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