; Lippincott Illustrated Reviews Pharmacology