Nursing Pharmacology Chapter 14:  General Anesthesia Comparative Pharmacology and Physiology

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  • 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

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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.