Anesthetics & Neuromuscular Blocking Agents
From MAC to sugammadex: how we put patients to sleep, numb them, and paralyze them safely
Inhaled anesthetics
Potency and MAC. The minimum alveolar concentration (MAC) is the alveolar concentration at which 50% of patients do not move in response to a surgical incision. Potency is the inverse of MAC and rises with lipid (oil:gas) solubility. Nitrous oxide has a MAC of about 104%, so it is too weak to use alone and serves as a supplement. MAC falls with age, hypothermia, pregnancy, acute intoxication, and other CNS depressants (opioids, sedatives), and rises with chronic alcohol use and hyperthermia.
Speed and the blood:gas coefficient. The blood:gas partition coefficient describes how much agent dissolves in blood. A low coefficient means little is taken up by blood, so alveolar and brain partial pressures rise quickly, giving rapid induction and rapid recovery (nitrous oxide, desflurane, sevoflurane). A highly soluble agent such as halothane is soaked up by blood, which acts as a sink, so induction and emergence are slow.
Systemic effects. Volatile agents increase cerebral blood flow through vasodilation, raising intracranial pressure, even as they lower cerebral metabolic demand. They depress myocardial contractility and lower blood pressure, depress ventilation (rising PaCO2, blunted response to hypoxia), relax bronchial and uterine smooth muscle, and reduce renal blood flow and GFR.
| Agent | Speed | Signature feature or toxicity |
|---|---|---|
| Nitrous oxide | Fast (low blood:gas) | Weak (MAC ~104%); B12 inactivation; expands closed gas spaces; diffusion hypoxia |
| Desflurane | Fast | Airway irritation; not used for mask induction |
| Sevoflurane | Fast | Sweet, nonpungent; agent of choice for mask induction in children |
| Halothane | Slow (high blood:gas) | Immune-mediated fulminant hepatitis; sensitizes heart to catecholamine arrhythmias |
| Methoxyflurane | Slow | Fluoride nephrotoxicity |
| Enflurane | Intermediate | Lowers seizure threshold |
Nitrous oxide. N2O oxidizes the cobalt of vitamin B12 and inactivates methionine synthase. Prolonged or repeated exposure, including recreational inhalation of whipped-cream chargers, causes megaloblastic anemia and subacute combined degeneration of the dorsal columns and corticospinal tracts. Because N2O is far more soluble in blood than nitrogen, it enters closed air spaces faster than nitrogen can leave, expanding a pneumothorax, obstructed bowel, the middle ear, or an intraocular gas bubble. When it is discontinued, N2O floods back into the alveoli and dilutes oxygen (diffusion hypoxia), so 100% oxygen is given at emergence.
Malignant hyperthermia
Mechanism. Malignant hyperthermia is an autosomal dominant pharmacogenetic disorder, usually from a mutation in RYR1 (the skeletal muscle ryanodine receptor), less often CACNA1S. Volatile anesthetics or succinylcholine trigger uncontrolled Ca2+ release from the sarcoplasmic reticulum, producing sustained contraction and a hypermetabolic state that burns ATP and generates CO2 and heat.
Presentation. Masseter or generalized rigidity, a rising end-tidal CO2 (often the first sign), tachycardia, hyperthermia, hyperkalemia, mixed respiratory and metabolic acidosis, and rhabdomyolysis with myoglobinuria.
- Stop the triggerDiscontinue the volatile agent; hyperventilate with 100% oxygen.
- Give dantroleneIV dantrolene blocks RYR1 Ca2+ release; repeat until signs resolve.
- SupportActive cooling; treat hyperkalemia, acidosis, arrhythmias, and myoglobinuria.
- Future anesthesiaNon-triggering technique: propofol-based IV anesthesia, nondepolarizing blockers, nitrous oxide.
Intravenous anesthetics and sedatives
Propofol. Propofol potentiates GABA-A receptors and is the standard agent for induction and sedation because recovery is fast and clear-headed, largely from redistribution of drug from brain to muscle and fat, with an antiemetic effect. It causes hypotension (vasodilation and myocardial depression), apnea, and injection pain, and its lipid vehicle can cause hypertriglyceridemia and pancreatitis. Prolonged high-dose infusion can cause propofol infusion syndrome: metabolic acidosis, rhabdomyolysis, hyperkalemia, arrhythmias, and renal failure.
Ketamine. Ketamine, a phencyclidine analog, blocks NMDA receptors and produces dissociative anesthesia with strong analgesia. It is sympathomimetic (raising heart rate, blood pressure, and cardiac output), bronchodilates, and preserves airway reflexes and respiratory drive, which suits hypotensive trauma patients and asthmatics. Drawbacks are emergence hallucinations and vivid dreams (blunted by a benzodiazepine), hypersalivation, and increased cerebral blood flow.
Etomidate. Etomidate modulates GABA-A with minimal cardiovascular or respiratory depression, so it is favored in unstable or cardiac patients. It inhibits adrenal 11β-hydroxylase, suppressing cortisol synthesis even after one dose, and causes myoclonus, nausea and vomiting, and injection pain.
Midazolam and dexmedetomidine. Midazolam, a short-acting benzodiazepine that increases GABA-A channel opening frequency, provides anxiolysis and anterograde amnesia for procedures; its respiratory depression, worse with opioids, is reversed by flumazenil, which can provoke seizures in benzodiazepine-dependent patients. Dexmedetomidine is a central α2 agonist that sedates while preserving respiratory drive, leaving patients arousable, but it causes bradycardia and hypotension.
Local anesthetics
Mechanism. Local anesthetics are weak bases. The uncharged form diffuses across the axon membrane, is reprotonated inside, and the charged form blocks voltage-gated Na+ channels from the intracellular side, binding preferentially to open and inactivated channels. In acidic, inflamed tissue such as an abscess, more drug remains charged outside the nerve and cannot enter, so larger doses are needed.
Fiber sensitivity. Small myelinated fibers (Aδ pain, B autonomic) are blocked first, then small unmyelinated C fibers (pain, temperature), then large myelinated fibers (Aβ touch and pressure, Aα motor). Pain disappears first and motor function last; recovery proceeds in reverse. Adding epinephrine vasoconstricts, slowing systemic absorption, which lengthens the block, lowers toxicity, and reduces bleeding.
| Feature | Esters | Amides |
|---|---|---|
| Examples | Procaine, chloroprocaine, tetracaine, benzocaine, cocaine | Lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine |
| Metabolism | Plasma pseudocholinesterase | Liver |
| Allergy | More common (PABA-related metabolites) | Rare |
| Notable | Benzocaine → methemoglobinemia; cocaine vasoconstricts | Bupivacaine most cardiotoxic; prilocaine → methemoglobinemia |
Systemic toxicity. Excess absorption or intravascular injection produces perioral numbness, metallic taste, and tinnitus, then seizures and CNS depression, then cardiovascular collapse. Bupivacaine is the most cardiotoxic, causing arrhythmias and refractory cardiac arrest; local anesthetic systemic toxicity is treated with IV 20% lipid emulsion plus seizure control and supportive care. Cocaine is the only local anesthetic that vasoconstricts, by blocking norepinephrine reuptake.
Benzocaine sprays and prilocaine oxidize hemoglobin iron to Fe3+: methemoglobinemia with cyanosis unresponsive to oxygen, chocolate-brown blood, and pulse oximetry stuck near 85% despite a normal PaO2. Treat with methylene blue, which is avoided in G6PD deficiency.
Neuromuscular blockers and reversal
Succinylcholine. Succinylcholine, essentially two acetylcholine molecules joined together, is a depolarizing nicotinic agonist that resists synaptic acetylcholinesterase. It causes fasciculations followed by flaccid paralysis (phase I block), which cholinesterase inhibitors potentiate rather than reverse. With prolonged exposure the receptors desensitize (phase II block), which behaves like a nondepolarizing block. It has the fastest onset and shortest duration of any blocker because plasma pseudocholinesterase hydrolyzes it, making it a classic rapid-sequence intubation drug.
Succinylcholine normally raises K+ by about 0.5 mEq/L, but after burns, crush injury, denervation (spinal cord injury, stroke), prolonged immobilization, or myopathies such as Duchenne dystrophy, extrajunctional ACh receptors spread across the muscle membrane and depolarization releases enough K+ to cause fatal arrhythmias. It also triggers malignant hyperthermia, causes bradycardia (especially in children) and myalgias, and produces hours of apnea in pseudocholinesterase deficiency.
Nondepolarizing blockers. Rocuronium, vecuronium, pancuronium, and cisatracurium competitively antagonize nicotinic receptors at the motor end plate, producing paralysis without fasciculation. Cisatracurium degrades spontaneously in plasma (Hofmann elimination), making it the choice in liver or kidney failure. Pancuronium is vagolytic and causes tachycardia, and atracurium releases histamine.
Reversal. Neostigmine inhibits acetylcholinesterase so that ACh outcompetes the blocker; glycopyrrolate is co-administered to block the muscarinic effects of the extra ACh (bradycardia, secretions) without crossing the blood-brain barrier. Sugammadex, a modified cyclodextrin, encapsulates rocuronium or vecuronium and reverses even deep blockade.
Spasmolytics
Baclofen. A GABA-B agonist acting in the spinal cord, used for spasticity from multiple sclerosis or spinal cord injury. Abrupt withdrawal, especially of intrathecal baclofen, causes seizures, hallucinations, hyperthermia, and rigidity.
Tizanidine. A central α2 agonist that reduces spasticity; it causes hypotension, sedation, dry mouth, and hepatotoxicity.
Cyclobenzaprine. Structurally related to tricyclic antidepressants and acting in the brainstem, it treats acute musculoskeletal spasm. It is anticholinergic and sedating and should not be combined with MAO inhibitors. Dantrolene, which acts directly on muscle, is another option for spasticity.