Drug toxicity and adverse drug reactions

Why this matters to the anaesthetist

Primary pharmacology requires a classification of ADRs, mechanisms of toxicity vs allergy, and classic anaesthetic poisons (LAST, MH, anaphylaxis, opioid OD, volatile hepatitis historical, methaemoglobinaemia). This leaf is the framework; crisis leaves hold algorithms.[1]

One-liner: Type A augmented (dose-related predictable) vs Type B bizarre (unpredictable allergy/idiosyncrasy); treat by stopping drug, supporting physiology, and using specific antidotes when they exist. [1]

Classification of adverse drug reactions

(Letter schemes vary slightly by textbook — know Type A vs B solidly.) [1]

Dose-dependent toxicity (Type A) mechanisms

1. On-target excess: same receptor/path, too much (opioid µ → apnoea).
2. Off-target: other receptors/channels at high concentration (LA → cardiac Na channels).
3. Metabolite toxicity: paracetamol NAPQI; halothane intermediates (historical).
4. Physiological cascade: histamine release (atracurium/mivacurium/morphine) causing flushing/hypotension without true allergy. [1]

Therapeutic index = TD50/ED50 concept — narrow TI drugs need monitoring (local anaesthetics, aminoglycosides, digoxin, lithium). [1]

Immunological reactions (Type B subset)

Gell–Coombs (see immunology leaf): [1]

• I: anaphylaxis (IgE) — NMBAs, antibiotics, latex, chlorhexidine.
• II: cytolytic (haemolysis, cytopenias).
• III: immune complex.
• IV: delayed rash, contact dermatitis; severe cutaneous adverse reactions. [1]

Anaphylactoid non-IgE mast-cell activation presents like anaphylaxis — same acute treatment. [1]

Idiosyncratic pharmacogenetic toxicity

• MH: RYR1/CACNA1S — volatile/sux trigger → uncontrolled SR Ca release (crisis leaf).
• Pseudocholinesterase deficiency: prolonged sux/mivacurium.
• G6PD: oxidant drug haemolysis; caution methylene blue in some contexts.
• Porphyria: barbiturates etc. induce ALA synthase — crisis risk.
• Slow acetylators / CYP variants: toxicity or failure (pharmacogenetics leaf). [1]

Local anaesthetic systemic toxicity (LAST) — physiology sketch

Excess free LA → CNS excitation then depression; cardiac Na/Ca/K channel block → arrhythmia, contractile failure. Risk↑ with: high dose, intravenous injection, high vascularity sites, low protein binding states, hypoxia/acidosis (ion trapping). [1]

Treatment pillars: stop injectate, airway/O2, benzodiazepine for seizures, lipid emulsion, ACLS with modified dosing (low adrenaline per guidelines), avoid vasopressin/Ca-channel blockers per LAST guidance. [1]

Malignant hyperthermia — mechanism sketch

Defective SR Ca release channel → sustained myoplasmic Ca → rigid hypermetabolism, CO2 surge, heat, rhabdomyolysis, hyperkalaemia. Dantrolene inhibits SR Ca release. Not an allergy. [1]

Opioid toxicity

µ-receptor: miosis, respiratory depression, coma. Reverse with naloxone (care re-narcotisation if short naloxone vs long opioid; pulmonary oedema rare). [1]

Methaemoglobinaemia

Oxidised Fe3+ Hb — cannot carry O2; left shift of remaining sites; chocolate blood; SpO2 ~85% plateau. Triggers: prilocaine, benzocaine, dapsone, nitrites. Treat methylene blue (care G6PD). [1]

Carbon monoxide / cyanide (context)

CO: content↓ + left shift; co-oximetry. Cyanide: histotoxic hypoxia (nitroprusside high dose teaching). Different mechanisms — do not conflate. [1]

Hepatotoxicity patterns

• Dose-related intrinsic: paracetamol.
• Idiosyncratic: rare immune or metabolic (halothane hepatitis classic exam story — IgG against TFA-protein adducts).
• Cholestatic vs hepatocellular LFTs. [1]

Prevention systems

• Two-person check, labelled syringes, lipid available, MH trolley, allergy history, max LA dose calculation, ETCO2 monitoring (MH early), depth/NM monitoring. [1]

Numbers / antidote board

[1] [1] [1]

Viva scripts

Classify ADRs with anaesthetic examples. [1]

LAST mechanism and lipid rationale (lipid sink / cardiometabolic theories — state sink as primary exam line). [1]

Distinguish anaphylaxis from MH. [1]

Extended viva dialogue

Examiner: Is atracurium flushing an allergy? [1]

Candidate: Often non-immunological histamine release — Type A pharmacologic effect — dose and rate related. True IgE anaphylaxis is Type B, can occur on re-exposure, and causes multi-system crisis; tryptase and allergy testing help afterwards. [1]

Examiner: Why give lipid in LAST? [1]

Candidate: Lipid emulsion creates an intravascular sink binding lipophilic local anaesthetic and may support cardiac metabolism; it is given with good ALS and seizure control, not instead of airway management. [1]

Clinical synthesis: Name the ADR type, the mechanism, and the specific antidote in that order — examiners listen for the structure. [1]

Naranjo-style causality thinking (light)

Timing, dechallenge, rechallenge, alternative causes — exam language for “was it the drug?” after events. [1]

Safe max dose concept for LA

mg/kg ceilings are starting safety rails; site vascularity, epinephrine, patient frailty, and free fraction matter more than a single number. Still state common teaching maxima then qualify. [1]

Worked SAQ

SAQ: Classify adverse drug reactions and illustrate with anaesthetic examples (8 marks)

Type A reactions are common, dose-related and predictable from pharmacology — opioid respiratory depression or propofol hypotension. Type B reactions are bizarre and host-dependent — IgE anaphylaxis to neuromuscular blockers or malignant hyperthermia. Other useful categories include chronic use effects, delayed effects, withdrawal phenomena and therapeutic failure from interactions. Management stops the drug, supports ABC, and uses specific antidotes when available (naloxone, lipid emulsion, dantrolene, adrenaline). [1]

Primary exam expansion — dense examiner pack

Full ADR classification with anaesthetic examples

Primary examiners love Type A versus Type B contrast with one example each. [1]

Anaphylaxis under anaesthesia — structured response

Triggers (frequency teaching): neuromuscular blockers, antibiotics (especially penicillins/teicoplanin patterns by region), chlorhexidine, latex, patent blue, colloids. Presentation may be pure cardiovascular collapse without rash under anaesthesia. Management skeleton: call for help, 100% oxygen, discontinue triggers, epinephrine IV per local anaphylaxis dosing, fluids, airway, start infusion if recurrent, tryptase timing (immediate, 1–2 h, baseline later), referral to allergy clinic. Differentiate from: latex-free pathway already failing, venous air, PE, MH, scombroid, non-IgE histamine release. [1]

LAST — local anaesthetic systemic toxicity

Mechanism: Na channel block in CNS then heart; lipophilicity and free fraction matter. Prodrome: tinnitus, metallic taste, circumoral numbness, agitation → seizures → coma. Cardiac: arrhythmias, conduction block, contractile failure (bupivacaine classically severe). Prevention: aspiration, incremental injection, ultrasound, dose limits, epinephrine markers, avoid injection into inflamed vascular beds. Treatment: stop injection, ABC, benzodiazepine for seizures (avoid large propofol as sole therapy in unstable patient), lipid emulsion 20% per local protocol (e.g. bolus then infusion teaching), ACLS modifications (avoid lignocaine as antiarrhythmic if LAST from amide; small epinephrine doses often taught), cardiopulmonary bypass as last resort in refractory cases. [1]

Malignant hyperthermia as Type B-ish pharmacogenetic crisis

Trigger volatiles/sux → uncontrolled SR Ca release → hypermetabolism, rising EtCO2, rigidity, hyperthermia, hyperkalaemia, rhabdomyolysis, DIC risk. Treatment: call for help, discontinue triggers, 100% O2 high flow, dantrolene, cool, treat hyperK, check ABG/CK/coags, ICU. Safe technique thereafter: trigger-free machine protocol or TIVA. [1]

Methaemoglobinaemia and CO as toxicology ADRs

Methaemoglobinaemia: oxidant LA (prilocaine, benzocaine), dapsone, nitrites — chocolate blood, SpO2 ~85% plateau, PaO2 normal, co-oximetry diagnosis, methylene blue (care in G6PD). CO: smoke, methylene chloride — content and left shift, co-oximetry, 100% O2. [1]

Opioid and sedative Type A stack

Respiratory depression is the dominant lethal Type A. Risk multiplies with: other sedatives, OSA, elderly, residual NMB, neuraxial opioid, renal failure (M6G). Monitoring: rate, depth, sedation score, SpO2 (late), EtCO2 when available. Naloxone: titrate to ventilation not full pain; observe renarcotisation (naloxone shorter than many agonists). [1]

NMB-related ADRs

Anaphylaxis; residual paralysis (PORC) → aspiration/hypoxia; sux: hyperK (burns, denervation, MH, myopathies), bradycardia, MH, prolonged block (BuChE); atracurium/mivacurium histamine; sugammadex: rare hypersensitivity, binds oral contraceptives teaching, TOF indication. [1]

Causality and documentation

Timing, dechallenge, alternative causes, tryptase, serum IgE where relevant, yellow-card/pharmacovigilance, allergy referral, medicolegal documentation of lot numbers for suspected product reactions. [1]

SAQ: classify ADRs with anaesthetic examples (8 marks)

Define ADR → Type A vs B with two examples each → expand one emergency (anaphylaxis or LAST) including immediate management → prevention strategies (dose limits, test doses, allergy history, checklists). [1]

Viva rapid fire

Q: Is atracurium flushing allergy? A: Often non-immune histamine release — Type A, rate/dose related. Q: Why lipid in LAST? A: Intravascular lipid sink for lipophilic LA plus possible metabolic cardiac support. Q: First drug in perioperative anaphylaxis? A: Epinephrine — not antihistamine first. [1]

High-yield viva battery and numbers lock-in

Emergency ADR algorithms — one-liners you must lead with

• Anaphylaxis: adrenaline first-line, not antihistamine.
• LAST: stop injection, ABC, benzos for seizures, lipid emulsion, modified ACLS.
• MH: trigger off, dantrolene, cool, treat hyperK, ICU.
• Opioid apnoea: ventilate, then titrated naloxone.
• Residual NMB: assess TOF, reverse appropriately, never extubate weak. [1]

Dose-related Type A examples bank

Propofol hypotension/apnoea; volatile myocardial depression; opioid rigidity/apnoea; local anaesthetic when excessive dose; neostigmine bradycardia/secretions; atropine tachycardia; vasopressor hypertension; residual volatile ileus/sedation. State mechanism (receptor or channel) in half a sentence each. [1]

Tryptase timing

Take samples at reaction, about 1–2 hours later, and baseline at >24 h. Elevated peak supports mast-cell activation; normal tryptase does not completely exclude anaphylaxis. Refer all suspected perioperative anaphylaxis to specialist allergy services for skin testing and future planning. [1]

Full viva dialogue (additional)

Examiner: Distinguish Type A and Type B with one anaesthetic example each. [1]

Candidate: Type A is augmented, dose-related, predictable pharmacology — for example opioid respiratory depression. Type B is bizarre/idiosyncratic, not predictable from the primary pharmacology dose–response — for example IgE-mediated anaphylaxis to a neuromuscular blocker. [1]

Examiner: Outline lipid emulsion dosing philosophy in LAST without inventing a single universal number if unsure. [1]

Candidate: I would follow the current association checklist immediately available on the machine or in the emergency folder — typically a bolus of 20 percent lipid followed by an infusion, with a ceiling dose — and simultaneously manage airway, seizures and circulation, preparing for prolonged CPR and cardiopulmonary bypass if refractory cardiac arrest. [1]

Exam traps

• Steroids/antihistamines as first drugs in anaphylaxis.
• Large propofol boluses as sole LAST therapy in collapsed patient.
• Assuming rash must be present for anaphylaxis under anaesthesia.
• Ignoring renarcotisation after single naloxone dose. [1]

References

1. [1]Dubrall D, et al. Patterns of Spontaneous Adverse Drug Reaction Reporting in Germany From 2012 to 2021 Pharmacol Res Perspect, 2026.PMID 42281142
2. [2]Guo C, et al. Malic Enzyme 1 Limits Acetaminophen-Induced Liver Injury by Sustaining Redox and Bioenergetic Homeostasis Metabolites, 2026.PMID 42346403
3. [3]Pham DT, et al. New long-acting local anesthetics: recent formulations and safety Curr Opin Anaesthesiol, 2026.PMID 42228505
4. [4]Michel MP, et al. Guidelines: Diagnosis and management of perioperative immediate hypersensitivity reactions 2025 Anaesth Crit Care Pain Med, 2026.PMID 42335666
5. [5]Jo Y, et al. Remimazolam-Induced Anaphylaxis After Spinal Anesthesia: A Case Report and Literature Review J Clin Med, 2026.PMID 42278971
6. [6]Sapkota S, et al. When Rhythm Control Backfires: A Case of Severe QT Prolongation and Polymorphic Ventricular Tachycardia Following Dual Antiarrhythmic Therapy Cureus, 2026.PMID 42255834
7. [7]McLaughlin D, et al. Sodium valproate: balancing benefits and risks especially in people of childbearing potential Aust Prescr, 2026.PMID 42312305
8. [8]Pocurull A, et al. Incidence of Drug-Induced Liver Injury in the Urban Primary Care Setting Clin Gastroenterol Hepatol, 2026.PMID 42314789