Overview and Definitions
Pharmacogenetics is the study of how genetic variation in an individual alters the response to a specific drug. Pharmacogenomics is the broader discipline examining how the entire genome influences drug responses, including multigene effects and gene-environment interactions. The foundational insight, attributed to Archibald Garrod's concept of "chemical individuality", is that inborn errors of metabolism represent extreme examples of biochemical variation that is present to a minor degree throughout the population, and that aberrant metabolism of exogenous substances can account for unusual reactions to drugs.
For the ICU trainee, pharmacogenetics is not an abstract science: it directly explains why some patients in the ICU exhibit prolonged neuromuscular blockade after succinylcholine, why others suffer a life-threatening hypermetabolic crisis after inhalational anaesthesia, why opioid dosing can be unpredictable, and why antiplatelet therapy may fail.
Types of Genetic Variation Affecting Drug Response
Genetic variation can be categorised by several characteristics:
| Characteristic | Description | Example |
|---|---|---|
| Frequency | Can range from population-wide polymorphism to single-individual rarity | CYP2D6 poor metaboliser ~7-10% of Europeans |
| Base pairs involved | Single nucleotide polymorphism (SNP), insertion/deletion, copy number variation | CYP2D6 gene duplication (ultra-rapid) |
| Location | Coding vs. non-coding region; promoter vs. exon | Promoter SNP → reduced transcription |
| Effect on protein | Absent protein, reduced function, normal function, enhanced function | Null allele, reduced-affinity enzyme |
Pharmacokinetic vs. Pharmacodynamic Variation
A key conceptual distinction:
- Pharmacokinetic variants alter absorption, distribution, metabolism, or elimination, changing the concentration of drug at the receptor. Examples: pseudocholinesterase deficiency (prolonged succinylcholine action), CYP2D6 variants (altered opioid/antiarrhythmic metabolism), N-acetyltransferase (NAT) deficiency (isoniazid toxicity).
- Pharmacodynamic variants alter the target itself, changing the drug-receptor interaction at a given concentration. Examples: malignant hyperthermia (abnormal ryanodine receptor), G6PD deficiency (haemolysis with oxidant drugs), long QT syndrome variants.
Historically, the first recognised pharmacogenetic traits were pharmacodynamic (G6PD deficiency with antimalarials, malignant hyperthermia with anaesthetics), with pharmacokinetic variants described shortly after.
Why Pharmacogenetic Allele Frequencies Are High
Unlike disease-causing mutations, pharmacogenetic variants have no selection pressure in the absence of drug exposure, the phenotype is imperceptible until the drug is administered. This explains why functionally significant variant alleles can be maintained at high population frequencies.
Key Pharmacogenetic Variants: Overview Table
| Enzyme/Gene | Variant Effect | Drugs Affected | Clinical Consequence |
|---|---|---|---|
| Pseudocholinesterase (BCHE) | Reduced activity / altered substrate affinity | Succinylcholine, mivacurium | Prolonged neuromuscular blockade |
| CYP2D6 | Poor metaboliser | Codeine, tramadol, opioids, antiarrhythmics | Toxicity (codeine) or lack of efficacy |
| CYP2D6 | Ultra-rapid metaboliser | Codeine | Opioid toxicity from rapid morphine conversion |
| CYP2C19 | Poor/rapid metaboliser | Clopidogrel, proton pump inhibitors | Antiplatelet failure or bleeding |
| TPMT | Reduced activity | Azathioprine, mercaptopurine | Severe myelosuppression |
| UGT1A1 | Reduced activity | Irinotecan | Severe diarrhoea/neutropenia |
| NAT2 | Slow acetylator | Isoniazid | Peripheral neuropathy, hepatotoxicity |
| RYR1 | Abnormal ryanodine receptor | Volatile anaesthetics, succinylcholine | Malignant hyperthermia |
| G6PD | Deficiency | Primaquine, dapsone, rasburicase | Haemolytic anaemia |
Malignant Hyperthermia (MH)
Pathophysiology
Malignant hyperthermia is a pharmacogenetic pharmacodynamic disorder, a potentially fatal hypermetabolic crisis triggered by exposure to volatile halogenated anaesthetic agents (halothane, sevoflurane, desflurane, isoflurane) and/or succinylcholine in genetically susceptible individuals.
The molecular basis involves mutations in the ryanodine receptor type 1 (RYR1) gene, located on chromosome 19q13.2. The RYR1 protein forms the calcium release channel of the sarcoplasmic reticulum in skeletal muscle. Mutations cause abnormal, uncontrolled release of calcium from the sarcoplasmic reticulum upon exposure to triggering agents.
The resulting cascade:
$$\text{Trigger agent} \rightarrow \text{RYR1 dysfunction} \rightarrow \uparrow [\text{Ca}^{2+}]_{\text{intracellular}} \rightarrow \text{Sustained muscle contraction} \rightarrow \text{Hypermetabolism}$$
- Sustained actin-myosin crossbridge cycling consumes ATP and $O_2$ at a massive rate
- Skeletal muscle glycogenolysis and oxidative phosphorylation are driven maximally
- Heat is generated in large quantities → hyperthermia (temperature can rise >1°C every 5 minutes)
- Metabolic consequences: lactic acidosis, hypercarbia, hyperkalaemia, rhabdomyolysis
Genetics
| Feature | Detail |
|---|---|
| Primary gene | RYR1 (ryanodine receptor 1) |
| Chromosome | 19q13.2 |
| Inheritance | Autosomal dominant (variable penetrance) |
| Other genes | CACNA1S (α1-subunit of L-type Ca²⁺ channel, ~1% of MH families) |
| Penetrance | Incomplete, not all carriers develop MH on every exposure |
| Epidemiology | Estimated susceptibility ~1:2,000-1:3,000 anaesthetic exposures; mortality without treatment ~70-80%, <5% with dantrolene |
The unexplained observation that younger patients are at much greater risk than older patients has raised the hypothesis that somatic (non-germline) genetic changes, somatic mosaicism, may contribute to variable expressivity, though this remains under investigation.
Clinical Features
| System | Feature |
|---|---|
| Metabolic | ↑↑ CO₂ production, metabolic + respiratory acidosis |
| Musculoskeletal | Masseter spasm (early), generalised rigidity, rhabdomyolysis |
| Temperature | Rapid rise in core temperature (late sign, hyperthermia is a late manifestation) |
| Cardiovascular | Tachycardia, dysrhythmias (due to hyperkalaemia and acidosis), hypotension |
| Biochemistry | Hyperkalaemia, raised CK (often >10,000 IU/L), myoglobinuria |
Critical point: $\uparrow \text{end-tidal } CO_2$ in an intubated patient under anaesthesia is often the earliest sign of MH. Rising temperature may be a later sign.
Treatment
| Priority | Intervention |
|---|---|
| 1. Remove trigger | Discontinue all volatile agents; change anaesthetic circuit |
| 2. Specific antidote | Dantrolene 2.5 mg/kg IV bolus, repeated every 5-10 min to max ~10 mg/kg |
| 3. Cooling | Active cooling: cold IV fluids, ice packs, body cavity lavage if necessary |
| 4. Treat hyperkalaemia | Insulin-dextrose, calcium gluconate, sodium bicarbonate |
| 5. Acidosis | Hyperventilation; sodium bicarbonate for severe acidosis |
| 6. Renal protection | IV fluid resuscitation, forced diuresis, monitor urine output for myoglobinuria |
| 7. Dysrhythmias | Avoid calcium channel blockers (interact with dantrolene); standard ACLS |
Dantrolene mechanism: Inhibits RYR1 directly, reducing calcium release from the sarcoplasmic reticulum, thereby terminating the hypermetabolic state.
Atypical Cholinesterase (Pseudocholinesterase Deficiency)
Normal Physiology
Pseudocholinesterase (plasma cholinesterase, butyrylcholinesterase; gene BCHE) is a serine esterase produced by the liver and present in plasma. It is responsible for the rapid hydrolysis of succinylcholine (and mivacurium) in the plasma, before these agents reach the neuromuscular junction in significant amounts during offset.
Normal succinylcholine duration of action: approximately 10-15 minutes (due to rapid plasma hydrolysis).
Pharmacogenetics of Pseudocholinesterase
Werner Kalow's seminal work in the 1950s demonstrated that inherited differences in pseudocholinesterase activity resulted from different affinities for substrate, implying different enzyme amino acid sequences, with family studies confirming a Mendelian (autosomal recessive) pattern of inheritance, with high, intermediate, and low enzyme activities reflecting homozygous normal, heterozygous, and homozygous atypical genotypes.
| Genotype | Dibucaine Number | Frequency | Succinylcholine Duration |
|---|---|---|---|
| Homozygous normal (E1u/E1u) | ~80 | ~96% | 10-15 min (normal) |
| Heterozygous (E1u/E1a) | ~60 | ~1:480 | Mildly prolonged (~20-30 min) |
| Homozygous atypical (E1a/E1a) | ~20 | ~1:3,200 | Markedly prolonged (2-3+ hours) |
| Silent gene (null allele) | ~0 | Rare | Very prolonged (hours) |
The dibucaine number reflects the percentage inhibition of cholinesterase activity by dibucaine (a local anaesthetic). Normal cholinesterase is ~80% inhibited; atypical enzyme is only ~20% inhibited, used diagnostically to characterise the phenotype.
$$\text{Dibucaine Number} = \% \text{ inhibition of cholinesterase activity by dibucaine}$$
Mechanism of Prolonged Block
The atypical enzyme has altered substrate affinity, reduced affinity for succinylcholine, such that plasma hydrolysis is greatly impaired. Succinylcholine persists in plasma and continues to occupy neuromuscular junction receptors.
Important clinical distinction: The block is a prolonged depolarising block (Phase I), which may convert to a Phase II (desensitisation) block if succinylcholine exposure is very prolonged. Unlike non-depolarising block, Phase I block is not reversed by neostigmine (and may be worsened). Management is supportive ventilation until block resolves spontaneously.
Acquired Causes of Low Pseudocholinesterase Activity
Reduced pseudocholinesterase activity can be acquired rather than genetic, which is particularly relevant to the ICU patient:
| Cause | Mechanism |
|---|---|
| Severe liver disease | Reduced hepatic synthesis |
| Malnutrition / cachexia | Reduced synthesis |
| Pregnancy / post-partum | Dilution and reduced synthesis |
| Organophosphate poisoning | Irreversible inhibition |
| Anticholinesterase drugs (neostigmine, pyridostigmine) | Competitive/irreversible inhibition |
| Burns | Protein loss |
| Hypothyroidism | Reduced synthesis |
| Renal failure | Reduced activity |
Other Pharmacogenetic Disorders of ICU Relevance
CYP2D6 and Opioid Metabolism
CYP2D6 metabolises codeine to morphine (the active analgesic). Poor metabolisers (~7-10% of Europeans) derive no analgesic benefit from codeine. Conversely, ultra-rapid metabolisers convert codeine to morphine at an accelerated rate, risking opioid toxicity, particularly dangerous in children and nursing mothers.
CYP2D6 poor metabolisers also exhibit accumulation of drugs such as certain antiarrhythmics, the original observation with debrisoquine and sparteine established that the same enzyme defect caused toxicity in both.
CYP2C19 and Clopidogrel
Clopidogrel is a prodrug requiring CYP2C19-mediated bioactivation to its active thiol metabolite. CYP2C19 loss-of-function alleles result in reduced platelet inhibition, antiplatelet therapy failure, with clinical significance in patients post-ACS or post-coronary stent, where inadequate platelet inhibition increases the risk of stent thrombosis.
G6PD Deficiency
G6PD deficiency is a pharmacodynamic pharmacogenetic disorder. G6PD maintains glutathione in the reduced state, protecting red cells from oxidative haemolysis. Exposure to oxidant drugs (rasburicase, used for tumour lysis syndrome in ICU; dapsone; high-dose primaquine) precipitates acute haemolytic anaemia. Rasburicase is absolutely contraindicated in G6PD deficiency.
ICU Relevance
Malignant Hyperthermia in the ICU
- Triggering agents used in ICU: Succinylcholine (for RSI), and volatile agents if ICU ventilators are equipped for inhalational sedation (e.g. AnaConDa device with isoflurane/sevoflurane for sedation)
- Safe alternatives for MH-susceptible patients: Total intravenous anaesthesia (propofol, ketamine, opioids); non-depolarising NMB agents (rocuronium, vecuronium, cisatracurium)
- Early recognition: Unexplained rising end-tidal $CO_2$, tachycardia, hyperthermia, metabolic acidosis, hyperkalaemia, should trigger consideration in any post-operative ICU admission
- Dantrolene availability: Must be stocked in all areas where triggering agents are used; dose 2.5 mg/kg IV, repeated as needed
- Post-acute care: Patients require ICU admission post-MH crisis, rhabdomyolysis, AKI (myoglobinuric), DIC, and recrudescence are recognised complications; dantrolene infusions may be continued for 24-48 hours
- Family screening: Survivors and first-degree relatives should be referred for caffeine-halothane contracture test (CHCT) or genetic testing (RYR1 mutation analysis)
Atypical Cholinesterase in the ICU
- Prolonged succinylcholine block may be recognised in any intubated patient who fails to recover neuromuscular function after RSI, train-of-four monitoring is essential
- Management: Maintain mechanical ventilation; do not administer neostigmine; ensure adequate sedation during prolonged block; monitor TOF until full recovery
- In the ICU, acquired cholinesterase deficiency (liver failure, organophosphate toxicity, burns) may prolong succinylcholine and mivacurium effect even in genetically normal individuals
- Rocuronium (reversed by sugammadex) is a preferred alternative for RSI in patients with known or suspected pseudocholinesterase deficiency
- Organophosphate poisoning presenting to ICU: severe acquired cholinesterase inhibition → prolonged effects of any ester-type drugs; management with atropine and pralidoxime
Population and Ethnicity Considerations
Pharmacogenetic variant frequencies differ across ethnic populations. Awareness is important when:
- Prescribing clopidogrel (higher frequency of CYP2C19 loss-of-function alleles in Asian populations)
- Using rasburicase (higher frequency of G6PD deficiency in African, Mediterranean, and Asian populations)
- Anticipating variable opioid responses in diverse ICU populations
Summary: Key Pharmacogenetic Concepts for CICM Exam
| Concept | Key Point |
|---|---|
| Pharmacogenetics | Genetic variation → variable drug response (PK or PD mechanism) |
| MH | RYR1 mutation → uncontrolled SR Ca²⁺ release → hypermetabolism; treat with dantrolene |
| Atypical cholinesterase | BCHE variants → reduced succinylcholine hydrolysis → prolonged block; treat supportively |
| CYP2D6 | Codeine metabolism varies: poor metabolisers lack efficacy; ultra-rapid metabolisers risk toxicity |
| CYP2C19 | Clopidogrel bioactivation: loss-of-function → antiplatelet failure |
| G6PD | Oxidant drugs → haemolysis; rasburicase contraindicated |
| High allele frequencies | No selection pressure prior to drug exposure maintains variant alleles at high frequencies |