Anesthesia Pharmacology: General Anesthesia

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