Inhalational Anaesthetic Agents

Volatile and gaseous agents delivered through the lungs to produce reversible loss of consciousness, amnesia, immobility and analgesia. NEET PG loves the quantitative side here — MAC values, blood:gas partition coefficients, and the organ-specific toxicities. Master the comparison tables and you can answer most questions.

Classification

Inhalational agents are divided by physical state at room temperature.

Class	Agents	Notes
Gaseous	Nitrous oxide (N₂O), Xenon	Stored as gas/liquefied gas in cylinders
Volatile liquids	Halothane, Isoflurane, Enflurane, Sevoflurane, Desflurane, Methoxyflurane	Delivered via vaporiser

Chemically, all modern volatile agents (except halothane) are fluorinated methyl-ethyl ethers. Halothane is a halogenated alkane (the only one without an ether linkage and the only one with a bromine atom). Desflurane is sevoflurane/isoflurane-like but with fluorine substituting the chlorine — making it very stable and poorly soluble.

High-yield: Halothane is the only agent that is NOT an ether — it is a halogenated hydrocarbon (alkane). It is also the only one containing bromine.

Mechanism of Action

The exact mechanism remains incompletely understood, but the older lipid-based theories have largely given way to a protein/receptor (ligand-gated ion channel) theory.

• Meyer–Overton correlation (lipid solubility theory): anaesthetic potency correlates directly with lipid solubility (oil:gas partition coefficient). The more lipid-soluble an agent, the lower its MAC and the more potent it is. This is a correlation, not the true mechanism, but it is heavily examined.
• Current understanding — protein targets:
  • Potentiation of inhibitory channels: GABA-A receptors (chloride influx → hyperpolarisation) and glycine receptors. This is the dominant action of most volatile agents.
  • Inhibition of excitatory channels: NMDA receptors (key for N₂O and xenon), nicotinic acetylcholine receptors.
  • Activation of two-pore domain K⁺ channels (TREK, TASK) → hyperpolarisation.

High-yield: Nitrous oxide and xenon act predominantly by NMDA receptor antagonism, NOT mainly through GABA — unlike the potent volatile agents.

The MAC Concept

MAC (Minimum Alveolar Concentration) = the alveolar concentration of an agent (at 1 atmosphere) that prevents movement in response to a surgical (skin) incision in 50% of subjects. It is the standard measure of potency of inhalational agents and is analogous to the ED₅₀.

• MAC is inversely proportional to potency — a low MAC means a high potency.
• MAC values are additive: 0.5 MAC N₂O + 0.5 MAC sevoflurane ≈ 1 MAC effect.
• The site of MAC (immobility) action is largely the spinal cord, not the brain.

Derived MAC values (memorise the multiples)

Term	Value	Endpoint
MAC-awake	~0.3–0.4 MAC	Concentration at which eye opening to command occurs (recovery / amnesia)
MAC (standard)	1.0 MAC	No movement to skin incision in 50%
MAC-BAR	~1.5–2.0 MAC	Blocks adrenergic/autonomic response to incision in 50%
MAC₉₅	~1.3 MAC	No movement in 95%
MAC-intubation	~1.3 MAC	Permits laryngoscopy/intubation without movement/coughing

High-yield: MAC-awake < MAC < MAC-BAR. The order of increasing concentration is MAC-awake → MAC → MAC-intubation/MAC₉₅ → MAC-BAR.

Factors affecting MAC

This is among the single most repeated NEET PG topics.

Factors that INCREASE MAC (more agent needed):

• Hyperthermia (up to 42°C; above that MAC falls)
• Chronic alcoholism
• Hypernatraemia
• Drugs increasing CNS catecholamines: acute amphetamine intoxication, cocaine, ephedrine, MAO inhibitors, levodopa
• Infancy — MAC is highest at ~6 months of age, then declines with age
• Red hair (genuinely tested — MC1R mutation)

Factors that DECREASE MAC (less agent needed):

• Increasing age (elderly), neonates (lower than infants)
• Hypothermia
• Hyponatraemia
• Pregnancy
• Acute alcohol intoxication
• Hypoxaemia (PaO₂ < 40), severe hypercarbia, severe anaemia/hypotension
• Lithium, lignocaine (lidocaine), opioids, benzodiazepines, α₂-agonists (clonidine, dexmedetomidine), ketamine, verapamil

High-yield: MAC peaks at around 6 months of age and then decreases by ~6% per decade thereafter. Pregnancy, acute alcohol, hypothermia and hyponatraemia all DECREASE MAC.

Factors that do NOT affect MAC: duration of anaesthesia, gender, type/site of surgical stimulation, K⁺/Mg²⁺ levels, hyper/hypothyroidism (debated), metabolic vs respiratory acid–base per se (only severe extremes matter), and PaCO₂ within physiological range.

Pharmacokinetics — Uptake & Distribution

The blood:gas partition coefficient is the key determinant of speed of induction and recovery.

• A LOW blood:gas coefficient = agent is poorly soluble in blood → the alveolar (and hence brain) partial pressure rises rapidly → FAST induction and FAST recovery.
• A HIGH blood:gas coefficient = highly soluble → blood acts as a large reservoir/sink that must fill before partial pressure rises → SLOW induction and recovery.

Speed of onset/offset order (fastest → slowest): Desflurane ≈ N₂O > Sevoflurane > Isoflurane > Enflurane > Halothane.

High-yield: Lower blood:gas solubility → faster onset and offset. Desflurane has the lowest blood:gas coefficient (~0.42) among volatile agents, giving the fastest recovery.

Factors speeding the rise of alveolar concentration (Fa/Fi)

1. Low solubility (low blood:gas coefficient) →
2. High inspired concentration / overpressure →
3. High fresh gas flow →
4. High alveolar ventilation →
5. Low cardiac output (less agent carried away from lungs) →
6. Concentration effect and the second gas effect.

• Concentration effect: the higher the inspired concentration of a gas, the faster its alveolar concentration approaches inspired (relevant with high-concentration N₂O).
• Second gas effect: rapid uptake of a large volume of a "first gas" (N₂O) concentrates and accelerates the uptake of a concurrently administered "second gas" (a volatile agent), speeding induction.

High-yield: Low cardiac output speeds inhalational induction (alveolar concentration rises faster) — the opposite of intravenous agents. Memorise the second gas effect with nitrous oxide as the "first gas."

Comparison of Individual Agents

Agent	MAC (%)	Blood:gas coeff.	Pungency	Metabolism	Signature feature/toxicity
Nitrous oxide	104 (incomplete anaesthetic)	0.47	Non-pungent	<0.004%	Diffusion hypoxia; expands air spaces; megaloblastic change
Halothane	0.75	2.4 (high)	Non-pungent	~20% (highest)	Halothane hepatitis; arrhythmias; malignant hyperthermia
Isoflurane	1.15	1.4	Pungent	~0.2%	Coronary steal (theoretical); pungent → not for inhalational induction
Sevoflurane	2.0	0.65	Non-pungent (sweet)	~3–5%	Compound A (nephrotoxic in rats); agent of choice for gas induction
Desflurane	6.0	0.42 (lowest)	Very pungent	~0.02%	Airway irritation, laryngospasm; sympathetic stimulation; needs heated vaporiser
Enflurane	1.7	1.8	Pungent	~2%	Tonic–clonic seizure activity (EEG spikes); fluoride

High-yield: MAC values to memorise: Halothane 0.75, Isoflurane 1.15, Enflurane 1.7, Sevoflurane 2.0, Desflurane 6.0, N₂O 104. The agent with the highest hepatic metabolism is halothane (~20%); the lowest is desflurane.

Agent-specific notes

Nitrous oxide (N₂O)

• Weak anaesthetic (MAC 104%, cannot reach 1 MAC at safe FiO₂) but a good analgesic and used as a carrier/adjuvant.
• 34 times more soluble than nitrogen → diffuses into air-filled spaces faster than nitrogen leaves, expanding closed gas spaces (pneumothorax, bowel obstruction, air embolism, middle ear, pneumocephalus, intraocular SF₆/gas bubble). Avoid in these conditions.
• Diffusion hypoxia on discontinuation: large volumes of N₂O flood the alveoli, diluting oxygen → give 100% O₂ for a few minutes after stopping.
• Inactivates vitamin B₁₂ by oxidising cobalt → inhibits methionine synthase → megaloblastic anaemia, agranulocytosis, and (with chronic abuse) subacute combined degeneration of the cord.
• Causes postoperative nausea and vomiting (PONV).

Halothane

• Smooth, non-pungent → was the classic paediatric induction agent (now replaced by sevoflurane).
• Cardiovascular: dose-dependent myocardial depression, bradycardia, sensitises myocardium to catecholamines → ventricular arrhythmias (limit adrenaline infiltration).
• Halothane hepatitis: two forms — a mild transient transaminitis, and a rare fulminant immune-mediated hepatic necrosis (trifluoroacetyl-protein adducts; risk factors: repeat exposure, obese middle-aged women, family history).
• Potent trigger of malignant hyperthermia.
• Most depresses ventilation and is the most potent bronchodilator (useful in status asthmaticus historically).

Isoflurane

• Maintains cardiac output; causes peripheral vasodilatation and a fall in SVR (compensatory tachycardia). Cheap, widely used for maintenance.
• "Coronary steal" concern is largely theoretical.
• Pungent — not suitable for inhalational induction.

Sevoflurane

• Agent of choice for inhalational (gas) induction, especially in children and difficult-airway cases — non-pungent, sweet, rapid.
• Reacts with soda lime/baralyme → Compound A (nephrotoxic in rats); minimised by using fresh gas flow ≥2 L/min. Clinical human nephrotoxicity is not established but examiners ask about Compound A.
• Produces inorganic fluoride on metabolism.

Desflurane

• Fastest recovery → ideal for day-care/obese patients. Boiling point ~23°C → requires a special electrically heated, pressurised vaporiser (Tec 6).
• Very pungent, causes coughing, breath-holding, laryngospasm → NOT used for induction.
• Rapid increases in concentration cause transient sympathetic surge (tachycardia, hypertension).

High-yield: Sevoflurane = inhalational induction agent of choice (non-pungent). Desflurane = fastest recovery but the most airway-irritant; never use it to induce.

Effects on Organ Systems (common to volatile agents)

• CVS: dose-dependent reduction in mean arterial pressure (halothane mainly ↓ contractility/CO; iso/des/sevo mainly ↓ SVR). Halothane → bradyarrhythmias; desflurane → tachycardia.
• Respiratory: all are dose-dependent respiratory depressants (↓ tidal volume, ↑ rate, blunted CO₂ response) and bronchodilators.
• CNS: ↑ cerebral blood flow and ↑ ICP (uncoupling from reduced metabolism); useful concept in neuroanaesthesia — keep volatile agents ≤1 MAC. Enflurane is epileptogenic.
• Neuromuscular: potentiate non-depolarising muscle relaxants; all volatile agents (and suxamethonium) can trigger malignant hyperthermia. N₂O does NOT trigger MH.
• Uterus: volatile agents cause dose-dependent uterine relaxation (useful for manual removal of placenta, but risk of postpartum haemorrhage). N₂O does not relax the uterus.

Malignant Hyperthermia (must-know complication)

A pharmacogenetic, autosomal dominant disorder of the skeletal muscle ryanodine receptor (RYR1) on chromosome 19, causing uncontrolled Ca²⁺ release.

Triggers: all volatile agents + suxamethonium (succinylcholine). Non-triggers: N₂O, propofol, etomidate, ketamine, barbiturates, all local anaesthetics, non-depolarising relaxants.

Clinical approach (flow): Rising end-tidal CO₂ (earliest and most sensitive sign) → masseter spasm/generalised rigidity → tachycardia/arrhythmia → hyperthermia (late) → mixed respiratory + metabolic acidosis, hyperkalaemia, myoglobinuria, rhabdomyolysis.

Management: ① Stop trigger agent & call for help → ② Dantrolene 2.5 mg/kg IV (drug of choice) repeated to 10 mg/kg → ③ 100% O₂, hyperventilate → ④ active cooling → ⑤ treat hyperkalaemia and arrhythmias → ⑥ maintain urine output (mannitol/bicarbonate).

Diagnostic test: Caffeine–halothane contracture test (in-vitro contracture test) on a muscle biopsy is the gold standard.

High-yield: Dantrolene is the drug of choice for malignant hyperthermia; the earliest sign is a rising end-tidal CO₂. The defective receptor is RYR1.

Key Differentials / "Which Agent?" Decisions

Clinical scenario	Best/avoid
Inhalational induction in a child	Sevoflurane (avoid desflurane, isoflurane — pungent)
Day-care surgery, obese patient	Desflurane (fastest recovery)
Pneumothorax, bowel obstruction, air embolism	Avoid N₂O (expands air spaces)
Neurosurgery / raised ICP	Limit volatile agents (≤1 MAC); avoid N₂O (expands pneumocephalus)
History of halothane hepatitis	Avoid halothane; use isoflurane/sevoflurane
Vitamin B₁₂ deficiency / SACD risk	Avoid N₂O
Asthmatic / bronchospasm	Volatile agents are bronchodilators (halothane, sevoflurane)

Recently asked / exam angle

• Single-best-answer on MAC values (e.g., "MAC of desflurane?" → 6%) and ranking agents by potency/solubility.
• "Lowest blood:gas partition coefficient" → desflurane; "speeds induction" reasoning.
• Factors increasing vs decreasing MAC — pregnancy decreases; red hair, hyperthermia, chronic alcohol increase; MAC peak at 6 months.
• Second gas effect / concentration effect definitions.
• Diffusion hypoxia and air-space expansion with N₂O; B₁₂/methionine synthase inactivation.
• Compound A with sevoflurane + soda lime; fluoride nephrotoxicity (historically methoxyflurane — high fluoride).
• Halothane hepatitis mechanism (TFA adducts) and risk profile.
• Malignant hyperthermia: trigger list, earliest sign (EtCO₂), drug of choice (dantrolene), defective gene (RYR1), diagnostic test.
• Enflurane → seizures/EEG spikes; isoflurane "coronary steal."
• "Agent of choice for inhalational induction" → sevoflurane.

Rapid revision

1. MAC = potency; inversely proportional — low MAC = high potency.
2. MAC values: Halothane 0.75, Isoflurane 1.15, Enflurane 1.7, Sevoflurane 2.0, Desflurane 6.0, N₂O 104.
3. Blood:gas coefficient = speed; lowest is desflurane (~0.42) → fastest induction/recovery.
4. Halothane is the only non-ether (alkane) and only bromine-containing agent; highest metabolism (~20%).
5. MAC increases: hyperthermia, chronic alcohol, red hair, hypernatraemia, infancy (peak 6 months); decreases: pregnancy, hypothermia, acute alcohol, elderly, opioids, α₂-agonists, lithium.
6. N₂O & xenon → NMDA antagonism; other volatiles → mainly GABA-A potentiation.
7. Second gas effect and concentration effect speed induction; low cardiac output speeds inhalational induction.
8. N₂O expands air spaces (avoid in pneumothorax/bowel obstruction), causes diffusion hypoxia, and inactivates methionine synthase (B₁₂) → megaloblastic anaemia, SACD.
9. Sevoflurane = inhalational induction agent of choice; forms Compound A with soda lime.
10. Desflurane = fastest recovery, most pungent, needs heated vaporiser; never for induction.
11. Halothane sensitises myocardium to catecholamines (arrhythmias) and causes immune halothane hepatitis.
12. Malignant hyperthermia: RYR1 defect, earliest sign rising EtCO₂, treat with dantrolene; N₂O is a non-trigger.