Chapter 14  ·  Module 4  ·  Visual Summary

Organ-Specific Effects of Inhalational Anesthetics

Pulmonary, hepatic, renal, skeletal muscle, and obstetrical pharmacology

Malignant Hyperthermia — High Yield

Pharmacogenetic Crisis

Malignant Hyperthermia: Mechanism, Presentation, Treatment

Component Key Facts
Genetics Ryanodine receptor type 1 (RYR1) gene mutation — gain-of-function; autosomal dominant; sarcoplasmic reticulum calcium release channel is pathologically sensitive to triggers
Triggers ALL volatile halogenated agents (halothane, isoflurane, sevoflurane, desflurane, enflurane) + succinylcholine. Nitrous oxide is NOT a trigger.
Mechanism Uncontrolled calcium release from sarcoplasmic reticulum → sustained skeletal muscle contracture → massive hypermetabolism → heat, CO2, lactic acid, rhabdomyolysis, hyperkalemia
Earliest sign Rapidly rising end-tidal CO2 unexplained by ventilation changes. Act on this — do not wait for fever (hyperthermia is a late sign).
Other signs Tachycardia, masseter spasm, generalized muscle rigidity, hyperthermia (>40–41°C), metabolic acidosis, cardiovascular collapse
Treatment 1. Stop trigger — discontinue all volatile agents, flush circuit with 100% O2, switch to total intravenous anesthesia. 2. Dantrolene 2.5 mg/kg IV (repeat q5 min as needed). 3. Active cooling, bicarbonate, treat hyperkalemia, fluids for myoglobinuria.
Dantrolene mechanism Binds ryanodine receptor type 1 → stabilizes sarcoplasmic reticulum calcium channel in closed state → stops uncontrolled calcium release
Prevention Total intravenous anesthesia (propofol + opioids + nondepolarizing agents). Nitrous oxide permitted. Dantrolene must be immediately available in every operating room.

Hepatotoxicity — Trifluoroacetylation Rank Order

Comparative Risk

Volatile Agent Hepatotoxic Risk by Metabolic Fraction

Agent Hepatic Metabolism Risk Level
Halothane ~20% (highest) Highest — immune hepatitis ~1:35,000; fatal on re-exposure
Enflurane ~2–5% Very low — cross-reactive hepatitis possible
Isoflurane ~0.2% Very low — rare case reports with prior halothane exposure
Sevoflurane ~3–5% (different pathway — hexafluoroisopropanol, not trifluoroacetyl) Minimal — does not generate trifluoroacetylated proteins
Desflurane <0.02% (lowest) Negligible — preferred in patients with prior halothane hepatitis

Pulmonary and Obstetrical Effects

Pulmonary

Key Effects

  • All agents: dose-dependent respiratory depression; hypercapnia under spontaneous ventilation; controlled ventilation is standard
  • Bronchodilation: all volatile agents; sevoflurane and halothane most potent; avoid desflurane in reactive airways
  • Hypoxic pulmonary vasoconstriction inhibition: all volatile agents; worsens oxygenation during one-lung ventilation; propofol does not inhibit — preferred for thoracic total intravenous anesthesia

Obstetrical

Key Effects

  • Uterine relaxation: all volatile agents; dose-dependent; risk of atony and hemorrhage at concentrations above 1.5 minimum alveolar concentration
  • Cesarean section: keep volatile agent at or below 0.5–0.75 minimum alveolar concentration; administer oxytocin after delivery
  • Placental transfer: all volatile agents cross freely; fetal drug accumulation is a function of induction-to-delivery interval
  • Nitrous oxide in labor: 50% concentration provides analgesia via N-methyl-D-aspartate antagonism; minimal uterine relaxation
  • Deliberate uterine relaxation: volatile agents or intravenous nitroglycerin for retained placenta, uterine inversion

Renal: All volatile agents transiently reduce glomerular filtration rate (hemodynamic). Fluoride-induced nephrotoxicity risk: enflurane (subclinical at standard doses) > sevoflurane (systemic fluoride elevated but intrarenal metabolism minimal — no clinically significant nephrotoxicity demonstrated). Compound A from sevoflurane at low flow: nephrotoxic in rats, not demonstrated in humans.