General Anaesthetics

General anaesthetics produce reversible loss of consciousness, analgesia, amnesia and immobility to permit surgery. They are classified into inhalational and intravenous agents, and a sound grasp of MAC, potency, induction kinetics and agent-specific toxicities is repeatedly tested in NEET PG pharmacology.

Definition & components of anaesthesia

General anaesthesia is a controlled, reversible state of drug-induced unconsciousness with five components that no single agent achieves ideally — hence "balanced anaesthesia" using drug combinations:

1. Hypnosis (loss of consciousness)
2. Analgesia (loss of pain sensation)
3. Amnesia (loss of recall)
4. Areflexia / immobility (suppression of reflexes)
5. Skeletal muscle relaxation

High-yield: No single agent provides all five components safely. Ketamine uniquely supplies hypnosis + profound analgesia; volatile agents give hypnosis + relaxation but poor analgesia; thiopentone and propofol give hypnosis with NO analgesia (may be antanalgesic).

Classification

Class	Examples	Key feature
Inhalational – volatile liquids	Halothane, Isoflurane, Desflurane, Sevoflurane, Enflurane, Methoxyflurane	Delivered via vaporiser; potency by MAC
Inhalational – gases	Nitrous oxide (N₂O), Xenon	N₂O is weak (MAC >100%), good analgesic
IV – inducing agents	Thiopentone, Propofol, Etomidate, Ketamine	Rapid onset, used for induction
IV – slower / dissociative	Ketamine, Benzodiazepines (midazolam), Dexmedetomidine	Sedation, conscious sedation

Theories & pharmacokinetics of inhalational agents

Meyer–Overton (lipid solubility) theory

High-yield: The Meyer–Overton correlation states that anaesthetic potency is directly proportional to lipid solubility (oil:gas partition coefficient). The more lipid-soluble the agent, the lower the MAC and the higher the potency.

Modern understanding: anaesthetics act on specific protein targets, chiefly enhancing inhibitory GABA_A and glycine receptors and inhibiting excitatory NMDA and neuronal nicotinic receptors. The lipid theory does not explain the "cut-off effect" or stereoselectivity, hence proteins are the true site.

MAC (Minimum Alveolar Concentration)

MAC = the alveolar concentration (at 1 atm) that prevents movement in 50% of subjects in response to a standard surgical (skin) incision.

High-yield: MAC is an index of potency — MAC ∝ 1/potency. The lower the MAC, the more potent the agent. MAC values are additive (1/2 MAC N₂O + 1/2 MAC isoflurane ≈ 1 MAC).

MAC values to memorise:

Agent	MAC (%)	Blood:gas coefficient	Comment
Methoxyflurane	0.16	12	Most potent; nephrotoxic (fluoride) — obsolete
Halothane	0.75	2.3	Hepatotoxic, sensitises to arrhythmia
Isoflurane	1.2	1.4	Coronary steal; pungent
Sevoflurane	2.0	0.65	Smooth induction; compound A
Desflurane	6.0	0.42	Fastest recovery; airway irritant
Nitrous oxide	105	0.47	Weak; excellent analgesic
Xenon	71	0.14	Ideal kinetics, expensive

High-yield: Blood:gas partition coefficient determines speed of induction/recovery. LOW solubility (low blood:gas) → FAST induction & recovery. Order of speed: Desflurane > Sevoflurane > N₂O > Isoflurane > Halothane.

Factors altering MAC

Increased MAC (need more): infants (peak at ~6 months), hyperthermia, chronic alcoholism, hypernatraemia, sympathomimetics (cocaine, amphetamine, ephedrine), red hair, MAOIs.

Decreased MAC (need less): elderly & neonates, hypothermia, pregnancy, acute alcohol intake, opioids, α₂-agonists (clonidine, dexmedetomidine), lithium, hyponatraemia, hypotension/hypoxia.

High-yield: MAC is highest in infants (~6 months) and decreases with both extremes of age thereafter. MAC is unaffected by sex, height, weight, and duration of anaesthesia.

Determinants of uptake — flow of induction

Speed of rise of alveolar (Fa) toward inspired (Fi) concentration governs induction:

↑ Inspired concentration → ↑ Alveolar ventilation → ↓ Cardiac output → ↓ Blood solubility → faster F_A/F_I rise → faster induction

• Concentration effect and second gas effect: high-volume uptake of N₂O concentrates the second (volatile) gas in the alveolus, speeding its uptake.
• Diffusion hypoxia (Fink effect): on stopping N₂O, rapid outpouring of N₂O into alveoli dilutes alveolar O₂ → hypoxia. Prevent by giving 100% O₂ for 3–5 min after discontinuing N₂O.

Individual inhalational agents

Halothane

• Halogenated alkane; potent, non-irritant — once popular for paediatric induction.
• Cardiovascular: dose-dependent myocardial depression, bradycardia, hypotension; sensitises myocardium to catecholamines → ventricular arrhythmias (avoid adrenaline).
• Halothane hepatitis: rare, immune-mediated (trifluoroacetyl-protein adducts), higher with repeat exposure in obese middle-aged women. Mortality high.
• Relaxes uterus (used in retained placenta historically) and bronchi (bronchodilator).
• Triggers malignant hyperthermia.

Isoflurane

• Currently a workhorse; pungent (not for inhalational induction).
• Maintains cardiac output; causes vasodilation. Coronary steal described (diverts flow from ischaemic to normal myocardium) — relevance debated.
• Least metabolised of older agents → safe for liver/kidney.

Desflurane

• Fastest onset and offset (lowest blood:gas, 0.42) — ideal for day-care, obese patients.
• Airway irritant — coughing, laryngospasm; not for induction.
• Requires a special heated (electrically warmed) vaporiser (boiling point 23.5°C).
• Can cause sympathetic stimulation (tachycardia, hypertension) on rapid increase.

Sevoflurane

• Agent of choice for inhalational induction, especially in children — sweet-smelling, non-irritant, rapid.
• Degraded by soda lime (CO₂ absorbent) to Compound A → theoretically nephrotoxic (avoid very low fresh gas flows).

Nitrous oxide

• Weak anaesthetic (MAC 105%) but strong analgesic and good amnesic; always used with another agent.
• "Laughing gas." Provides "second gas effect."
• Diffuses into air-filled spaces (34× more soluble than N₂): contraindicated in pneumothorax, bowel obstruction, air embolism, middle-ear/ophthalmic (intraocular gas) surgery, pneumocephalus.
• Chronic exposure inactivates methionine synthase (oxidises vitamin B₁₂) → megaloblastic anaemia, neuropathy (subacute combined degeneration).

Intravenous anaesthetics

Thiopentone (thiopental)

• Ultra-short-acting barbiturate; potentiates GABA_A (↑ duration of Cl⁻ channel opening).
• Onset within one arm–brain circulation (~10–20 s); short action due to redistribution from brain to muscle/fat, NOT metabolism.
• No analgesia (antanalgesic at low dose); ↓ cerebral blood flow, ICP and metabolism → useful in neuroprotection / raised ICP.
• Contraindicated in acute intermittent porphyria (induces ALA synthase) and status asthmaticus (laryngospasm, bronchospasm).
• Hazards: accidental intra-arterial injection → intense vasospasm, gangrene; venous thrombosis; histamine release.

Propofol

• Most widely used IV inducer; "milk of anaesthesia" — formulated in soybean oil/egg lecithin emulsion.
• Rapid, smooth induction and very rapid, clear-headed recovery → ideal for day-care surgery and TIVA (total IV anaesthesia).
• Antiemetic; ↓ BP (vasodilation + myocardial depression); pain on injection.
• No analgesia. Supports microbial growth (strict asepsis).

High-yield – Propofol infusion syndrome (PRIS): seen with high-dose (>4 mg/kg/h) prolonged (>48 h) infusion, especially in critically ill/children. Features: metabolic acidosis, rhabdomyolysis, hyperkalaemia, lipidaemia, cardiac failure/arrhythmia, acute kidney injury. Often fatal — stop infusion immediately.

Ketamine

• Phencyclidine derivative; produces "dissociative anaesthesia" — a cataleptic, eyes-open trance with intense analgesia and amnesia.
• Mechanism: non-competitive NMDA-receptor antagonist (blocks glutamate).

High-yield: Ketamine is the only IV anaesthetic that stimulates the cardiovascular system (↑ HR, BP, CO via sympathetic stimulation) and is a bronchodilator → useful in shock/hypovolaemia and asthmatics. It also raises ICP and intra-ocular pressure — avoid in head injury and open-globe injury.

• Emergence phenomena: vivid dreams, hallucinations, delirium — reduced by benzodiazepines (midazolam) and dim, quiet recovery.
• Maintains airway reflexes and respiration; increases secretions (premedicate with anticholinergic). Used in burns dressing, paediatric/field anaesthesia.

Etomidate

• Imidazole; potentiates GABA_A. Greatest cardiovascular stability → preferred for induction in haemodynamically unstable / cardiac patients.
• Low histamine release, no analgesia.
• Adverse: myoclonus, pain on injection, high incidence of postoperative nausea/vomiting, and adrenocortical suppression (inhibits 11-β-hydroxylase) — avoid infusions, caution in sepsis.

Comparison of IV agents

Agent	Mechanism	CVS effect	Analgesia	Signature toxicity
Thiopentone	GABA_A ↑	↓ BP	None	Porphyria, intra-arterial gangrene
Propofol	GABA_A ↑	↓ BP	None	Propofol infusion syndrome
Ketamine	NMDA block	↑ BP/HR	Strong	Emergence delirium, ↑ ICP/IOP
Etomidate	GABA_A ↑	Stable	None	Adrenal suppression, myoclonus

Stages of anaesthesia (Guedel's signs)

Classically described for ether (slow induction):

1. Stage I – Analgesia: from start to loss of consciousness; pain dulled.
2. Stage II – Excitement / delirium: loss of consciousness to onset of regular breathing — dangerous (struggling, vomiting, laryngospasm, irregular breathing, dilated pupils). Aim to pass through rapidly.
3. Stage III – Surgical anaesthesia: regular breathing to respiratory paralysis; divided into 4 planes by eye signs, pupils, reflexes.
4. Stage IV – Medullary paralysis: respiratory & vasomotor collapse → death if not reversed.

High-yield: Stage II is the danger phase; rapidly-acting IV inducers (thiopentone, propofol) shorten it. Eye-signs/Guedel's classification is unreliable with modern balanced anaesthesia.

Malignant hyperthermia

High-yield: Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic crisis triggered by all volatile anaesthetics + succinylcholine. Defect in the ryanodine receptor (RYR1) of skeletal muscle → uncontrolled Ca²⁺ release from sarcoplasmic reticulum.

• Earliest sign: unexplained rise in end-tidal CO₂ with masseter rigidity/muscle rigidity, then hyperthermia, tachycardia, acidosis, hyperkalaemia, rhabdomyolysis (↑CK, myoglobinuria).
• Drug of choice (treatment): Dantrolene (blocks ryanodine receptor Ca²⁺ release) — give immediately, plus stop trigger, 100% O₂, active cooling, treat hyperkalaemia and arrhythmia.

Mnemonic for MH triggers — "Some Have All Died In Surgery": Succinylcholine, Halothane, All volatiles (A for the family), Desflurane, Isoflurane, Sevoflurane.

Preanaesthetic medication

• Anticholinergics (glycopyrrolate/atropine): ↓ secretions, prevent bradycardia.
• Benzodiazepines (midazolam): anxiolysis, amnesia.
• Opioids (fentanyl, morphine): analgesia.
• Antiemetics (ondansetron), H₂ blockers/PPIs (aspiration prophylaxis).

Complications

• Respiratory: laryngospasm, bronchospasm, aspiration, diffusion hypoxia (N₂O).
• Cardiovascular: hypotension, arrhythmia (halothane + adrenaline).
• Hepatic: halothane hepatitis. Renal: fluoride (methoxyflurane, enflurane), Compound A (sevoflurane).
• PONV (postoperative nausea/vomiting) — least with propofol, more with etomidate/opioids/N₂O.
• Malignant hyperthermia, propofol infusion syndrome, emergence delirium (ketamine).
• Neurotoxicity: N₂O–B₁₂ inactivation; concern over repeated paediatric exposure.

Key differentials / "which agent" pointers

• Day-care surgery / fastest recovery → Desflurane (inhaled) or Propofol (IV).
• Paediatric gas induction → Sevoflurane.
• Shock / asthma / field → Ketamine.
• Cardiac-unstable induction → Etomidate.
• Raised ICP, neuroprotection → Thiopentone (avoid ketamine).
• Status asthmaticus, porphyria → avoid thiopentone.

Recently asked / exam angle

• MAC definition and "MAC ∝ 1/potency" — direct recall; methoxyflurane most potent (lowest MAC), N₂O weakest.
• Blood:gas coefficient and speed of induction — desflurane fastest, halothane slowest; match-the-following format.
• Ketamine — NMDA antagonist, dissociative anaesthesia, only IV agent raising BP, contraindicated in head injury (↑ICP); emergence reactions prevented by benzodiazepines.
• Malignant hyperthermia — ryanodine receptor (RYR1), triggered by volatiles + suxamethonium, dantrolene is the answer; earliest sign = ↑ EtCO₂.
• Propofol infusion syndrome — features (lactic acidosis, rhabdomyolysis, cardiac failure) and risk factors.
• Nitrous oxide — second gas effect, diffusion hypoxia (Fink), contraindicated in pneumothorax/bowel obstruction, B₁₂/methionine synthase inactivation → megaloblastic anaemia.
• Etomidate — adrenal suppression via 11-β-hydroxylase inhibition; best CVS stability.
• Meyer–Overton — potency ∝ lipid (oil:gas) solubility.
• Halothane — hepatitis, arrhythmia with adrenaline.

Rapid revision

• MAC ∝ 1/potency; lowest MAC = most potent (methoxyflurane); N₂O MAC ≈ 105%.
• Low blood:gas solubility → fast induction/recovery: Desflurane > Sevoflurane > N₂O > Isoflurane > Halothane.
• MAC is highest at ~6 months of age; unaffected by sex, height, weight, duration.
• Sevoflurane = paediatric inhalational induction (sweet, non-irritant); degraded to nephrotoxic Compound A.
• Desflurane needs a heated vaporiser; airway irritant — not for induction.
• N₂O — second gas effect, diffusion hypoxia (give 100% O₂ at end), avoid in pneumothorax/bowel obstruction; inactivates methionine synthase (B₁₂).
• Thiopentone — action terminated by redistribution, no analgesia, contraindicated in porphyria; intra-arterial injection causes gangrene.
• Propofol — antiemetic, rapid recovery, TIVA; propofol infusion syndrome with high-dose prolonged use.
• Ketamine — NMDA antagonist, dissociative anaesthesia, ↑BP/HR, bronchodilator; raises ICP/IOP; emergence delirium controlled by midazolam.
• Etomidate — most CVS stable, causes adrenal suppression (11-β-hydroxylase) and myoclonus.
• Malignant hyperthermia — RYR1 defect, volatiles + succinylcholine triggers, earliest sign ↑EtCO₂; treat with dantrolene.
• Halothane — hepatitis + sensitises myocardium to catecholamines (avoid adrenaline).