Outline genetic variability.

Explain the mechanisms and significance of pharmacogenetic disorders (eg malignant hyperpyrexia, porphyria, atypical cholinesterase and disturbance of cytochrome function).

Genetic polymorphism occurs when several functionally distinct genes exist within a population. Genetic polymorphism is:

  • Common
  • Important in determining an individuals susceptibility to adverse drug reactions
  • A goal of personalised medicine
    Aims to adjust drug therapies for interpatient variability.

Pharmacogenetic disorders


A condition where plasma cholinesterase is unable to breakdown suxamethonium, prolonging its duration of action. This disease:

  • May be congenital or acquired
    • Congenital is autosomal recessive
      Has four alleles
      • Usual
      • Atypical (dibucaine-resistant)
      • Silent (absent)
      • Fluoride-resistance
    • Acquired is due to a loss of plasma cholinesterase
      • Pregnancy
      • Organ failure
        • Hepatic
        • Renal
        • Cardiac
      • Malnutrition
      • Hyperthyroidism
      • Burns
      • Malignancy
      • Drugs
        • OCP
        • Ketamine
        • Lignocaine and ester local anaesthetics
        • Metoclopramide
        • Lithium
  • Has been traditionally measured using the dibucaine number
    Dibucaine is:
    • An amide local anaesthetic which inhibits plasma cholinesterase
      Different forms are inhibited to different extents, with greater inhibition indicating a less severe mutation.
      • Percentage inhibition correlates with different genotypes, e.g.:
        • Normal (Eu:Eu) has a dibucaine number of 80 (80% inhibited)
        • Dibucaine resistant (Ea:Ea) has a dibucaine number of 20 (20% inhibited)
      • Note that acquired disease will have a normal dibucaine number, as the enzyme itself is working correctly, however does not exist in a large enough quantity to metabolise suxamethonium rapidly


A common x-linked recessive condition that may cause haemolysis following administration of oxidative drugs. These include:

  • Aspirin
  • Sulfonamides
  • Some antibiotics

Malignant Hyperthermia

Autosomal dominant deficiency in the skeletal muscle ryanodine receptor gene resulting in a defect of intracellular calcium regulation. This mutation:

  • Causes massive calcium release from sarcoplasmic reticulum in the presence of volatile anaesthetic agents (and potentially suxamethonium)
    Leads to:
    • Increased muscle activity
    • Rapid increase in body temperature and lactic acidosis
    • High mortality from hyperthermia, hyperkalaemia/rhabdomyolysis, leading to ventricular arrhythmia and cardiac arrest
  • Mutation present in 1:5,000 - 1:50,000
  • Presents with:
    • Initially:
      • Tachycardia
      • Masseter spasm
      • Hypercapnea
      • Arrhythmia
    • Intermediate:
      • Hyperthermia
      • Sweating
      • Combined metabolic and respiratory acidosis
      • Hyperkalaemia
      • Muscle rigidity
    • Late:
      • Rhabdomyolysis
        • Myoglobinuria
        • Elevated CK
      • Coagulopathy
      • Cardiac arrest
  • Management consists of:
    • Cease administration of volatile
      • Start TIVA
    • Give dantrolene
      • increments up to
      • 20mg vials reconstituted with 60ml sterile water
        • 3g mannitol as additive
        • Highly alkaline
          Damaging if extravasation occurs.
    • Treat complications:
      • Hyperkalaemia
      • Hyperthermia
      • Acidosis
      • Arrhythmias
      • Renal failure


Autosomal dominant deficiency in the first step of haeme synthesis. These mutations:

  • Result in a partial deficiency of enzymes
  • Lead to accumulation of porphyrin precursors
  • May be precipitated by many drugs:
    • Ketamine
    • Clonidine
    • Ketorolac
    • Diclofenac
    • Phenytoin
    • Erythromycin
    • Barbiturates


  1. Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale's Pharmacology. Sixth Edition. Churchill Livingstone.
  2. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
  3. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
Last updated 2019-07-18

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