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Pharmacogenetics — CYP Polymorphisms + High-Yield Examples
TEXTPharmacology IV · 7 min read
Why two patients on the same warfarin dose end up at INR 1.5 vs 6.2. CYP2D6, CYP2C9, CYP2C19, pseudocholinesterase — the named polymorphisms that show up on the exam.
After this lesson you can
2 min read6 sections- Apply CYP2C9 + VKORC1 to warfarin dosing.
- Adjust INR target by indication.
- Manage warfarin reversal.
- Plan periop bridging.
CYP system primer
Phase I (oxidation/reduction/hydrolysis).
- CYP3A4 (~50% of drugs)
- CYP2D6
- CYP2C9
- CYP2C19
- CYP1A2
- CYP2E1
Genetic polymorphisms 4 phenotypes: poor metabolizer (PM, no functional alleles), intermediate (IM), extensive ('normal', EM), ultra-rapid (UM, multiple gene copies).
PMs accumulate parent drug; UMs may fail therapy or accumulate toxic active metabolites.
CYP2D6 — codeine + tramadol disaster
UM (1-7% of population, higher in N.
Africans/Ethiopians/Saudis): generates excess morphine fatal respiratory depression.
FDA black box on codeine + tramadol for breastfeeding mothers + post-tonsillectomy pediatrics.
PM (~7% Caucasians): no analgesia from codeine.
Tramadol same activation pathway.
Boxed warning for both.
Implication: avoid codeine + tramadol in pediatrics + breastfeeding; switch to morphine, hydromorphone, or non-opioid.
CYP2C9 + VKORC1 — warfarin
Genotype-guided dosing (e.g., warfarinDosing.org) outperforms clinical algorithms in trial settings.
CPIC guideline available.
Asian patients on average need lower warfarin doses (VKORC1 variant frequency); African-American on average higher.
CYP2C19 — clopidogrel + PPIs
FDA boxed warning.
Alternative: prasugrel, ticagrelor (not CYP2C19-dependent).
Genotyping increasingly available pre-PCI.
CYP2C19 also metabolizes PPIs (omeprazole, esomeprazole) — PMs have higher exposure + better acid suppression.
Pseudocholinesterase deficiency — succinylcholine
Atypical variant (autosomal recessive).
Heterozygote (~1:25-50): block 10-20 min vs normal 5-10 min.
Homozygote (~1:3200): block 4-8 HOURS.
Diagnosis: dibucaine number (normal >70, heterozygote 30-70, homozygote <30).
- liver disease
- pregnancy
- malnutrition
- plasmapheresis
- organophosphates
- echothiophate eye drops
Mivacurium also affected (same enzyme).
Treatment of prolonged block: sedation + ventilation until spontaneous recovery; FFP/cholinesterase concentrate not standard.
Malignant hyperthermia — RYR1 + CACNA1S
RYR1 gene encodes ryanodine receptor (Ca-release channel) in skeletal muscle SR; CACNA1S is the voltage sensor that triggers RYR1.
Triggers: succinylcholine + halogenated volatiles.
Susceptibility testing: caffeine-halothane contracture test (CHCT, gold standard, requires muscle biopsy in MH center), or genetic testing for known RYR1/CACNA1S variants.
Negative genetic test does NOT rule out (only ~50% of MH families have an identified mutation).
Family member with confirmed MH = avoid triggers, plan trigger-free anesthetic (TIVA + non-volatile machine), dantrolene available
⚠ Common pitfalls
- Standard warfarin start in CYP2C9*3 — overshooting INR + bleeding.
- Reversing INR aggressively with FFP alone — slow + volume; PCC faster.
- Bridging routinely with heparin — recent data show minimal benefit + increased bleeding.
- Forgetting that vitamin K crosses placenta + reverses fetal anticoagulation.
💎 Clinical pearls
- VKORC1 mutations affect warfarin sensitivity — pharmacogenetic dosing reduces ED visits.
- PCC (4-factor): rapid INR reversal in minutes; FFP requires hours + 2 L volume.
- Vitamin K 5-10 mg IV/PO for non-urgent reversal; bridging not always needed for low-risk surgery.
- Mechanical valves: bridging heparin still standard; many other indications no longer require.
Recap
- VKORC1 mutations affect warfarin sensitivity — pharmacogenetic dosing reduces ED visits.
- PCC (4-factor): rapid INR reversal in minutes; FFP requires hours + 2 L volume.
- Vitamin K 5-10 mg IV/PO for non-urgent reversal; bridging not always needed for low-risk surgery.
- Mechanical valves: bridging heparin still standard; many other indications no longer require.
Mark each section done to complete the module.