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Volatile Anesthetics — MAC, Solubility, Second-Gas, Diffusion, Agent Comparison
TEXTPharmacology · 8 min read
Every volatile decision reduces to potency (MAC) and speed (solubility). Two numbers tell you almost everything — but the agents differ in airway, hemodynamics, metabolism, and absorbent chemistry.
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4 min read7 sectionsMAC definitions — the family of thresholds
Minimum alveolar concentration (MAC) is the steady-state end-tidal % of inhaled anesthetic at 1 atm that prevents purposeful movement to a standardized surgical stimulus (skin incision) in 50% of patients.
MAC values at age 40: halothane 0.75%, isoflurane 1.15%, sevoflurane 2.0%, desflurane 6.0%, N2O 104%.
MAC values are additive across agents (0.5 MAC sevo + 0.5 MAC N2O ≈ 1 MAC effect).
Factors that modify MAC
- youth (peak at 6 mo, ~1.8× adult)
- hyperthermia
- chronic alcohol use
- acute sympathomimetics (cocaine, amphetamine)
- hypernatremia
- hyperthyroidism (modest)
- red hair (~20% increase)
- age (~6% per decade after 40)
- hypothermia (~5% per °C)
- hyponatremia
- pregnancy (~30% by term — progesterone)
- acute alcohol intoxication
- opioids (dose-dependent — fentanyl 3 ng/mL ≈ 60% MAC reduction)
- alpha-2 agonists (dexmedetomidine ~30-50%)
- lithium
- lidocaine infusion
- severe anemia (Hgb <5)
- severe hypoxia
- gender
- height
- weight
- duration of anesthesia
- PaCO2 in physiologic range
- hyper/hypokalemia
Blood:gas partition coefficient — the speed metric
LOWER λ = faster equilibration between alveolar + brain partial pressures = faster induction + emergence.
- desflurane 0.42
- N2O 0.47
- sevoflurane 0.65
- isoflurane 1.4
- halothane 2.4
Counterintuitive but correct: a HIGHLY blood-soluble agent (high λ) goes more slowly because the blood acts as a deep reservoir that must fill before alveolar/brain pressure rises.
Clinical implication: desflurane + sevoflurane permit rapid titration + extubation; isoflurane is slower, especially after prolonged exposure when fat compartment loads.
![Blood-gas partition coefficient (λ): ratio of [agent in blood] to [agent in gas] at equilibrium; lower λ = faster onset/offset; Des 0.42, Sevo 0.65, Iso 1.4, N2O 0.47; lower solubility means more rapid wash-in and wash-out.](https://pfcaitzjiuhtyrjwevzj.supabase.co/storage/v1/object/sign/manual-panels/381dd445-6bf3-4e6a-a5c5-787bd8c472ac.png?token=eyJraWQiOiJzdG9yYWdlLXVybC1zaWduaW5nLWtleV82NWQ1NTMxOC1iZWMzLTQxY2MtOGVhMC1lZjNhNjY5ZGU5M2IiLCJhbGciOiJIUzI1NiJ9.eyJ1cmwiOiJtYW51YWwtcGFuZWxzLzM4MWRkNDQ1LTZiZjMtNGU2YS1hNWM1LTc4N2JkOGM0NzJhYy5wbmciLCJzY29wZSI6ImRvd25sb2FkIiwiaWF0IjoxNzgxMDQwMjE4LCJleHAiOjE3ODEwNDM4MTh9.Co3_KWvuUo_ei4Yfj2EJhs--yPTXTWjbrIoShMg2ePk)
Concentration effect, second-gas effect, diffusion hypoxia
Concentration effect: the higher the inspired concentration of a gas, the more rapidly the alveolar concentration rises — relevant only for N2O at high inspired concentrations (67-70%) because of volume contraction.
- rapid uptake of N2O concentrates a co-administered volatile (sevoflurane) in the residual alveolar gas
- accelerating its uptake — modest
- clinically marginal
- useful in mask induction
Diffusion hypoxia: at emergence after N2O, the large reservoir of dissolved N2O rapidly leaves blood + dilutes alveolar O2 — supplement 100% O2 for 5-10 min after discontinuation.
Oil:gas partition coefficient correlates with potency (Meyer-Overton hypothesis): higher lipid solubility = lower MAC.
Sevoflurane vs desflurane vs isoflurane — practical comparison
Sevoflurane: pleasant smell, non-pungent, only volatile suitable for mask induction (peds + adult difficult-airway), bronchodilator, modest hypotension via SVR ↓ + small contractility ↓, fluoride generation up to 50 μM (no clinical nephrotoxicity at clinical doses), compound A formation with low-flow + dry CO2 absorbents (limit FGF ≥2 L/min for >2 MAC-hr in older absorbent formulations; modern Amsorb/Litholyme don't produce compound A).
- lowest λ fastest emergence (predictable for obese, long cases)
- pungent (NEVER use for mask induction — coughing, laryngospasm, breath-holding above 6%)
- sympathetic stimulation if rapidly increased >1 MAC (HR + BP rise)
- CO production with dry strong-base absorbents (baralyme — historical, off market)
- cheap
- coronary vasodilator (theoretical steal — clinically minimal)
- slower emergence
- pungent at induction concentrations
Metabolism, toxicity, absorbent chemistry
Hepatic metabolism (% of absorbed drug): halothane 20% (immune hepatitis 1:6,000-35,000 — TFA-conjugated antigen), sevoflurane 5% (free fluoride), isoflurane 0.2%, desflurane 0.02% (minimal TFA exposure → essentially no hepatitis risk).
Compound A (a vinyl ether nephrotoxin in rats) forms when sevoflurane interacts with strong bases (KOH/NaOH) in older soda lime + baralyme, especially with low FGF + high temperature; clinical nephrotoxicity in humans never demonstrated at FGF ≥1 L/min, but FDA label recommends FGF ≥2 L/min when MAC-hours exceed 2. Carbon monoxide forms when desflurane (and to a lesser extent iso, enflurane) reacts with DESICCATED strong-base absorbents (typically Monday-morning machines left flowing all weekend) — replace absorbent if color indicator dry, or use Amsorb (no strong base).
Clinical agent selection algorithm
Long obese case where rapid extubation matters: desflurane after airway secured.
Patient with malignant hyperthermia susceptibility: AVOID ALL volatile agents + sux TIVA with propofol + remifentanil.
Neuro case requiring tight CMRO2/CBF control: keep volatile <1 MAC (above 1 MAC, uncoupling causes vasodilation despite metabolic suppression); consider TIVA for awake craniotomy or severely elevated ICP.
Pregnancy at term for C-section under GA: any volatile <0.5 MAC after delivery to avoid uterine atony.
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