10.5 Drug Interactions, Adverse Effects, Pharmacogenomics & Toxicology
Key Takeaways
Drug interactions are pharmacokinetic (absorption, CYP450 or P-glycoprotein metabolism, protein binding, renal excretion) or pharmacodynamic (additive, synergistic, potentiating or antagonistic effects at the target).
Grapefruit juice inhibits intestinal CYP3A4, St. John's wort induces CYP3A4 and P-glycoprotein, tyramine-rich foods cause hypertensive crisis with MAO inhibitors, and calcium or iron chelate tetracyclines and fluoroquinolones.
Pharmacogenomic red flags include CYP2D6 ultrarapid codeine metabolism, CYP2C19 loss-of-function with clopidogrel, TPMT or NUDT15 variants with thiopurines, HLA-B15:02 with carbamazepine, HLA-B58:01 with allopurinol and G6PD deficiency with oxidant drugs.
Since 2015, FDA prescription labeling describes pregnancy and lactation risk in narrative sections instead of the former A, B, C, D and X letter categories; classic teratogens include warfarin, isotretinoin, valproate, ACE inhibitors, methotrexate and thalidomide.
Key antidotes include N-acetylcysteine for acetaminophen, naloxone for opioids, fomepizole for methanol and ethylene glycol, hydroxocobalamin for cyanide, digoxin immune Fab for digoxin, glucagon for beta-blockers and sodium bicarbonate for tricyclic cardiotoxicity.
10.5 Drug Interactions, Adverse Effects, Pharmacogenomics & Toxicology
The pharmacology outline lists drug interactions (potentiation, neutralization, genetic factors, drug-drug, supplements and food), adverse effects (allergies, toxicity, specific side effects and teratogenic effects), pharmacogenomics, drug resistance and toxicology. Podiatric patients are often older and take many drugs, so these interactions decide whether a routine antifungal, antibiotic or analgesic is safe.
Classifying Drug Interactions
| Type | Definition | Example |
|---|---|---|
| Additive | Combined effect equals the sum of the separate effects | Two CNS depressants (opioid plus benzodiazepine) |
| Synergism | Combined effect exceeds the sum | Beta-lactam plus aminoglycoside against enterococci |
| Potentiation | A drug with little effect of its own enhances another | Clavulanate protects amoxicillin from beta-lactamase; probenecid raises penicillin levels |
| Chemical antagonism (neutralization) | Drugs bind each other directly | Protamine neutralizes heparin; chelators bind metals |
| Pharmacologic antagonism | Competition at the same receptor | Naloxone displaces opioids |
| Physiologic antagonism | Opposing effects through different receptors | Epinephrine reverses histamine-induced bronchospasm |
Pharmacokinetic Interactions
- Absorption: calcium, magnesium, aluminum and iron chelate tetracyclines and fluoroquinolones; sucralfate binds fluoroquinolones; itraconazole capsules need gastric acid, so acid suppression lowers absorption.
- Distribution: displacement from albumin (sulfonamides displacing warfarin) transiently raises the free drug fraction; it matters most when clearance is also reduced.
- Metabolism: CYP450 inducers (rifampin, carbamazepine, phenytoin, St. John's wort) cause therapeutic failure; inhibitors (azoles, clarithromycin, ritonavir, grapefruit) cause toxicity. The examples in 10.1 and 10.4 (fluconazole-warfarin, itraconazole-atorvastatin) are classics.
- Transporters: P-glycoprotein inhibitors (verapamil, clarithromycin, amiodarone) raise digoxin and dabigatran levels.
- Excretion: NSAIDs, thiazides and ACE inhibitors reduce lithium clearance; probenecid blocks tubular secretion of penicillins and methotrexate; high-dose NSAIDs and proton pump inhibitors can raise methotrexate levels.
Supplement and Food Interactions
| Substance | Mechanism | Consequence |
|---|---|---|
| Grapefruit juice | Furanocoumarins irreversibly inhibit intestinal CYP3A4 | Higher simvastatin, lovastatin, some calcium channel blockers and cyclosporine |
| St. John's wort | Induces CYP3A4 and P-glycoprotein; serotonergic | Lowers cyclosporine, oral contraceptives, warfarin and antiretrovirals; serotonin syndrome with SSRIs |
| Tyramine (aged cheese, cured meats, tap beer) | Not degraded when MAO is inhibited | Hypertensive crisis with MAO inhibitors and linezolid |
| Vitamin K-rich greens | Supplies cofactor for clotting factor synthesis | Large swings in intake destabilize the INR on warfarin |
| Ethanol | Disulfiram-like reaction; CNS depression; CYP2E1 induction | Labeling warns with metronidazole; acetaminophen hepatotoxicity risk |
| Ginkgo, garlic, fish oil, high-dose vitamin E | Antiplatelet effects | Bleeding with anticoagulants and around surgery |
Pharmacogenomics
Inherited differences in drug-metabolizing enzymes, transporters, targets and HLA alleles explain much variation in response:
| Gene or variant | Drug | Clinical effect |
|---|---|---|
| CYP2D6 ultrarapid metabolizer | Codeine, tramadol | Excess morphine (or O-desmethyltramadol) formation causes respiratory depression; codeine is contraindicated in children younger than 12 |
| CYP2C19 poor metabolizer | Clopidogrel (prodrug) | Reduced activation and more stent thrombosis (boxed warning) |
| CYP2C9 and VKORC1 | Warfarin | Lower dose requirements and bleeding risk |
| TPMT or NUDT15 deficiency | Azathioprine, 6-mercaptopurine | Life-threatening myelosuppression |
| DPYD (DPD deficiency) | 5-fluorouracil, capecitabine | Severe or fatal toxicity; labeling advises considering DPYD testing |
| HLA-B*15:02 | Carbamazepine, phenytoin | Stevens-Johnson syndrome and TEN, especially in people of Asian ancestry |
| HLA-B*58:01 | Allopurinol | Severe cutaneous reactions; testing recommended in high-risk ancestries |
| HLA-B*57:01 | Abacavir | Hypersensitivity syndrome |
| G6PD deficiency | Dapsone, primaquine, rasburicase, sulfonamides, methylene blue | Hemolysis |
| NAT2 slow acetylator | Isoniazid, hydralazine, procainamide | Neuropathy, drug-induced lupus |
| Butyrylcholinesterase variants | Succinylcholine | Prolonged apnea |
| RYR1 | Volatile anesthetics, succinylcholine | Malignant hyperthermia |
Adverse Drug Reactions
- Type A (augmented): predictable and dose-related; for example, bleeding with anticoagulants or hypoglycemia with sulfonylureas.
- Type B (bizarre): unpredictable and not dose-related; for example, anaphylaxis, SJS/TEN or idiosyncratic hepatotoxicity.
Allergies. About 10% of patients report a penicillin allergy, but most are not truly allergic when tested. Cross-reactivity with cephalosporins depends mainly on R1 side-chain similarity and is low overall. Cefazolin has a unique side chain. Current allergy practice parameters allow most patients with a non-anaphylactic penicillin history to receive a cephalosporin, and many hospitals use cefazolin even after reported anaphylaxis when penicillin skin testing is not available.
Toxicity and specific side effects. These are covered with each drug class: aminoglycoside oto- and nephrotoxicity, fluoroquinolone tendinopathy, NSAID gastropathy and nephropathy, and drug-induced lupus (hydralazine, procainamide, isoniazid, minocycline, TNF inhibitors).
Teratogenic effects. The 2015 Pregnancy and Lactation Labeling Rule replaced the A/B/C/D/X letter categories with narrative risk summaries.
| Teratogen | Effect |
|---|---|
| Warfarin | Nasal hypoplasia and stippled epiphyses (warfarin embryopathy) |
| Isotretinoin and high-dose vitamin A | Craniofacial, cardiac and CNS defects |
| Valproate, carbamazepine | Neural tube defects |
| Phenytoin | Fetal hydantoin syndrome (including nail and distal phalangeal hypoplasia) |
| ACE inhibitors and ARBs | Renal dysgenesis, oligohydramnios |
| Methotrexate, misoprostol, mycophenolate | Fetal loss and malformations |
| Thalidomide | Phocomelia (14.3) |
| Tetracyclines | Tooth discoloration, bone growth effects |
| Lithium | Ebstein anomaly |
Drug Resistance and Tolerance
Resistance can be microbial (5.6), tumor-related (efflux pumps such as P-glycoprotein and target mutations) or pharmacologic tolerance, meaning a reduced effect after repeated dosing from receptor downregulation or desensitization. Examples include opioid tolerance and tachyphylaxis, a rapid tolerance seen with nitrates and indirect sympathomimetics.
Clinical Toxicology
Toxidromes
| Toxidrome | Vital signs | Pupils | Skin | Other |
|---|---|---|---|---|
| Sympathomimetic (cocaine, amphetamines) | High heart rate, blood pressure and temperature | Dilated | Diaphoretic | Agitation, seizures |
| Anticholinergic | High heart rate and temperature | Dilated | Dry, flushed | Delirium, urinary retention |
| Cholinergic (organophosphates) | Bradycardia | Constricted | Wet | Bronchorrhea, fasciculations (10.2) |
| Opioid | Respiratory depression | Pinpoint | Normal | Coma |
| Sedative-hypnotic | Normal to low | Normal | Normal | Coma with relatively preserved vital signs |
| Serotonin syndrome | High heart rate and temperature | Dilated | Diaphoretic | Clonus and hyperreflexia |
Antidotes Worth Memorizing
| Poison | Antidote |
|---|---|
| Acetaminophen | N-acetylcysteine |
| Opioids | Naloxone |
| Benzodiazepines | Flumazenil (can provoke seizures in chronic users) |
| Organophosphates | Atropine plus pralidoxime |
| Anticholinergic agents | Physostigmine (selected cases) |
| Digoxin | Digoxin immune Fab |
| Beta-blockers | Glucagon |
| Calcium channel blockers | IV calcium, high-dose insulin euglycemia therapy |
| Tricyclic antidepressants (wide QRS) | Sodium bicarbonate |
| Methanol, ethylene glycol | Fomepizole (and hemodialysis) |
| Cyanide | Hydroxocobalamin |
| Carbon monoxide | 100% oxygen or hyperbaric oxygen |
| Methemoglobinemia | Methylene blue (avoid in G6PD deficiency) |
| Iron | Deferoxamine |
| Lead | Succimer, edetate calcium disodium, dimercaprol |
| Isoniazid seizures | Pyridoxine |
| Sulfonylurea hypoglycemia | Dextrose plus octreotide |
| Heparin | Protamine |
| Warfarin | Vitamin K plus 4-factor PCC |
| Dabigatran | Idarucizumab |
| Local anesthetic systemic toxicity | 20% lipid emulsion (11.4) |
| Malignant hyperthermia | Dantrolene |
Tip
Before prescribing oral terbinafine, an azole, a fluoroquinolone, a macrolide or an NSAID, reconcile every medication, supplement and food pattern. Most dangerous interactions are predictable from CYP3A4, CYP2C9, CYP1A2, QT and renal-clearance effects.
A 70-year-old taking lithium for bipolar disorder is given naproxen for acute plantar fasciitis. Ten days later he has coarse tremor, ataxia and confusion. What is the mechanism of this interaction?
Naproxen reduces renal prostaglandin-dependent blood flow and lithium clearance, raising lithium levels
Naproxen induces hepatic CYP3A4, increasing conversion of lithium to a neurotoxic metabolite
Naproxen displaces lithium from albumin, raising the free fraction
Naproxen blocks P-glycoprotein efflux of lithium from the brain
A child is prescribed codeine after a toe fracture and becomes unresponsive with pinpoint pupils and shallow breathing after standard doses. Which pharmacogenomic explanation is most likely?
CYP2C19 poor metabolism preventing codeine activation
TPMT deficiency causing accumulation of codeine glucuronide
HLA-B*58:01 triggering an immune-mediated reaction
CYP2D6 ultrarapid metabolism converting excess codeine to morphine
A patient on chronic warfarin needs an oral antifungal for onychomycosis. Which statement about the interaction risk is most accurate?
Terbinafine is a strong CYP3A4 inducer that predictably lowers the INR to subtherapeutic levels
Griseofulvin strongly inhibits CYP2C9 and is the antifungal most likely to cause bleeding
Fluconazole and other azoles can raise the INR, so monitor closely or choose an alternative
Topical efinaconazole is contraindicated with warfarin because it is highly absorbed systemically
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