• Volatile Anesthetics and Drug Clearance

  • Interference with drug clearance by:

    • Reduced hepatic blood flow

    • Inhibition of drug metabolizing enzymes

  • Drug Clearance

    • Example:   propranolol (Inderal); clearance decreased about 60% by inhaled anesthetics

    • Drugs which are metabolized by oxidation: inhibited by halothane (Fluothane); Halothane (Fluothane) does not inhibit morphine clearance (based on glucuronidation pathways)

    • Conclusion: volatile anesthetic-mediated inhibition of drug metabolizing enzymes is a more significant factor than effects on hepatic blood flow

• Hepatotoxicity Overview

  • Postoperative hepatic dysfunction: associated with most volatile anesthetics, specially halothane (Fluothane).

  • Probable mechanism of liver damage following anesthesia/surgery: inadequate hepatocyte oxygenation (oxygen supply vs. oxygen demand)

    •  Decreased alveolar ventilation and/or

    •  Decreased hepatic blood flow

  • Contributing Factors:

    •  preexisting liver disease, e.g. hepatic cirrhosis

• Hepatotoxicity: Halothane (Fluothane)

  • Two types of halothane (Fluothane)-mediated hepatotoxicity

    •  Type I: mild, self-limited postoperative hepatotoxicity; Frequency = 20%

      •  Symptoms/characteristics:

        • Nausea, fever, increased liver transaminase enzyme activity, lethargy

      •  Probable Mechanism: nonspecific effect due to altered hepatic blood flow which attenuates hepatocyte oxygenation

    • Type II: rare, halothane (Fluothane) hepatitis; Frequency = 1/10,000 -- 1/30,000 adult patients

      • Consequences:

        •  Dramatic hepatic necrosis

        •  Death

      • Probable Mechanism: most likely immune-mediated hepatotoxicity;

        • Primary evidence: presence of immunoglobulin G antibodies in about 70% of patients with halothane (Fluothane) hepatitis diagnosis

        •  Antibodies are against modified liver microsomal proteins on hepatocyte surfaces (modification due to reactive oxidative halothane (Fluothane) metabolite (trifluroacetyl halide))

  • Halothane (Fluothane) Hepatitis

    • Clinical Presentations-suggestive of immune-mediated mechanism:

      1. Fever

      2. Rash

      3. Arthralgia

      4. Eosinophilia

      5. Prior halothane (Fluothane) exposure

    • Risk Factors:

      1. Female gender

      2. Middle age

      3. Obesity

      4. Previous, multiple halothane (Fluothane) exposures

• Enflurane (Ethrane), Isoflurane (Forane), and Desflurane (Suprane)

  • Mild postoperative hepatic dysfunction-- due to altered hepatic blood flow

    • These anesthetics can promote formation of acetylator liver proteins which may cause hepatotoxicity (type II) similar to that caused by halothane (Fluothane); frequency < halothane (Fluothane)

• Skeletal Muscle Effects and Volatile Anesthetics

  •  Neuromuscular Junction

    • Ether-derivative fluorinated volatile anesthetics cause skeletal muscle relaxation about 2 fold greater than that observed with comparable halothane (Fluothane) dosage

    • Nitrous oxide: no skeletal muscle relaxation

    • Nitrous oxide (low NO concentration) + opioids results in skeletal muscle rigidity (observed at > 1 MAC nitrous oxide alone (delivered in hyperbaric chamber))

    •  Volatile anesthetics:

      •  Dose-dependent augmentation of neuromuscular-blocking drug effects

      •  Nitrous oxide: no significant augmentation of neuromuscular-blocking drug effects

  •  Malignant Hyperthermia and volatile anesthetics

    •  Desflurane (Suprane) and sevoflurane (Sevorane, Ultane) and other volatile anesthetics can cause malignant hyperthermia (in genetically susceptible individuals)

    •  Most potent trigger (volatile anesthetics): halothane (Fluothane)

    •  Relatively weak trigger (compared to volatile anesthetics) nitrous oxide

• Obstetrical Effects and Volatile Anesthetics

  •  Volatile anesthetics-obstetrical effects

    •  Similar between agents, dose-dependent reduction in uterine smooth muscle contractility

      •  May contribute to blood loss because of reduced uterine muscle tone

        • Blood loss associated with therapeutic abortion is greater for patients anesthetized with volatile anesthetics compared to those patients receiving nitrous oxide + barbiturate + opioid anesthesia

        • Uterine relaxation induced by volatile anesthetics may facilitate removal of retained placenta

    •  Prominent effect at concentrations > 1 MAC (less noticeable at analgesic concentrations, < 0.5 MAC)

    •  Volatile anesthetics and the fetus

      •  Volatile anesthetics (0.5 MAC) +50% nitrous oxide (amnestic) during cesarean section: no detectable neonatal effects

  •  Nitrous Oxide-obstetrical effects: no effect on uterine smooth muscle at analgesic concentrations used in vaginal delivery

    •  Nitrous oxide analgesia for vaginal delivery -- more rapidly developing than that observed for most volatile agents (possible exceptions: desflurane (Suprane) and sevoflurane (Sevorane, Ultane)) (after about 10 minutes, all inhaled drugs provide comparable analgesic effects).

• Renal Effects-Volatile Anesthetics: Overview

  • Volatile anesthetics:

    •  Dose-dependent reduction in renal blood flow

    •  Dose-dependent reduction in glomerular filtration rates

    •  Dose-dependent reduction urine output

  • Mechanism: reduction in systemic blood-pressure and cardiac output (preoperative titration reduces or eliminates many renal function changes induced by volatile anesthetic use)

• Fluoride-induced renal toxicity

  • Example: methoxyflurane (extensive metabolism, 70% of absorbed dose) to inorganic fluoride, a renal toxin-- concentration dependencies:

    • No effects: < 40 um/L

    • Subclinical effects: 50-80 um/L

    • Clinical toxicity: > 80 um/L

    • Convention: renal toxicity may occur at concentrations above 50 um/L; not absolute indication, e.g. renal toxicity is not observed at 50 um/L following enflurane (Ethrane) or sevoflurane (Sevorane, Ultane)

  • Characteristics of fluoride-induced nephrotoxicity

    • Polyuria

    • Hypernatremia

    • Hyperosmolarity

    • Increased plasma creatinine concentration

    • Inability to concentrate urine

• Vinyl Halide Nephrotoxicity

  • Soda lime and Baralyme, CO₂ absorbants, react with sevoflurane (Sevorane, Ultane) and eliminate hydrogen chloride to form breakdown products

  • Major breakdown product: fluoromethyl-2,2-difluro-1-(trifluoromethyl) vinyl ether (Compound A)

    •  Dose-dependent nephrotoxin in rats (proximal renal tubular injury)

  • Maximum Compound A concentration in anesthesia breathing circuit:

    • 20 ppm at 1 liters/minute

    • 8 ppm at 3 liters/minute

    • 2 ppm at 6 liters/minute

  • Recommendation: use at least two liters/minute fresh gas flow rate for sevoflurane (Sevorane, Ultane) administration (minimizing Compound A accumulation in breathing circuit)

    • With 1.5 MAC sevoflurane (Sevorane, Ultane): Compound A concentration range: 40-42 ppm; For 8 hour or 4 hour procedures, transient evidence of injury (greater in 8 hour group).

      • Glomerular injury (albuminuria)

      • Proximal renal tubule (glucosuria and increased urinary excretion of glutathione-S-transferase)

      • Distal renal tubule's (increased urinary excretion of glutathione-S-transferase)

    • Under comparable conditions, desflurane (Suprane) does not produce renal injury

    • In children: sevoflurane (Sevorane, Ultane) anesthesia: four hours in duration; fresh gas flow rate 2 liters/minute resulted in a Compound A concentration of less than 15 ppm; no evidence of renal toxicity

Stoelting, R.K., "Inhaled Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 36-76

Wray, D.L.,Rothstein, P., Thomas, S. J."Anesthesia for Cardiac Surgery", in Clincial Anesthesia, 3rd Edition, (Barash, P.G, Cullen, B. F. and Stoelting, R. K., eds) Lippincott-Raven Publishers, 1997, pp 835-867.

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