6.7 Anesthetics
Anesthetics produce reversible loss of sensation and consciousness. General anesthetics enable surgery by causing unconsciousness, amnesia, analgesia, and muscle relaxation. Local anesthetics block peripheral nerve conduction.
General Anesthesia - Stages
Stage I - Analgesia
Patient conscious but drowsy, pain reduced
Used for minor procedures (dental work)
Stage II - Excitement/Delirium
Loss of consciousness, irregular breathing, possible agitation
Goal: pass through this stage quickly (dangerous)
Stage III - Surgical Anesthesia
Regular breathing, muscle relaxation, loss of reflexes
Target depth for surgery
Stage IV - Medullary Depression
Respiratory/cardiovascular collapse
Overdose—requires resuscitation
Inhaled General Anesthetics
Mechanism
Unclear—multiple theories: GABAA potentiation, glutamate (NMDA) inhibition, neuronal K⁺ channel activation
Lipid solubility correlates with potency (Meyer-Overton rule)
Minimum Alveolar Concentration (MAC)
Alveolar concentration preventing movement in 50% of patients to surgical stimulus
Measure of potency: Lower MAC = more potent
Additive effect: 0.5 MAC of two agents = 1.0 MAC total
Blood:Gas Partition Coefficient
Solubility in blood—determines speed of induction/recovery
Low coefficient (e.g., nitrous oxide, desflurane) → rapid onset/offset
High coefficient (e.g., halothane) → slow onset/offset
Volatile Halogenated Anesthetics
Sevoflurane
Low blood solubility → rapid induction/recovery
Pleasant smell—often used for inhalation induction in children
Minimal cardiac/respiratory depression
Desflurane
Lowest blood solubility → fastest onset/offset
Pungent—not for induction
Requires heated vaporizer
Isoflurane
Intermediate properties, widely used
Coronary vasodilation (potential "coronary steal")
Less metabolism than older agents
Halothane
Older agent, largely replaced
Hepatotoxicity (halothane hepatitis, rare but serious)
Myocardial sensitization to catecholamines → arrhythmias
Nitrous Oxide (N₂O)
Properties
Weak anesthetic (MAC = 105% at 1 atm—cannot use alone)
Very low blood solubility → extremely rapid onset/offset
Good analgesia, minimal cardiac/respiratory effects
Clinical Use
Adjunct with volatile agents (↓ MAC of primary agent)
Dental procedures, labor analgesia
Adverse Effects
Diffusion into closed air spaces → expands pneumothorax, bowel obstruction
Inactivates vitamin B₁₂ (methionine synthase inhibition)—avoid prolonged use
PONV (postoperative nausea/vomiting)
Intravenous General Anesthetics
Propofol
GABAA agonist, rapid onset (~30 sec), short duration
Induction agent, maintenance (TIVA), sedation
Antiemetic properties
Side effects: Hypotension, respiratory depression, injection pain
Propofol infusion syndrome (high dose, prolonged) → fatal
Etomidate
GABAA agonist, minimal cardiovascular effects
Preferred in hemodynamically unstable patients
Side effects: Myoclonus, adrenocortical suppression (even single dose)
PONV common
Ketamine
NMDA receptor antagonist—"dissociative anesthesia"
Unique: analgesia, sympathomimetic (↑ BP, HR), bronchodilation
Preserves airway reflexes and spontaneous breathing
Side effects: Emergence delirium, hallucinations, ↑ ICP, ↑ IOP
Also used for depression (low-dose IV infusion)
Benzodiazepines (Midazolam)
GABAA positive modulator—anxiolysis, amnesia, sedation
Premedication, procedural sedation, induction (slower than propofol)
Reversible with flumazenil
Malignant Hyperthermia
Life-Threatening Reaction
Rare genetic disorder (RYR1 or CACNA1S mutation) triggered by volatile anesthetics or succinylcholine
Pathophysiology: Uncontrolled Ca²⁺ release from sarcoplasmic reticulum → sustained muscle contraction
Symptoms: Hyperthermia (↑↑ temp), muscle rigidity (early: masseter spasm), hypercarbia, tachycardia, rhabdomyolysis (↑ CK)
Treatment: Stop triggering agent immediately, dantrolene (RyR antagonist), cooling, supportive care
Mortality ~5% with prompt treatment (was 80% before dantrolene)
Local Anesthetics
Mechanism
Block voltage-gated Na⁺ channels in axons
Bind intracellular channel pore—must cross membrane in uncharged form (weak bases)
Use-dependent block: preferentially affect active neurons
Structure
Esters: Procaine, benzocaine, tetracaine
Metabolized by plasma esterases → PABA (allergenic)
Amides: Lidocaine, bupivacaine, mepivacaine, ropivacaine
Metabolized by liver CYPs, less allergenic, longer duration
Differential Blockade
Small, myelinated fibers blocked first (pain, temperature)
Large, myelinated fibers last (motor, proprioception)
Progression: pain → temperature → touch → pressure → motor
Common Local Anesthetics
Lidocaine
Most widely used, intermediate duration (~1-2h)
Topical, infiltration, nerve blocks, epidural
Also antiarrhythmic (Class Ib—ventricular arrhythmias)
With epinephrine: ↑ duration, ↓ systemic absorption
Bupivacaine
Long-acting (3-9h), high potency
Epidural anesthesia (labor, postoperative pain)
Cardiotoxic—difficult to resuscitate from overdose
Ropivacaine
Similar to bupivacaine but less cardiotoxic
Preferentially blocks sensory over motor (lower concentrations)
Procaine
Prototype ester, short-acting
Rarely used now (replaced by amides)
Local Anesthetic Toxicity
CNS Toxicity
Progression: Perioral numbness, tinnitus, visual disturbances → seizures → CNS depression, coma
Initial excitation (inhibitory neuron blockade) → generalized depression
Cardiovascular Toxicity
↓ Contractility, vasodilation, arrhythmias (prolonged QRS, VT/VF)
Bupivacaine most cardiotoxic (high lipophilicity, tight Na⁺ channel binding)
Treatment of Systemic Toxicity
IV lipid emulsion (Intralipid): "Lipid sink" sequesters lipophilic local anesthetic
Supportive care, avoid vasopressin (worsens), consider ECMO for refractory cardiac arrest