Principles of Anesthetic Agents & Muscle Relaxants

• Anesthetic protocols typically combine multiple drug classes for balanced anesthesia
• Three main categories:
  • Inhaled (volatile) agents — maintain general anesthesia
  • Intravenous agents — induce and/or maintain anesthesia
  • Local anesthetics — provide regional or topical blockade
• Neuromuscular blockers are frequently co-administered to facilitate intubation and provide skeletal muscle relaxation
• Adjunctive medications include:
  • Benzodiazepines — preoperative anxiolysis and amnesia
  • Opioids — analgesia and anesthetic-sparing effects
  • Antiemetics — prophylaxis against postoperative nausea

• Administered via inhalation as volatile liquids or gases
• Delivered through specialized vaporizers and anesthesia circuits
• Eliminated primarily through exhalation (minimal hepatic metabolism for most agents)

Potency & MAC

• MAC (minimum alveolar concentration) — the alveolar concentration at which 50% of patients do not move in response to a surgical incision
• MAC serves as the ED₅₀ for inhaled anesthetics — a direct measure of potency
• Inverse relationship: higher lipid solubility → lower MAC → greater potency (Meyer-Overton correlation)
• MAC values are additive when multiple agents are used together
• Clinical factors that reduce MAC:
  • Advanced age (elderly patients)
  • Concurrent administration of opioids or sedative-hypnotics
  • Hypothermia
  • Pregnancy
• Factors that increase MAC:
  • Hyperthermia
  • Chronic alcohol use
  • Thyrotoxicosis

Onset & Recovery

• Blood-gas partition coefficient determines the speed of equilibration between alveolar air and blood
• Low blood solubility (low blood-gas ratio):
  • Rapid rise in alveolar partial pressure
  • Fast induction and emergence
  • Easier titration during surgery
• High blood solubility (high blood-gas ratio):
  • Slow rise in alveolar partial pressure (blood acts as a reservoir)
  • Delayed onset and prolonged recovery
  • Greater tendency for accumulation in fatty tissues

Agent-Specific Considerations

• Nitrous oxide:
  • Minimal cardiovascular depression
  • Associated with diffusional hypoxia upon emergence (washout displaces oxygen)
  • Chronic exposure linked to spontaneous abortion and bone marrow suppression
  • Contraindicated in pneumothorax, bowel obstruction, or any air-filled space
• Sevoflurane:
  • Minimal cardiovascular effects
  • Non-pungent — suitable for inhalational induction in children
  • Undergoes minor hepatic metabolism (compound A formation with CO₂ absorbents)
• Desflurane:
  • Extremely low blood solubility — fastest recovery among volatile agents
  • Pungent — not used for inhalational induction
  • Sympathetic stimulation at rapid concentration increases (tachycardia, hypertension)

• Used for induction (rapid loss of consciousness) and sometimes maintenance of general anesthesia
• Advantages: rapid onset, no environmental pollution, and ease of administration
• Disadvantages: limited titratability compared to inhaled agents; dependence on hepatic/renal clearance

Agent Details

• Midazolam:
  • Water-soluble benzodiazepine (lipophilic at physiological pH)
  • Produces sedation, anxiolysis, and anterograde amnesia
  • Depresses respiratory drive in dose-dependent fashion
  • Reversed with flumazenil (competitive antagonist at GABAₐ receptor)
• Propofol:
  • First-line agent for induction — rapid onset (~30 seconds)
  • Postoperative nausea and vomiting (PONV) prophylaxis — intrinsic antiemetic property
  • Negative inotrope and vasodilator — can cause hypotension
  • Pain on injection; risk of bacterial contamination (lipid emulsion)
• Fentanyl:
  • Synthetic opioid — 80–100× more potent than morphine
  • Used as adjunct to reduce MAC of inhaled agents
  • Minimal hemodynamic disturbance (unlike morphine which releases histamine)
  • Side effects: respiratory depression, bradycardia, chest wall rigidity (rapid bolus)
• Ketamine:
  • Noncompetitive NMDA-receptor antagonist — produces dissociative state
  • Preserves airway reflexes and spontaneous breathing
  • Sympathomimetic — increases heart rate, blood pressure, and cardiac output
  • Raises intracranial and intraocular pressure
  • Emergence phenomena: vivid dreams, hallucinations, delirium (reduced with benzodiazepine premedication)
  • Used in hemodynamically unstable patients, asthma, and procedural sedation

• Provide reversible regional or topical anesthesia by blocking voltage-gated sodium channels
• Two major chemical classes based on the linkage between the lipophilic and hydrophilic moieties:
  • Esters — metabolized by plasma and tissue esterases
  • Amides — metabolized by hepatic amide hydrolysis

Mechanism of Action

• Sequential steps:
  • Lipophilic non-ionized form diffuses across the axonal membrane
  • Inside the nerve, the drug becomes ionized (charged form) at physiological pH
  • Ionized form binds to the intracellular face of the inactivated Na⁺ channel
  • Binding stabilizes the channel in the inactivated state, slowing recovery
  • Threshold for action potential rises; propagation fails when sufficient channels are blocked
• Use-dependent blockade: fibers with higher firing rates are more sensitive (frequency-dependent block)

Nerve Fiber Sensitivity

• Order of blockade (most to least sensitive):
  • B & C fibers (small, unmyelinated or thinly myelinated) — pain and autonomic
  • Aδ fibers — fast pain, temperature
  • Aβ & Aγ — touch, pressure, motor
  • Aα — proprioception, motor
• Recovery occurs in the reverse order
• Clinical correlate: pain sensation is lost first, then temperature, touch, and finally motor function

Clinical Enhancement

• Addition of a vasoconstrictor (e.g., epinephrine, phenylephrine — α₁ agonists):
  • Reduces local absorption into systemic circulation
  • Prolongs duration of action
  • Decreases systemic toxicity
• Exception: cocaine intrinsically causes vasoconstriction by blocking norepinephrine reuptake (no epinephrine needed)

Side Effects & Toxicity

• Neurotoxicity: high concentrations or intraneural injection can cause permanent nerve damage
• Cardiovascular toxicity: bradycardia, hypotension, arrhythmias, and cardiac arrest (particularly bupivacaine — potent cardiotoxin)
• Allergic reactions:
  • Esters — more common due to PABA (para-aminobenzoic acid) metabolite formation
  • Amides — rare cross-reactivity; methylparaben preservative may trigger allergy
• Systemic toxicity (CNS):
  • Initial excitation (circumoral numbness, tinnitus, dizziness, agitation)
  • Progresses to seizures, then CNS depression, coma, and respiratory arrest

• Used during anesthesia to facilitate tracheal intubation, mechanical ventilation, and surgical exposure
• Target the nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction
• Nicotinic receptor structure: pentameric ligand-gated ion channel (5 subunits: 2α, β, δ, ε/γ)
• Two acetylcholine molecules bind to the two α-subunits → channel opens → Na⁺ influx → depolarization → muscle contraction
• Two major classes: nondepolarizing (competitive antagonists) and depolarizing (agonists that cause persistent depolarization)

Nondepolarizing (Competitive) Blockers

• Prototype: Rocuronium
• Mechanism: competitively block ACh binding at the α-subunits → prevent channel opening
• Clinical features:
  • Progressive paralysis: small muscles (face, eyes) → limbs → respiratory muscles (diaphragm last)
  • No effect on cardiac or smooth muscle (receptor subtype specificity)
  • No CNS penetration (quaternary ammonium compounds)
  • Train-of-four stimulation: fade (decreasing twitch height with successive stimuli)
• Reversal: acetylcholinesterase inhibitors (neostigmine, edrophonium) — increase ACh levels to compete at the receptor
• Specific agents:
  • Atracurium: spontaneous degradation (Hofmann elimination) — safe in hepatic/renal impairment; metabolite laudanosine can cause seizures at high doses
  • Cisatracurium: isomer of atracurium — produces less laudanosine; also Hofmann elimination
  • Vecuronium, Pancuronium: rely on hepatic/renal clearance

Depolarizing Blockers

• Specific agent: Succinylcholine (two ACh molecules linked together)
• Two phases of action:
  • Phase I (depolarization): binds to nAChR → persistent depolarization → fasciculations → flaccid paralysis (due to sodium channel inactivation)
  • Phase II (desensitization): prolonged exposure causes receptor desensitization; resembles nondepolarizing block
• Train-of-four: no fade in Phase I (equal twitch heights); fade appears in Phase II
• AChE inhibitors:
  • Worsen Phase I block (increase ACh, more depolarization)
  • May reverse Phase II block (but unpredictable)
• Metabolism: rapidly hydrolyzed by plasma pseudocholinesterase (butyrylcholinesterase) — short duration (~5–10 min)

Centrally Acting Muscle Relaxants

• Act in the central nervous system (not at the neuromuscular junction)
• Benzodiazepines — positive allosteric modulators at GABAₐ receptors
• Baclofen — GABAₐ agonist at GABA_B receptors in the spinal cord
• Clinical use: spasticity (cerebral palsy, multiple sclerosis, spinal cord injury)
• Do not produce paralysis — reduce hypertonicity and muscle spasms

• Life-threatening hypermetabolic crisis triggered by certain anesthetic agents in genetically susceptible individuals
• Associated triggers:
  • Succinylcholine (depolarizing muscle relaxant)
  • Volatile inhaled anesthetics (especially halothane, sevoflurane, desflurane)
• Genetic basis: autosomal dominant mutations in genes encoding:
  • Ryanodine receptor (RyR1) on skeletal muscle sarcoplasmic reticulum — most common
  • Dihydropyridine receptor (L-type calcium channel) — less common

Pathophysiology

• Trigger agents cause uncontrolled Ca²⁺ release from the sarcoplasmic reticulum via RyR1
• Elevated intracellular calcium leads to:
  • Sustained muscle contraction (rigidity)
  • Accelerated metabolism → heat production (hyperthermia)
  • Increased O₂ consumption and CO₂ production (respiratory and metabolic acidosis)
  • Rhabdomyolysis → hyperkalemia, myoglobinuria
  • Sympathetic activation → hypertension, tachycardia

Clinical Presentation

• Early signs:
  • Unexplained tachycardia
  • Elevated end-tidal CO₂ (despite increased minute ventilation)
  • Muscle rigidity (especially masseter spasm after succinylcholine)
• Progressive signs:
  • Rapid temperature rise (≥ 1°C per 5 minutes)
  • Mixed respiratory and metabolic acidosis
  • Hyperkalemia, cardiac arrhythmias
  • Rhabdomyolysis → dark urine (myoglobin)
  • Disseminated intravascular coagulation (DIC) in severe cases

Treatment

• Dantrolene — specific antidote:
  • Directly inhibits Ca²⁺ release from the sarcoplasmic reticulum
  • Does not act on NMJ or cardiac muscle
  • Administered as an IV bolus (2.5 mg/kg), repeated as needed up to 10 mg/kg
• Supportive measures:
  • Discontinue all trigger agents
  • Hyperventilate with 100% O₂
  • Active cooling (cold IV fluids, ice packs, lavage)
  • Correct acidosis (sodium bicarbonate)
  • Treat hyperkalemia (insulin/glucose, calcium, kayexalate)
  • Monitor for arrhythmias and DIC