---

Anaesthetic Pharmacology - Detailed Notes

Sources: Katzung's Basic and Clinical Pharmacology (16th Ed.) & Lippincott Illustrated Reviews: Pharmacology

---

PART 1: OVERVIEW AND DEFINITIONS

Levels of Sedation/Anaesthesia (Lippincott, p.665)

Three Stages of General Anaesthesia (Lippincott, p.666)

1. Induction - from administration of anaesthetic to onset of unconsciousness
2. Maintenance - sustained period of anaesthesia
3. Emergence (Recovery) - from discontinuation of anaesthetic to return of consciousness and protective reflexes

---

PART 2: MECHANISM OF GENERAL ANAESTHETIC ACTION

Molecular Targets

• GABA-A receptors (chloride channel) - primary target
• Glycine receptors
• K₂ₚ, Kv1, KATP potassium channels

• Nicotinic and muscarinic ACh receptors
• Glutamate receptors: AMPA, kainate, NMDA
• Serotonin: 5-HT₂ and 5-HT₃ receptors

Components of Anaesthesia (Katzung, p.693)

1. Immobility - mediated primarily by spinal cord inhibition; quantified by MAC
2. Amnesia - involves hippocampus, amygdala, prefrontal cortex; occurs at very low MAC (0.2-0.4 MAC)
3. Unconsciousness - requires disruption of thalamocortical loops and the reticular activating system

---

PART 3: INHALED ANAESTHETICS

Classification

• Gaseous anaesthetics: Nitrous oxide (N₂O), Xenon - gas at room temperature (high vapour pressure, low boiling point)
• Volatile anaesthetics: Halothane, Isoflurane, Enflurane, Desflurane, Sevoflurane - liquids at room temperature, require precision vaporisers

Minimum Alveolar Concentration (MAC)

• MAC = the end-tidal (alveolar) concentration of inhaled anaesthetic that eliminates movement in 50% of patients exposed to a noxious stimulus (skin incision)
• MAC = ED₅₀ expressed as % of gas in mixture
• Inverse of MAC = index of potency (high MAC = low potency)
• MAC values (approximate): Nitrous oxide ~104%, Desflurane ~6%, Isoflurane ~1.2%, Sevoflurane ~2%

• Hyperthermia
• Drugs that increase CNS catecholamines
• Chronic ethanol abuse

• Increased age
• Hypothermia
• Pregnancy
• Sepsis
• Acute intoxication
• Concurrent IV anaesthetics
• α₂-adrenergic agonists (clonidine, dexmedetomidine)

Pharmacokinetics: Uptake and Distribution

1. Alveolar wash-in: Time proportional to functional residual capacity (FRC); inversely proportional to ventilation rate. Independent of gas properties.
2. Uptake (removal to peripheral tissues): Product of:
   • Solubility of gas in blood (blood:gas partition coefficient)
   • Cardiac output
   • Alveolar-venous partial pressure gradient
3. Blood:gas partition coefficient (B:G):
   • LOW B:G = less soluble in blood = less uptake from alveoli = faster equilibration = faster induction and emergence
   • HIGH B:G = more soluble = slower induction

Individual Inhaled Agents

Isoflurane

• Intermediate B:G (~1.4); irritant odour, not suitable for inhalation induction in children
• Potent bronchodilator; decreases SVR more than cardiac output
• Causes dose-dependent respiratory depression and cerebral vasodilation (increases ICP)
• Undergoes minimal hepatic metabolism (~0.2%)
• Used for maintenance

Desflurane

• Very low B:G (~0.42) - fastest emergence
• Requires heated vaporiser (boiling point near room temperature)
• Pungent, very airway-irritating - cannot be used for inhalation induction
• Similar cardiovascular profile to isoflurane
• Causes dose-dependent heart rate increase
• Only ~0.02% metabolised

Sevoflurane

• Low B:G (~0.65) - fast induction and emergence
• Non-pungent - ideal for inhalation induction, especially in children (Lippincott, p.666)
• Smooth bronchodilation; less cardiovascular depression than halothane
• Undergoes ~3-5% hepatic metabolism - produces Compound A (nephrotoxic in rats; low flow anaesthesia with sevoflurane is used cautiously)
• Drug of choice for paediatric inhalation induction

Halothane

• High B:G (~2.4) - slow induction and emergence
• Halothane hepatitis: idiosyncratic immune-mediated hepatotoxicity; rare but potentially fatal. Due to oxidative metabolism (20-30%) producing reactive trifluoroacetyl metabolites
• Sensitises myocardium to catecholamines - risk of arrhythmias
• More profound cardiovascular depression than isoflurane
• No longer commonly used in developed countries

Nitrous Oxide (N₂O)

• "Laughing gas" - potent sedative but cannot alone produce general anaesthesia (MAC ~104%; cannot reach MAC at safe oxygen concentrations)
• Used at 30-50% concentration for moderate sedation (dentistry) or combined with volatile agents to reduce their required concentration
• Does not depress respiration; maintains cardiovascular hemodynamics and muscle strength
• Poorly soluble (low B:G ~0.47) - moves very rapidly in and out of body
• Hazard in closed body compartments: Diffuses into air-filled spaces faster than nitrogen leaves, increasing volume (pneumothorax, bowel distension, middle ear, sinuses)
• Diffusion hypoxia on emergence - overcome by delivering high inspired oxygen
• Inhibits methionine synthase - avoid in patients with B₁₂ deficiency or long procedures

Organ System Effects of Inhaled Anaesthetics

Malignant Hyperthermia (MH)

• Trigger agents: Halogenated hydrocarbon anaesthetics + succinylcholine
• Mechanism: Autosomal dominant mutation (most common: RYR1 - ryanodine receptor 1, skeletal muscle Ca²⁺ release channel) → uncontrolled Ca²⁺ release → skeletal muscle hypermetabolism
• Features: High fever, muscle rigidity, metabolic acidosis, hyperkalaemia, rhabdomyolysis, circulatory collapse
• Treatment: Dantrolene (blocks SR Ca²⁺ release) + withdraw triggering agents + aggressive cooling + support respiratory, circulatory, renal function

---

PART 4: INTRAVENOUS ANAESTHETICS

Propofol

• Mechanism: Enhances GABA-A mediated Cl⁻ conductance
• Chemistry: 2,6-diisopropylphenol; prepared as lipid emulsion (white, egg lecithin/soyabean oil); contains no preservative → aseptic technique essential
• Pharmacokinetics: Onset 30-40 sec; initial redistribution t½ ~2-4 min; extensive hepatic metabolism; context-sensitive half-time increases with prolonged infusion
• NOT significantly altered by moderate hepatic or renal failure

• Significant decrease in BP (systemic vasodilation + mild myocardial depression)
• Does NOT sensitise heart to catecholamines
• Reduces intracranial pressure (decreased CBF and cerebral O₂ consumption)

• Potent respiratory depressant - produces apnoea at induction doses
• Reduces tidal volume more than respiratory rate
• Blunts hypoxic and hypercapnic ventilatory responses
• Reduces upper airway reflexes more than thiopental - well suited for LMA placement

• Antiemetic properties - very low PONV
• Pain on injection (common; reduced by pre-injection lidocaine, larger veins, opioid premedication)
• Excitatory phenomena (twitching, yawning, hiccups) occasionally
• Does not provide analgesia

• Induction: 1-2.5 mg/kg IV (children need higher: 2.5-3.5 mg/kg)
• Maintenance: 100-200 mcg/kg/min infusion
• Sedation (ICU/procedures): 25-75 mcg/kg/min
• Anti-emetic: 10-20 mg IV bolus

• Rare, potentially fatal
• After prolonged high-dose infusion (especially in ICU)
• Features: metabolic acidosis, arrhythmias, rhabdomyolysis, cardiac failure

Ketamine

• Mechanism: NMDA receptor antagonist (glutamate antagonist)
• Unique: Produces dissociative anaesthesia (eyes open, nystagmus, preserved airway reflexes, but profound analgesia and amnesia)
• Cardiovascular: STIMULATES CVS - increases HR, BP, CO (due to sympathomimetic - increased catecholamine release); useful in haemodynamically compromised patients
• Bronchodilation: Increases airway secretions (give with antisialagogue e.g. atropine/glycopyrrolate); useful in asthmatic patients
• CNS: Increases CBF and ICP - avoid in raised ICP
• Emergence reactions: Hallucinations, vivid dreams, dysphoria (reduced by premedication with benzodiazepine)
• Analgesia: Excellent - useful for procedural analgesia, burn dressings
• Dose: 1-2 mg/kg IV for induction; 4-6 mg/kg IM

Thiopental (Thiopentone)

• Mechanism: Barbiturate; potentiates GABA-A (increases channel open duration at higher doses)
• Ultra-short acting due to high lipid solubility and rapid redistribution from brain to muscle then fat
• Potent anaesthetic; weak analgesic
• Onset: <1 min; duration brief due to redistribution (NOT rapid metabolism - only ~15%/hr hepatic metabolism)
• Decreases BP (reflex tachycardia), decreases ICP (decreases CBF and CMR)
• No longer available in many countries including USA
• Contraindicated in porphyria

Methohexital

• Barbiturate; still used for electroconvulsive therapy (ECT)
• Unlike other barbiturates, it lowers seizure threshold (pro-convulsant) - makes it useful for ECT

Etomidate

• Mechanism: GABA-A potentiation
• Cardiovascular stability - minimal cardiovascular depression; drug of choice for induction in haemodynamically unstable patients
• Causes adrenocortical suppression (inhibits 11-β-hydroxylase) - single dose transiently suppresses cortisol; avoid prolonged infusion
• Myoclonic movements common
• High incidence of nausea/vomiting
• Pain on injection
• Does NOT provide analgesia

Benzodiazepines (Midazolam, Diazepam, Lorazepam)

• Mechanism: Enhance GABA-A (increase Cl⁻ channel opening frequency)
• Used as premedication (anxiolysis, sedation, amnesia) and adjuncts
• Midazolam - most commonly used; water-soluble at pH <4 (becomes lipophilic at physiological pH); CYP3A4 substrate (beware interactions with clarithromycin, erythromycin)
• Minimal cardiovascular depression
• Potential respiratory depressants, especially IV
• Reversal: Flumazenil (competitive antagonist at GABA-A benzodiazepine site)

Dexmedetomidine

• Mechanism: Highly selective α₂-adrenergic receptor agonist
• Produces sedation WITHOUT respiratory depression
• Decreases MAC of volatile anaesthetics
• Used for ICU sedation, procedural sedation, adjunct in regional anaesthesia
• Cardiovascular: bradycardia, hypotension

Opioids as Anaesthetic Adjuncts

• Used for analgesia during balanced anaesthesia (inhaled agents alter consciousness but not pain)
• Common: fentanyl, remifentanil, alfentanil, morphine
• Reduce MAC of volatile agents
• Risk: respiratory depression, chest wall rigidity (high-dose fentanyl), PONV

---

PART 5: LOCAL ANAESTHETICS

Mechanism of Action

• Local anaesthetics bind preferentially to the inactivated state of the Na⁺ channel
• Rapidly firing fibres (nociceptive) are more susceptible
• Membrane hyperpolarisation (alkalosis) reduces LA effect; depolarisation (acidosis, as in infected tissue) enhances it - but also protonates the drug so less crosses into the cell

• Also affect K⁺, Ca²⁺ channels; NMDA, G-protein coupled, 5-HT₃, neurokinin-1 receptors
• Antithrombotic effects; modulate inflammation
• Blunting of surgical stress response

Chemical Structure

• Procaine, cocaine, chloroprocaine, tetracaine, benzocaine
• Produce PABA metabolite - allergenic

• Lidocaine, bupivacaine, ropivacaine, mepivacaine, levobupivacaine, prilocaine
• True allergic reactions very rare
• More stable, longer shelf-life

Key Pharmacological Properties

Differential Nerve Block (Order of Blockade)

Individual Local Anaesthetics

Vasoconstrictors

• Delays systemic absorption → prolongs duration, reduces toxicity
• Provides haemostasis
• Avoid in: end-arteries (digits, penis, nose, ear, tongue), IV regional with certain agents, Raynaud's

Local Anaesthetic Toxicity

• Initial: circumoral numbness, tinnitus, metallic taste, restlessness, confusion
• Progressive: muscle twitching, seizures
• Severe: CNS depression, coma, respiratory arrest

• Arrhythmias, bradycardia, hypotension, cardiac arrest
• Bupivacaine most cardiotoxic (binds Na⁺ channels with very high affinity; slow dissociation)

• Airway management, seizure control (benzodiazepines)
• Intralipid (20% lipid emulsion) IV - "lipid sink" mechanism traps the lipophilic LA molecule from cardiac tissue
• Cardiovascular resuscitation (avoid vasopressin; prefer epinephrine in small doses)
• Avoid propofol as substitute for intralipid (lipid content too low)

Techniques of Administration

---

PART 6: NEUROMUSCULAR BLOCKING AGENTS

Depolarising Blockers

• Mechanism: Acts as persistent ACh agonist → sustained depolarisation → desensitisation block
• Fastest onset (45-60 sec) and shortest duration (~10 min) - drug of choice for rapid sequence induction (RSI)
• Metabolised by plasma cholinesterase (pseudocholinesterase)
• Adverse effects:
  • Malignant hyperthermia (trigger)
  • Hyperkalaemia (dangerous in: burns, crush injuries, denervation, immobilisation, upper motor neuron lesions)
  • Bradycardia (especially with repeat doses)
  • Increased IOP, ICP, intragastric pressure
  • Muscle fasciculations → postoperative myalgia
  • Prolonged block in pseudocholinesterase deficiency

Non-Depolarising Blockers

• Selective relaxant-binding agent (modified γ-cyclodextrin)
• Encapsulates rocuronium or vecuronium in 1:1 ratio → water-soluble complex
• Provides rapid reversal of profound neuromuscular blockade (neostigmine cannot achieve this)
• Excreted renally

---

PART 7: ANAESTHETIC ADJUNCTS

Anticholinergics (Premedication)

• Atropine, glycopyrrolate - reduce oral/airway secretions, prevent bradycardia
• Glycopyrrolate does NOT cross BBB - preferred

Alpha-2 Agonists

• Dexmedetomidine, clonidine - decrease MAC, provide sedation without respiratory depression

Anti-emetics

• Ondansetron (5-HT₃ antagonist)
• Dexamethasone
• Propofol (inherent antiemetic)

Reversal Agents

---

PART 8: TOXICITY SUMMARY

---

KEY MNEMONICS AND CLINICAL PEARLS

• Amide LAs have the letter "i" twice: lIdocaIne, bupIvacaIne, ropIvacaIne, mepIvacaIne
• Low blood:gas coefficient = fast: "Desflurane and Sevoflurane are fast; Halothane is slow"
• MH treatment = DANTROLENE (block the ryanodine receptor)
• Ketamine is the only IV agent that stimulates CVS and provides true analgesia
• Etomidate = haemodynamic stability + adrenal suppression
• Sugammadex = only way to reverse profound rocuronium block immediately
• RSI = succinylcholine (or high-dose rocuronium) + cricoid pressure for full stomach/risk of aspiration
• Bupivacaine cardiotoxicity: lipid emulsion (Intralipid 20%) is the antidote
• Differential block order: Autonomic (C, B fibres) > Pain/temp (Aδ, C) > Touch > Motor (Aα) - last to go, first to return

---