Isoflurane

Introduction / Chemistry

Pharmacokinetics / Physical Properties

• Blood solubility is intermediate (lower than halothane/enflurane, higher than sevoflurane/desflurane), giving medium speed of induction and emergence.
• Not suitable for inhalational induction due to pungent odor causing breath-holding, coughing, laryngospasm, and hypersalivation.
• Typically used for maintenance after induction with IV agents; maintenance concentration ~1-2 MAC (1-2%).
• Metabolized to trifluoroacetic acid; minimal fluoride release; not a mutagen, teratogen, or carcinogen.

Mechanism of Action

• Enhancement of GABA-A receptor activity (main mechanism)
• Inhibition of NMDA receptors
• Inhibition of store-operated calcium entry (SOCE) in airway smooth muscle
• Activation of two-pore domain K+ channels, causing membrane hyperpolarization

Organ System Effects

1. Cardiovascular System

• Dose-dependent decrease in blood pressure - primarily due to decreased systemic vascular resistance (vasodilation in skin and muscle)
• Cardiac output is well maintained (unlike halothane) - minimal left ventricular depression in vivo
• Compensatory reflex tachycardia (partial baroreceptor preservation)
• Rapid concentration changes: transient tachycardia and hypertension from sympathetic stimulation
• Potent coronary vasodilator - may theoretically cause coronary steal (diverting blood from stenotic vessels via vasodilation of normal vessels), though this concern is largely historical
• Minimal sensitization to catecholamine-induced arrhythmias (unlike halothane); epinephrine can safely be used up to 4.5 mcg/kg

2. Respiratory System

• Concentration-dependent respiratory depression with more pronounced fall in minute ventilation; tachypnea is less pronounced than with other agents
• Potently blunts ventilatory response to hypoxia and hypercapnia (even at 0.1 MAC)
• Good bronchodilator - useful in asthmatic patients; though it is an airway irritant, it produces less bronchospasm than its pungency might suggest
• Not suitable for inhalational induction due to airway irritation

3. CNS / Cerebral

• At >1 MAC: increases cerebral blood flow (CBF) and intracranial pressure (ICP) (less pronounced than halothane; reversed by hyperventilation)
• Reduces cerebral metabolic oxygen requirements
• At 2 MAC: produces electrically silent EEG (burst suppression)
• No need to pre-establish hyperventilation before use (unlike halothane)

4. Neuromuscular

• Relaxes skeletal muscle (central effects)
• Potentiates both depolarizing and non-depolarizing neuromuscular blocking agents - dose reduction of muscle relaxants required
• Relaxes uterine smooth muscle - not recommended for obstetric analgesia/vaginal delivery

5. Renal

• Reduces renal blood flow, GFR, and urinary output (concentrated urine)
• Despite some fluoride generation, nephrotoxicity is extremely unlikely; prolonged sedation (>24 hrs) may raise fluoride levels to 15-50 µmol/L without kidney impairment

6. Hepatic

• Reduces total hepatic and splanchnic blood flow
• Hepatic artery perfusion is preserved (better than halothane), so hepatic oxygen supply is better maintained
• No hepatotoxicity reported; liver function tests unaffected

Biotransformation and Toxicity

• Only <0.2% undergoes oxidative metabolism in the liver (by CYP2E1) to trifluoroacetic acid
• Minimal fluoride ion production - no clinically significant nephrotoxicity
• No hepatotoxicity
• Can trigger malignant hyperthermia (as with all volatile halogenated agents)

Contraindications and Drug Interactions

• Malignant hyperthermia - absolute contraindication in susceptible patients
• Severe hypovolemia - may not tolerate vasodilating effects
• Drug interactions:
  • Epinephrine safe up to 4.5 mcg/kg
  • Non-depolarizing NMBAs: potentiated (reduce dose)
  • Opioids/N₂O: reduce required concentration of isoflurane

Comparison Highlights (vs. Other Agents)