ANESTHETICS - COMPREHENSIVE PHARMACOLOGY NOTES

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PART I: OVERVIEW AND PRINCIPLES OF ANESTHESIA

What Is Anesthesia?

• Preoperative drugs: anxiolysis, analgesia, prevention of side effects
• Induction agents: rapid onset IV anesthetics
• Maintenance agents: inhaled ± IV anesthetics
• Neuromuscular blockers: for intubation and surgical relaxation
• Analgesics: opioids + multimodal agents

Stages of Anesthesia (Classic Guedel's Stages)

Goals of General Anesthesia (Goodman & Gilman)

1. Minimize deleterious direct and indirect effects of anesthetic agents
2. Sustain physiologic homeostasis during surgery (blood loss, ischemia, fluid shifts, hypothermia)
3. Improve postoperative outcomes by blocking/treating the surgical stress response

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PART II: MECHANISMS OF GENERAL ANESTHESIA

Historical Perspective - Meyer-Overton Rule

Molecular Targets (Goodman & Gilman)

• Most IV anesthetics act predominantly through GABA-A receptors (GABA-gated Cl- channels)
• At clinical concentrations, general anesthetics increase sensitivity of GABA-A receptors to GABA, enhancing inhibitory neurotransmission
• They bind to specific allosteric sites on the GABA-A protein (do NOT compete with GABA at its binding site)
• Propofol and etomidate inhibit responses to noxious stimuli via specific β subunits of certain GABA-A receptors
• Agents: propofol, barbiturates, etomidate, halogenated inhalational agents, neurosteroids

• Glycine-gated Cl- channels in spinal cord and brainstem
• Inhalational anesthetics enhance glycine receptor activity → important for inhibiting responses to noxious stimuli
• Propofol, neurosteroids, and barbiturates also potentiate glycine currents
• Etomidate and ketamine do NOT potentiate glycine receptors

• Ketamine: potent NMDA receptor antagonist
• Nitrous oxide: NMDA antagonist (primary mechanism)
• Xenon: NMDA antagonist

• Two-pore K+ channels: some inhaled agents activate these, hyperpolarizing neurons
• Neuronal nicotinic ACh receptors: inhibited by subanesthetic concentrations of inhalational agents
• HCN1 channels (hyperpolarization-activated cyclic nucleotide-gated): may mediate sedative effects

Anatomic Sites of Anesthetic Action (Katzung)

1. Cerebral cortical hemispheres
2. Thalamus
3. Reticular activating system (brainstem)

• Immobility: mediated primarily by neural inhibition within the spinal cord
• Amnesia: hippocampus, amygdala, prefrontal cortex, sensory and motor cortices
• Unconsciousness: thalamo-cortical networks

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PART III: INHALED (INHALATIONAL) ANESTHETICS

Pharmacokinetic Principles - ADME

Factors Determining Rate of Induction

• Replacement of normal lung gases with inspired anesthetic mixture
• Time ∝ functional residual capacity (FRC)
• Time ∝ 1/ventilatory rate
• Independent of physical properties of the gas

• The ratio of anesthetic concentration in blood vs. gas phase at equilibrium
• Think of blood as a pharmacologically inactive reservoir
• LOW solubility (e.g., nitrous oxide, desflurane): Little dissolves in blood → equilibrium achieved rapidly → FAST induction
• HIGH solubility (e.g., isoflurane): More gas dissolves in blood → more molecules required to raise arterial partial pressure → SLOW induction

• CO is inversely correlated with induction time
• High CO (e.g., anxiety, fever): More blood flow carries drug away from alveoli → slower equilibration → slower induction
• Low CO (shock, heart failure): Faster induction (less uptake by circulation)

• Larger gradient = greater uptake = slower rise in P_alv = slower induction

• Determined by same factors in reverse
• Agents with low blood:gas coefficients (desflurane, sevoflurane) have fastest recovery
• High solubility agents (isoflurane) have prolonged recovery

Minimum Alveolar Concentration (MAC)

• Introduced by Edmond Eger (Katzung)
• Defined as: alveolar partial pressure of inhaled anesthetic at which 50% of unparalyzed patients remain immobile at surgical skin incision
• 1.0 MAC = 50% of patients immobile
• Amnesia prevented at 0.2-0.4 MAC
• MAC values are additive (e.g., 0.5 MAC sevoflurane + 0.5 MAC N2O = 1.0 MAC combined)

• Advanced age
• Hypothermia
• Opioids, benzodiazepines
• Nitrous oxide (additive)
• Pregnancy
• Alpha-2 agonists

• Young age (infants have highest MAC)
• Hyperthermia
• Chronic alcohol/drug use
• Hyperthyroidism

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Specific Inhaled Anesthetic Agents

A. VOLATILE HALOGENATED HYDROCARBONS

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1. ISOFLURANE (Forane)

• Blood:gas coefficient: ~1.4 (intermediate solubility)
• Only ~0.2% metabolized (most stable of the volatile agents)
• Slow induction and recovery vs. newer agents

• Dose-dependent CNS depression
• At 0.5 MAC: CBF decreased (CMR reduction > vasodilation)
• At 1.0 MAC: CBF unchanged
• At 1.5 MAC: CBF increased (vasodilation > CMR reduction) → may increase ICP
• Hyperventilation mitigates ICP rise

• Decreases systemic arterial blood pressure (dose-dependent)
• Causes systemic vasodilation (reduces SVR)
• Minimal cardiac depression at clinical doses
• May cause coronary steal phenomenon (theoretical concern) - vasodilation of coronary vessels may divert blood from ischemic areas
• Least cardiac depression of volatile agents

• Dose-dependent respiratory depression
• Reduces tidal volume, increases respiratory rate
• Net effect: reduced minute ventilation, increased PaCO2
• Bronchodilator (less so than sevoflurane)
• Pungent odor - airway irritant, not suitable for inhalational induction

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2. SEVOFLURANE (Ultane)

• Blood:gas coefficient: ~0.65 (low solubility → fast onset/offset)
• ~5% metabolized by hepatic CYP2E1 → hexafluoroisopropanol + inorganic fluoride
• Reacts with soda lime (CO2 absorbent) to produce Compound A (pentafluoroisopropenyl fluoromethyl ether) - potentially nephrotoxic in animals, clinical significance debated
• Desiccated CO2 absorbent reaction: exothermic, can cause airway burns or CO production

• Drug of choice for inhalational induction in adults AND children (replaced halothane) - non-pungent, rapid onset, no airway irritation (Goodman & Gilman)
• Induction concentrations: 2-4%
• Widely used for maintenance

• Concentration-dependent decrease in BP (systemic vasodilation)
• Concentration-dependent decrease in cardiac output
• Does NOT cause tachycardia → preferred in patients prone to myocardial ischemia

• Concentration-dependent reduction in tidal volume
• Increased respiratory rate (does not compensate)
• Net: reduced minute ventilation, increased PaCO2
• NOT irritating to airway
• Most potent bronchodilator of all inhalational anesthetics (Goodman & Gilman)

• Similar effects to isoflurane on CBF, CMRO2, ICP
• Can increase ICP in poor intracranial compliance; hyperventilation prevents this
• Emergence delirium in children (sevoflurane-specific concern)

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3. DESFLURANE (Suprane)

• Blood:gas coefficient: ~0.45 (LOWEST of volatile agents → fastest onset and offset)
• Minimal metabolism (<0.02%)
• Boiling point near room temperature (22.8°C) → requires a special pressurized heated vaporizer
• Very rapid emergence - ideal for outpatient surgery

• Dose-dependent decrease in BP
• At concentrations >1 MAC or with rapid concentration increases: causes sympathetic activation → tachycardia, hypertension (a unique feature vs. other volatile agents)

• Dose-dependent respiratory depression
• Pungent, airway-irritating → NOT suitable for inhalational induction (causes coughing, laryngospasm, bronchospasm)
• Used for maintenance only
• Less bronchodilation than sevoflurane

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4. NITROUS OXIDE (N2O)

• Blood:gas coefficient: ~0.47 (very low solubility → rapid induction/offset)
• Minimal metabolism; small amount reduced in GI tract by bacteria
• Cannot achieve surgical anesthesia alone (MAC = 104% in oxygen) → must be combined with other agents or used under hyperbaric conditions

• Adjunct agent: reduces MAC of volatile agents (additive effect)
• Analgesic and anxiolytic properties
• "Laughing gas" - mild euphoria
• Used at 50-70% concentration with oxygen

• Mild sympathomimetic effect (stimulates SNS) → maintains HR and BP
• May slightly increase PVR (pulmonary vascular resistance)
• Caution in pulmonary hypertension

• Minimal respiratory depression at clinical doses

• Minimal effects on CBF at clinical concentrations
• Does NOT trigger malignant hyperthermia

• Diffusion hypoxia (Fink effect): At end of N2O anesthesia, large amounts diffuse out of blood into alveoli, diluting O2. Administer 100% O2 for 5-10 min after N2O discontinuation
• Expansion of closed gas spaces: Diffuses into air-filled cavities faster than N2 exits (N2O 34x more soluble than N2). Contraindicated in: pneumothorax, bowel obstruction, middle ear surgery, pneumocephalus, vitreoretinal surgery
• Vitamin B12/methionine synthase inhibition: N2O irreversibly oxidizes cobalt center of vitamin B12 → inactivates methionine synthase → impairs folate metabolism → megaloblastic anemia with prolonged/repeated exposure
• Teratogenic potential: Prolonged exposure raises concern (avoid in pregnant patients)
• Environmental concern: Potent greenhouse gas

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Malignant Hyperthermia (MH) - Critical Complication

• Genetic mutation in RYR1 gene (ryanodine receptor type 1 in skeletal muscle SR)
• Mutant RYR1 releases massive amounts of Ca2+ from sarcoplasmic reticulum uncontrollably
• Results in: drastic increase in skeletal muscle oxidative metabolism

• Hypercapnia (earliest reliable sign)
• Muscle rigidity (masseter spasm early)
• Hyperthermia (can reach 44°C+)
• Metabolic/respiratory acidosis
• Rhabdomyolysis
• Hyperkalemia → cardiac arrhythmias

• Stop triggering agent immediately
• Administer dantrolene (specific antidote) - blocks RYR1 receptor, prevents further Ca2+ release
• Dantrolene dose: 2.5 mg/kg IV, repeat until symptoms resolve
• Active cooling
• Correct acidosis, hyperkalemia
• Maintain urine output (prevent myoglobinuric AKI)

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PART IV: INTRAVENOUS (IV) ANESTHETICS

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1. PROPOFOL (Diprivan)

• Onset: 30-60 seconds (one arm-brain circulation time)
• Duration: 5-10 min (due to rapid redistribution to muscle and fat)
• Highly lipophilic, large Vd
• Metabolism: Hepatic conjugation (glucuronide/sulfate) + extrahepatic (lung, kidney) → rapid clearance
• Context-sensitive half-life relatively short, suitable for TIVA (total IV anesthesia) and infusions

• Induction of general anesthesia
• Maintenance of anesthesia (infusion)
• Sedation in ICU (mechanically ventilated patients)
• Procedural sedation

• CNS: Dose-dependent CNS depression; decreases CMRO2 and CBF; reduces ICP → useful in neurosurgery
• Antiemetic properties (unique among anesthetics) → reduces PONV
• Cardiovascular: Significant vasodilation (reduces SVR) AND negative inotropy → marked decrease in BP; blunts baroreceptor reflex → hypotension
• Respiratory: Potent respiratory depressant; apnea common at induction doses; reduces laryngeal reflexes

• Pain on injection (ameliorated by lidocaine pretreatment or injection into large vein)
• Hypotension (most common serious effect)
• Apnea
• Propofol infusion syndrome (PRIS): Rare but potentially fatal; occurs with high doses (>5 mg/kg/h) for prolonged periods (>48h) - characterized by metabolic acidosis, rhabdomyolysis, renal failure, cardiac failure, lipemic plasma. Mechanism: impairment of mitochondrial respiratory chain
• Contains egg/soybean emulsion - caution in egg allergy (though most egg allergies are to egg white proteins, not lecithin)
• Does NOT trigger MH

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2. KETAMINE (Ketalar)

• NMDA glutamate receptor antagonist (blocks phencyclidine binding site) - PRIMARY mechanism
• Also: opioid receptor agonist, sigma receptor agonist, Na+ channel blocker, GABA potentiation

• Onset: IV ~1 min, IM ~3-5 min
• Duration: 10-15 min (IV), 15-30 min (IM)
• Routes: IV, IM, oral, intranasal, rectal
• Redistribution + hepatic metabolism (N-demethylation to norketamine - active metabolite)

• Produces a cataleptic state (dissociation between thalamocortical and limbic systems)
• Patient may appear awake (eyes open, nystagmus) but is unresponsive
• Provides analgesia, amnesia, and anesthesia simultaneously

• CNS:
  • Increases CMRO2, CBF, and ICP - generally contraindicated in raised ICP (though recent evidence is less absolute)
  • Excellent analgesia
  • Emergence phenomena: hallucinations, vivid dreams, dysphoria, delirium (more common in adults; reduced by benzodiazepine premedication)
• Cardiovascular (UNIQUE - stimulant):
  • Increases HR, BP, CO, SVR via sympathetic stimulation
  • Drug of choice in hemodynamically unstable patients (trauma, hemorrhagic shock)
  • In patients with depleted catecholamines (septic shock, end-stage heart failure): may act as direct myocardial depressant
• Respiratory:
  • Minimal respiratory depression (preserves respiratory drive)
  • Bronchodilator → useful in asthmatic patients
  • Maintains laryngeal reflexes (but not reliably - does not protect against aspiration)
  • Increased salivary and bronchial secretions (premedicate with glycopyrrolate/atropine)

• Trauma/hemodynamically unstable patients (prehospital, ER)
• Induction in asthmatic patients
• Procedural sedation (especially in children, burn patients)
• Subanesthetic doses for analgesia (perioperative pain, opioid-sparing)
• Refractory status epilepticus
• Treatment-resistant depression (esketamine - Spravato)

• Emergence phenomena (hallucinations, delirium) - reduced with benzodiazepines
• Increased secretions
• Raises ICP and CMRO2
• Nystagmus

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3. ETOMIDATE (Amidate)

• Onset: ~30-60 sec
• Duration: 3-5 min (redistribution)
• Metabolism: rapid hydrolysis by plasma esterases and hepatic esterases → inactive metabolites

• CNS: Decreases CMRO2, CBF, ICP (like propofol) - useful in neurosurgery and raised ICP
• Cardiovascular: Minimal cardiovascular depression - most cardiovascularly stable IV induction agent. Small decrease in SVR, minimal effect on HR and CO
• Respiratory: Minimal respiratory depression
• Adrenal suppression: Inhibits 11β-hydroxylase → single induction dose suppresses cortisol synthesis for 6-8 hours. Avoid for prolonged infusion (ICU sedation) due to risk of adrenal insufficiency

• Induction in cardiovascularly compromised patients (cardiac disease, hemodynamic instability)
• RSI (rapid sequence intubation) - particularly when cardiovascular stability is needed

• Myoclonus (involuntary muscle movements) on induction (~30-60% incidence)
• Adrenocortical suppression (even single dose reduces cortisol)
• Pain on injection
• High PONV incidence
• No analgesic properties
• Contraindicated as infusion for ICU sedation

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4. BARBITURATES (Thiopental, Methohexital)

• GABA-A receptor potentiation - bind to a distinct site from benzodiazepines
• At high concentrations: directly activate GABA-A channels without GABA
• Also inhibit AMPA and kainate glutamate receptors

• Ultra-short acting IV agent
• Highly lipophilic → rapid redistribution to brain (onset ~30 sec) then redistribution to muscle/fat
• Slow hepatic metabolism; prolonged infusions cause accumulation (context-sensitive half-life increases markedly)
• Causes significant cardiovascular depression (more than propofol)
• Reduces CMRO2, CBF, ICP
• Does NOT cause nausea → antiemetic

• More potent than thiopental
• Faster metabolism → shorter duration
• Still used for ECT (electroconvulsive therapy) induction
• Causes excitatory phenomena (hiccough, involuntary movements)

• CNS: Dose-dependent CNS depression; reduces ICP, CMRO2, CBF
• Cardiovascular: Myocardial depression, vasodilation → hypotension; compensatory tachycardia
• Respiratory: Dose-dependent respiratory depression; can cause apnea
• NO analgesic properties (may be anti-analgesic at subanesthetic doses)

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5. DEXMEDETOMIDINE (Precedex)

• Sedation, analgesia, anxiolysis WITHOUT significant respiratory depression (unique property)
• Activates α2 receptors in locus coeruleus (hyperpolarizes neurons) → sedation that resembles natural sleep
• Analgesia via spinal α2 receptors (decreasing substance P and norepinephrine release)
• Decreases anesthetic/opioid requirements (MAC reduction)

• ICU sedation (patients can be aroused and follow commands - "cooperative sedation")
• MAC (monitored anesthesia care) - procedural sedation
• Adjunct in general anesthesia (opioid-sparing)
• Awake fiberoptic intubation
• Pediatric sedation

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PART V: LOCAL ANESTHETICS

History (Katzung/Goodman & Gilman)

• 1884: Carl Koller demonstrates cocaine's corneal anesthesia (Heidelberg)
• Cocaine: significant CNS/cardiac toxicity + addiction potential
• Benzocaine: synthesized from benzoic acid ester - too hydrophobic for injection, restricted to topical use
• Procaine (Einhorn): first useful injectable LA - ester linked
• Tetracaine (1928): longer duration, but significant toxicity in high-volume blocks → restricted to spinal anesthesia
• Lidocaine (Löfgren, 1948): first amino-amide LA → longer duration, less toxicity than tetracaine; remains the most versatile LA
• Bupivacaine: more lipophilic, more potent, longer acting, but greater cardiac toxicity
• Levobupivacaine (S-enantiomer) and Ropivacaine (S-enantiomer): developed to reduce cardiac toxicity

Structure of Local Anesthetics

1. Lipophilic aromatic ring (benzene ring/derivative)
2. Ionizable tertiary amine (hydrophilic end)
3. Intermediate chain connecting the two via either an ester or amide linkage

• Esters: procaine, tetracaine, cocaine, chloroprocaine, benzocaine
• Amides: lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine
• Memory aid: Amides have two 'i's in their generic name (lIdocaIne, bupIvacaIne, etc.)

Mechanism of Action of Local Anesthetics

• Four homologous domains (I-IV), each with 6 transmembrane segments (S1-S6)
• S4 = voltage sensor (positively charged)
• S5-S6 + P loop = pore-forming region
• Inactivation gate = intracellular loop between domains III and IV (IFM motif)

• Located in the center of the transmembrane pore (hydrophobic inner vestibule)
• Contributions from S6 segments of domains I, III, and IV
• LAs access binding site via two pathways:
  1. Hydrophilic pathway: Ionized (charged) form travels through open channel gate from cytoplasm (use-dependent blockade)
  2. Hydrophobic pathway: Neutral (uncharged) form crosses lipid membrane to reach binding site from inside

• LAs bind preferentially to the open and inactivated states of the Na+ channel (not resting state)
• Rapidly firing neurons (high-frequency) accumulate more block than resting neurons
• This produces frequency-dependent (use-dependent) block - more active neurons are blocked preferentially
• Clinical relevance: pain fibers (high frequency) are blocked preferentially

• Most LAs are weak bases (pKa 8-9)
• At physiologic pH (~7.4): equilibrium between ionized (BH+) and free base (B) forms
• Only the uncharged (free base) form penetrates the nerve sheath and membrane
• Only the charged (ionized) form binds to Na+ channel from inside
• In infected (acidic) tissue: equilibrium shifts toward ionized form → reduced penetration → poor LA efficacy in infected tissues

• Smaller and myelinated fibers blocked before larger unmyelinated fibers
• Order of blockade: pain > temperature > touch > proprioception > motor
• Clinically: sensory block before motor block
• B fibers (preganglionic autonomic) are most sensitive
• Aδ and C fibers (pain, temperature) blocked next
• Aβ (touch, pressure) and Aα (motor) blocked last and at higher concentrations

Classification of Local Anesthetics

ESTERS

AMIDES

Addition of Epinephrine to Local Anesthetics

• Purpose: Vasoconstriction → reduces systemic absorption → prolongs duration of action + reduces systemic toxicity
• Also increases intensity (density) of block
• Contraindications to epi-containing LA:
  • Digital blocks (fingers, toes, penis) - end-arteries, risk of ischemic necrosis
  • MAVO (patients on MAO inhibitors)
  • Thyrotoxicosis/pheochromocytoma
  • IV regional anesthesia (Bier block)
  • Cocaine use (already vasoconstrictive + cardiac stimulant)

Systemic Toxicity of Local Anesthetics

• Tinnitus, perioral numbness (early warning signs)
• Dizziness, visual disturbances
• Tremors, muscle twitching
• Seizures (tonic-clonic)
• CNS depression, coma, respiratory arrest (at high levels)

• Decreased cardiac conduction velocity
• Reduced myocardial contractility
• Vasodilation → hypotension
• Cardiac arrhythmias
• Bupivacaine: unusually severe cardiac toxicity - blocks cardiac Na+ channels in both open AND inactivated states; dissociates very slowly ("fast in, slow out") → persistent cardiac arrhythmias including VF that are difficult to resuscitate
• Enhanced by: acidosis, hypercarbia, hypoxia

• Airway management, O2
• Treat seizures with benzodiazepines
• Lipid emulsion therapy (20% Intralipid): "Lipid sink" - binds free LA molecules in plasma, rapidly reverses cardiovascular toxicity. Particularly effective for bupivacaine toxicity. Dose: 1.5 mL/kg IV bolus, then infusion

Regional Anesthesia Techniques (Goodman & Gilman)

• Applied to mucous membranes, conjunctiva, or skin
• Lidocaine sprays, EMLA cream (eutectic mixture of lidocaine + prilocaine - 2.5% each)
• Benzocaine for superficial analgesia

• Injected directly into tissue
• Wide variety of agents used

• Subcutaneous injection around operative field to block incoming nerve supply
• Does not require specific nerve identification

• Injection adjacent to specific peripheral nerves or nerve plexuses
• Requires knowledge of anatomy
• Large volumes/concentrations needed vs. infiltration
• Examples: brachial plexus blocks, femoral nerve block, sciatic nerve block

• IV injection of LA into exsanguinated limb (tourniquet applied)
• Prilocaine commonly used (low systemic toxicity)
• Do NOT use bupivacaine (cardiac toxicity risk if tourniquet deflated)
• Risk of toxicity with tourniquet failure or deflation

• Injection into subarachnoid space (CSF)
• Agents: bupivacaine, tetracaine, lidocaine (controversially - transient neurological symptoms)
• Level determined by: baricity (hyperbaric/isobaric/hypobaric solutions), patient position, volume/dose
• Complications: hypotension (sympathetic block), post-dural puncture headache, urinary retention, high spinal (respiratory arrest)

• Injection into epidural space (outside dura)
• Larger volumes required vs. spinal
• Bupivacaine widely used (differential sensory > motor block)
• Epidural catheters allow continuous infusion
• Complications: hypotension, dural puncture headache (accidental), epidural hematoma/abscess, systemic toxicity

Specific Local Anesthetics - Additional Details

• Only LA with intrinsic vasoconstrictive properties (blocks norepinephrine reuptake)
• CNS stimulant → euphoria → addiction
• Topical use only in ENT (nasal surgery) - provides anesthesia AND vasoconstriction
• Highly toxic: arrhythmias, MI, seizures, stroke

• Antiarrhythmic (Class IB): blocks cardiac Na+ channels; used for ventricular arrhythmias
• Topical: EMLA, viscous lidocaine, lidocaine sprays
• IV infusion: systemic analgesia, opioid-sparing, anti-hyperalgesia

• Used only topically (insoluble in water)
• Risk of methemoglobinemia (benzocaine oxidizes iron in Hb from Fe2+ to Fe3+)
• Treat MetHb with methylene blue (1-2 mg/kg IV)

• Lidocaine 2.5% + Prilocaine 2.5%
• Eutectic mixture: melting point of combination lower than individual components → liquid formulation achievable
• Applied to intact skin 60-90 min before procedure
• Prilocaine component: risk of methemoglobinemia in infants

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PART VI: NEUROMUSCULAR BLOCKING AGENTS (NMBAs)

Classification

DEPOLARIZING NMBAs

SUCCINYLCHOLINE (Anectine, Scoline)

• Binds nicotinic ACh receptors at NMJ
• Causes persistent depolarization (not hydrolyzed by acetylcholinesterase)
• Phase I block: sustained depolarization, fasciculations, then paralysis
• Prolonged exposure → Phase II (dual) block: gradually resembles non-depolarizing block

• Onset: 60 sec (fastest onset of all NMBAs - gold standard for RSI)
• Duration: 5-10 min (ultra-short; hydrolyzed by plasma pseudocholinesterase/butyrylcholinesterase)
• Route: IV, IM

• RSI (Rapid Sequence Intubation) - preferred agent when fastest paralysis + short duration needed
• Ideal when difficult airway anticipated (reversible in minutes)

• Hyperkalemia: Succinylcholine depolarizes all muscle membranes, causing K+ efflux. Normal rise ~0.5 mEq/L. In burns, massive trauma, denervation injuries, prolonged immobility, or myopathies → upregulation of extrajunctional ACh receptors → massive K+ release → fatal hyperkalemia
• Malignant hyperthermia: triggers MH (see above)
• Masseter muscle rigidity: can occur without systemic MH; monitor
• Bradycardia: especially in children (muscarinic effect of succinylcholine at cardiac muscarinic receptors); premedicate with atropine in pediatric patients
• Increased intraocular pressure (IOP), intragastric pressure
• Myalgia: post-fasciculation muscle pain (defasciculating dose of non-depolarizing NMBA beforehand helps)
• Prolonged block in pseudocholinesterase deficiency (genetic variants - dibucaine number test)

• Burns (>24-48h post-burn)
• Massive trauma
• Crush injuries
• Denervation/upper motor neuron injuries
• Myopathies (e.g., Duchenne's muscular dystrophy - rhabdomyolysis)
• Hyperkalemia

NON-DEPOLARIZING NMBAs

SHORT-ACTING

INTERMEDIATE-ACTING

LONG-ACTING

Reversal of Non-Depolarizing NMBAs

• Increase ACh at NMJ → compete with and displace NMBA from receptor
• Also increase ACh at muscarinic receptors → bradycardia, salivation, bronchoconstriction → must be combined with atropine or glycopyrrolate
• Cannot reverse deep block reliably

• Novel reversal agent specifically for rocuronium and vecuronium
• Cyclodextrin molecule that encapsulates rocuronium/vecuronium in plasma, creating a concentration gradient that pulls drug off receptors
• Rapid, complete reversal even from deep block
• No muscarinic side effects (no need for anticholinergic)
• Dose: 2 mg/kg (moderate block), 4 mg/kg (deep block), 16 mg/kg (RSI reversal within 3 min)

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PART VII: PREOPERATIVE AND ADJUNCT DRUGS

Preoperative Medications (Lippincott)

• Benzodiazepines (midazolam): anxiolysis, amnesia, reduces anesthetic requirements
• Anticholinergics (glycopyrrolate, atropine): reduce secretions, prevent bradycardia
• Opioids: preoperative analgesia
• Antacids/H2 blockers: reduce aspiration risk
• Antiemetics (ondansetron, metoclopramide, dexamethasone): prevent PONV

Analgesia - Multimodal Approach (Katzung/Lippincott)

• NSAIDs/COX-2 inhibitors (ketorolac, celecoxib): anti-inflammatory analgesia; caution in coagulopathy, peptic ulcer disease
• Acetaminophen (IV formulation: Ofirmev): effective adjunct; caution in hepatic impairment
• Gabapentinoids (gabapentin, pregabalin): reduce opioid consumption; neuropathic pain; side effects: somnolence, dizziness
• Ketamine (subanesthetic): NMDA antagonism → opioid-sparing
• Dexmedetomidine: α2 agonist, opioid-sparing sedation-analgesia
• Regional blocks: excellent opioid-sparing

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PART VIII: COMPARATIVE SUMMARY TABLES

Inhaled Anesthetic Comparison

IV Anesthetic Comparison

Local Anesthetic Classification

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PART IX: HIGH-YIELD EXAM POINTS

1. Meyer-Overton rule (lipid solubility = anesthetic potency) has exceptions → discarded unitary theory
2. MAC = 50% of patients immobile at skin incision; amnesia at 0.2-0.4 MAC; values are additive
3. Lower blood:gas coefficient = faster onset and recovery (desflurane fastest, isoflurane slowest of modern agents)
4. High CO = slow induction; Low CO = fast (but dangerous - watch hemodynamics)
5. Sevoflurane = best for inhalational induction (non-pungent) AND best bronchodilator
6. Desflurane = fastest recovery; needs heated vaporizer; pungent → maintenance only; sympathetic activation with rapid increases
7. N2O = NMDA antagonist; cannot produce surgical anesthesia alone (MAC 104%); expands gas cavities; inhibits methionine synthase; diffusion hypoxia on emergence
8. MH: triggered by halogenated agents + succinylcholine; treat with dantrolene (RYR1 blocker)
9. Propofol: GABA-A; antiemetic; lowers ICP; PRIS with prolonged high-dose infusion; pain on injection
10. Ketamine: NMDA antagonist; stimulates CVS; increases ICP; dissociative; bronchodilator; emergence delirium (give BZD)
11. Etomidate: most cardiovascularly stable; adrenal suppression (single dose); myoclonus
12. Barbiturates: contraindicated in acute porphyria
13. Succinylcholine: fastest onset NMBA; triggers MH + hyperkalemia (avoid in burns/denervation/myopathies); pseudo-cholinesterase-dependent
14. Atracurium/Cisatracurium: safe in organ failure (Hofmann elimination); cisatracurium preferred (less histamine)
15. Rocuronium reversed by sugammadex (no muscarinic effects); alternative to succinylcholine in RSI
16. Local anesthetics: block voltage-gated Na+ channels; ionized form binds receptor; uncharged form penetrates membrane; use-dependent block
17. Esters hydrolyzed by plasma pseudocholinesterase → PABA → allergy; Amides metabolized hepatically
18. Bupivacaine cardiac toxicity: "fast in, slow out" Na+ channel kinetics; treat with 20% Intralipid
19. Prilocaine + Benzocaine → methemoglobinemia (treat with methylene blue)
20. Cocaine: only LA with vasoconstrictor property (NE reuptake inhibition)
21. Infected tissue → acidic → LA ionized → poor efficacy
22. Differential block: pain/temp blocked first (Aδ, C fibers); motor last (Aα)
23. Diffusion hypoxia on N2O discontinuation → administer 100% O2

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• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter on General Anesthetics, Local Anesthetics
• Goodman & Gilman's The Pharmacological Basis of Therapeutics - Chapter 24 (General Anesthesia), Chapter 25-26 (Local Anesthetics)
• Lippincott Illustrated Reviews: Pharmacology - Chapter 20 (Anesthetics)
• Miller's Anesthesia, 10th Edition
• Morgan and Mikhail's Clinical Anesthesiology, 7th Edition