18.1 Pharmacogenomics, Adverse Drug Events & High-Risk Drug Interactions in Emergency Care
Key Takeaways
Carriers of HLA-B*15:02 have a high risk of SJS/TEN with carbamazepine, oxcarbazepine and phenytoin or fosphenytoin, so another antiseizure drug is chosen when the result is known.
CYP2D6 ultrarapid metabolizers convert codeine and tramadol to active opioids too quickly; FDA contraindicates both drugs in children under 12 and after tonsillectomy or adenoidectomy in patients under 18.
Carbapenems lower valproate concentrations by 60 to 100% within about 24 hours, and raising the valproate dose does not overcome the interaction.
In CDC surveillance, anticoagulants, antibiotics, diabetes agents and opioids cause the largest share of ED visits for adverse drug events.
The Naranjo scale classifies causality as definite (9 or more), probable (5 to 8), possible (1 to 4) or doubtful (0 or less).
18.1 Pharmacogenomics, Adverse Drug Events & High-Risk Drug Interactions in Emergency Care
Note
Exam scope: 2025 outline subtopics 2A4 (Pharmacokinetics, Pharmacodynamics and Pharmacogenomics) and 2C6 (Adverse Drug Events and Drug Interactions). Pharmacokinetic changes in critical illness are covered in Section 1.3, and dosing during renal replacement therapy in Section 11.4.
Pharmacogenomics in the ED
Genotype results are rarely available in the ED, but more patients now have prior results in the health record, and some gene-drug pairs are severe enough to change emergency choices. The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes guidelines that translate a known genotype into a prescribing decision.
| Gene | Drugs | Consequence and action |
|---|---|---|
| HLA-B*15:02 (most common in people of East and Southeast Asian ancestry) | Carbamazepine, oxcarbazepine, phenytoin, fosphenytoin | High risk of SJS/TEN. Avoid these drugs in carriers who have not taken them safely before; FDA labeling advises screening at-risk patients before starting carbamazepine |
| HLA-A*31:01 | Carbamazepine | DRESS and other hypersensitivity reactions |
| HLA-B*58:01 | Allopurinol | SJS/TEN and DRESS; ACR suggests testing patients of Southeast Asian or African American descent before starting it |
| HLA-B*57:01 | Abacavir | Hypersensitivity reaction; testing is required before use |
| CYP2D6 | Codeine, tramadol; also ondansetron and some antidepressants | Ultrarapid metabolizers can develop fatal opioid toxicity; poor metabolizers get no analgesia |
| CYP2C19 | Clopidogrel; also voriconazole, some SSRIs and PPIs | Poor or intermediate metabolizers activate less clopidogrel; use prasugrel or ticagrelor after ACS or PCI |
| CYP2C9 and VKORC1 | Warfarin; phenytoin (CYP2C9) | Lower doses are needed for sensitive genotypes |
| G6PD deficiency | Rasburicase, pegloticase, primaquine, tafenoquine, dapsone, methylene blue | Hemolysis, and methemoglobinemia with rasburicase; contraindicated or requires caution |
| RYR1 / CACNA1S | Volatile anesthetics, succinylcholine | Malignant hyperthermia susceptibility; avoid the triggers and keep dantrolene available |
| Butyrylcholinesterase (pseudocholinesterase) deficiency | Succinylcholine, mivacurium | Paralysis lasting hours; ask about family history of prolonged paralysis |
| DPYD | Fluorouracil, capecitabine | Severe or fatal toxicity. Uridine triacetate is the antidote for overdose or early-onset severe toxicity when started within 96 hours |
| TPMT, NUDT15 | Azathioprine, mercaptopurine | Severe myelosuppression |
FDA action on codeine and tramadol (2017): both are contraindicated in children under 12 and after tonsillectomy or adenoidectomy in patients under 18, and are not recommended during breastfeeding. Ultrarapid CYP2D6 metabolism caused deaths from respiratory depression.
Adverse Drug Events (ADEs)
Definitions
- Adverse drug event: any injury resulting from medication use, whether or not an error occurred.
- Adverse drug reaction: a harmful, unintended response at normal doses.
- Medication error: a preventable event in prescribing, transcribing, dispensing, administering or monitoring that may or may not cause harm (Section 14.1).
| Type | Description | Examples |
|---|---|---|
| Type A (augmented) | Predictable from the drug's pharmacology and dose-related; most ADEs | Bleeding with anticoagulants, hypoglycemia with insulin, respiratory depression with opioids |
| Type B (bizarre) | Unpredictable, immunologic or idiosyncratic | Anaphylaxis, SJS/TEN, DRESS |
CDC's national surveillance of ED visits finds that anticoagulants, antibiotics, diabetes agents and opioids account for the largest share of ED visits for adverse drug events. In older adults, anticoagulants and diabetes agents lead the list.
Assessing Causality: The Naranjo Scale
The Naranjo algorithm scores 10 questions about timing, dechallenge, rechallenge, alternative causes, drug levels and previous reports.
| Total score | Category |
|---|---|
| 9 or more | Definite |
| 5 to 8 | Probable |
| 1 to 4 | Possible |
| 0 or less | Doubtful |
Report serious reactions to FDA MedWatch and vaccine reactions to VAERS (Section 14.1).
Severe Cutaneous Adverse Reactions
| Feature | SJS/TEN | DRESS |
|---|---|---|
| Usual onset after starting the drug | 4 to 28 days | 2 to 8 weeks |
| Skin | Painful dusky lesions, blisters, skin detachment (under 10% of the body surface in SJS, over 30% in TEN), mucosal erosions | Widespread rash, facial swelling |
| Systemic | Fever, mucosal involvement in at least two sites | Fever, eosinophilia, atypical lymphocytes, organ involvement (liver most often, also kidney, lung, heart) |
| Common culprits | Allopurinol, carbamazepine, lamotrigine (especially with fast titration or valproate), phenytoin, sulfonamides, oxicam NSAIDs, nevirapine | Antiseizure drugs, allopurinol, vancomycin, minocycline, sulfonamides |
| Management | Stop the drug immediately, burn or ICU care, eye care; prognosis by SCORTEN | Stop the drug; systemic corticosteroids for organ involvement |
Record the causative drug as an allergy, not just an intolerance, and tell the patient never to take it again.
Drug-Induced QT Prolongation
Risk rises with female sex, older age, hypokalemia, hypomagnesemia, bradycardia, structural heart disease, kidney or liver impairment and combinations of QT-prolonging drugs. Common ED examples are ondansetron, droperidol, haloperidol, methadone, azithromycin, fluoroquinolones, citalopram and quetiapine. Correct potassium and magnesium, check a baseline ECG when combining drugs in at-risk patients, and give IV magnesium for torsades de pointes (Section 2.2).
High-Risk Drug Interactions the ED Pharmacist Must Catch
| Combination | Mechanism and result | Action |
|---|---|---|
| Carbapenem + valproate | Valproate concentrations fall 60 to 100% within about 24 hours, and raising the dose does not overcome it; breakthrough seizures | Choose a non-carbapenem antibiotic or switch to another antiseizure drug |
| Linezolid or methylene blue + SSRIs, SNRIs, MAO inhibitors | MAO inhibition causes serotonin syndrome | Avoid, or monitor closely when there is no alternative (Section 17.7) |
| Trimethoprim-sulfamethoxazole + warfarin | CYP2C9 inhibition raises the INR | Choose another antibiotic or monitor the INR |
| Trimethoprim-sulfamethoxazole + ACE inhibitor, ARB or spironolactone | Trimethoprim blocks potassium excretion, causing hyperkalemia | Check potassium; avoid in older adults with CKD |
| Metronidazole or fluconazole + warfarin | CYP2C9 inhibition raises the INR | Adjust warfarin and monitor |
| Clarithromycin or erythromycin + simvastatin, colchicine, calcium channel blockers or DOACs | CYP3A4 and P-gp inhibition: rhabdomyolysis, fatal colchicine toxicity, hypotension, bleeding | Use azithromycin or doxycycline; hold the statin |
| Nirmatrelvir-ritonavir + many drugs | Strong CYP3A4 inhibition (for example amiodarone, some statins, tacrolimus, some DOACs) | Screen every prescription for interactions |
| Rifampin + DOACs, warfarin, tacrolimus, hormonal contraceptives | Strong enzyme induction causes loss of effect | Avoid the combination or monitor closely |
| PDE5 inhibitors + nitrates | Profound hypotension | No nitrate within 24 hours of sildenafil or 48 hours of tadalafil |
| Opioids + benzodiazepines | Additive respiratory depression (FDA boxed warning) | Avoid co-prescribing; prescribe naloxone |
| Lithium + NSAIDs, ACE inhibitors, ARBs or thiazides | Lower lithium clearance and toxicity | Avoid or monitor levels (Section 17.7) |
| Allopurinol + azathioprine or mercaptopurine | Xanthine oxidase inhibition causes myelosuppression | Reduce the thiopurine dose sharply or avoid |
| Clopidogrel + omeprazole or esomeprazole | CYP2C19 inhibition reduces clopidogrel activation | Use pantoprazole if a PPI is needed |
| Ceftriaxone + calcium-containing IV solutions in neonates | Fatal precipitation | Never give together in neonates up to 28 days old |
A 40-year-old woman with epilepsy who takes valproate 1,000 mg twice daily is admitted with septic shock from an ESBL-producing E. coli pyelonephritis. Meropenem is started. Two days later she has breakthrough seizures and her valproate concentration is 9 mcg/mL. What is the best recommendation?
Add a loading dose of IV valproate, then continue meropenem
Switch from meropenem to imipenem, which does not interact
Switch to another active antibiotic or bridge with another antiseizure drug
Double the valproate dose and recheck the concentration in 24 hours
A 28-year-old man of Han Chinese ancestry is in status epilepticus that continues after two doses of lorazepam. His record shows he is HLA-B*15:02 positive, and he has never taken phenytoin or carbamazepine. Which second-line drug is most appropriate?
Carbamazepine loading by nasogastric tube
Oxcarbazepine 600 mg by nasogastric tube
Levetiracetam 60 mg/kg IV (maximum 4,500 mg)
Fosphenytoin 20 mg PE/kg IV
A pharmacist is reviewing discharge prescriptions. Which order should be stopped because of an FDA contraindication tied to CYP2D6 metabolism?
Ibuprofen with acetaminophen for a 15-year-old after a wrist sprain
Hydromorphone for a 40-year-old woman after a femur fracture
Ondansetron orally disintegrating tablets for a 6-year-old with gastroenteritis
Codeine with acetaminophen for a 10-year-old after a fracture
A patient develops a rash 10 days after starting a new drug. Applying the Naranjo algorithm gives a total score of 6. How should causality be classified?
Doubtful
Possible
Definite
Probable
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