18.2 Pharmacodynamics, Pharmacogenetics & Clinically Important Drug Interactions in Women's Health
Key Takeaways
A drug reaches steady state, and is mostly eliminated after stopping, in about 4–5 half-lives; potency (dose needed) and efficacy (maximum effect) are different properties.
CYP2D6 ultrarapid metabolizers convert codeine and tramadol to more active opioids, so the FDA warns against their use while breastfeeding and in children under 12.
Rifampin, rifabutin, and enzyme-inducing antiseizure drugs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, and topiramate above 200 mg/day) make combined pills and progestin-only pills US MEC Category 3; DMPA and IUDs are preferred.
Common non-rifamycin antibiotics do not reduce hormonal contraceptive effectiveness (US MEC Category 1).
Combined hormonal contraceptives lower lamotrigine levels by about half, risking seizures during active pills and toxicity in the hormone-free week.
Pharmacodynamics: What the Drug Does to the Body
- Agonists activate receptors; partial agonists (buprenorphine) cap the maximum effect; antagonists block receptors (mifepristone at the progesterone receptor; naloxone at the opioid receptor).
- Selective receptor modulators act as agonists in some tissues and antagonists in others:
- Tamoxifen (a SERM): antagonist in breast, agonist in endometrium (polyps, hyperplasia, cancer) and bone.
- Raloxifene: antagonist in breast and endometrium, agonist in bone.
- Ulipristal (an SPRM): delays ovulation for emergency contraception.
- GnRH agonists (leuprolide) cause an initial flare, then downregulate the pituitary; GnRH antagonists (elagolix, relugolix) suppress immediately without a flare.
- Potency vs. efficacy: Potency is the dose needed for an effect; efficacy is the maximum achievable effect. A more potent drug is not necessarily more effective.
- Therapeutic index: The gap between effective and toxic doses. Narrow-index drugs (warfarin, lithium, digoxin, phenytoin, aminoglycosides, levothyroxine) need level monitoring and careful attention to interactions.
- Tolerance and tachyphylaxis: Diminishing response with repeated doses (nitrates, H2 blockers, opioids).
Half-Life and Dosing Math
- Half-life (t½): Time for the plasma concentration to fall by 50%; it is proportional to volume of distribution divided by clearance.
- Steady state is reached after about 4–5 half-lives of regular dosing, and about the same time is needed to eliminate most of a drug after stopping. For example, a drug with an 8-hour half-life reaches steady state in about 32–40 hours.
- A loading dose reaches the target concentration faster (for example, magnesium sulfate or amiodarone).
- First-order kinetics: A constant fraction is eliminated per unit time (most drugs). Zero-order kinetics: A constant amount is eliminated (phenytoin at high doses, alcohol), so small dose increases can cause large level jumps.
- Long half-life drugs such as fluoxetine (norfluoxetine about 1–2 weeks) cause little discontinuation syndrome but take weeks to wash out; semaglutide's long half-life is why it is stopped 2 months before conception.
Pharmacogenetics
| Gene | Drugs Affected | Clinical Consequence |
|---|---|---|
| CYP2D6 | Codeine, tramadol, tamoxifen, many SSRIs and TCAs | Ultrarapid metabolizers make excess morphine from codeine, which can cause respiratory depression in the patient or a breastfed infant; the FDA (2017) contraindicates codeine and tramadol in children under 12 and warns against their use while breastfeeding. Poor metabolizers form less endoxifen from tamoxifen |
| CYP2C19 | Clopidogrel, PPIs, citalopram and escitalopram, sertraline | Poor metabolizers get less clopidogrel activation (higher stent thrombosis) and higher citalopram levels |
| CYP2C9 and VKORC1 | Warfarin | Variants predict lower dose needs and bleeding risk |
| HLA-B*15:02 | Carbamazepine, oxcarbazepine, phenytoin | Strongly predicts Stevens-Johnson syndrome/toxic epidermal necrolysis, especially in people of Asian ancestry; test before starting carbamazepine |
| HLA-B*58:01 | Allopurinol | Severe cutaneous reactions |
| TPMT and NUDT15 | Azathioprine, mercaptopurine | Deficiency causes life-threatening myelosuppression; test before starting |
| DPYD | Fluorouracil, capecitabine | Deficiency causes severe toxicity |
| G6PD deficiency (X-linked) | Nitrofurantoin, sulfonamides, dapsone, primaquine, rasburicase | Hemolysis; also relevant to the newborn when nitrofurantoin is given near term |
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines translate genotype results into dosing advice.
Drug Interactions Every WHNP Should Know
Interactions That Reduce Hormonal Contraception
| Interacting Drug | Effect | US MEC Guidance |
|---|---|---|
| Rifampin, rifabutin | Strong CYP3A4 induction lowers estrogen and progestin levels | Combined pills, patch, ring, and POPs Category 3; implant Category 2; DMPA and IUDs Category 1 |
| Enzyme-inducing antiseizure drugs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, topiramate >200 mg/day) | Lower hormone levels | Combined methods and POPs Category 3; implant Category 2; DMPA and IUDs Category 1 |
| St. John's wort | CYP3A4 induction | Breakthrough bleeding and pregnancy; advise a different method or avoid the herb |
| Some antiretrovirals (efavirenz; ritonavir-boosted regimens) | Lower contraceptive levels, particularly with implants and pills | Check current interaction resources; IUDs and DMPA are unaffected |
| Ulipristal acetate | Progestins and ulipristal reduce each other's effect | Wait at least 5 days after ulipristal before starting hormonal contraception |
| Tirzepatide | Delayed gastric emptying lowers oral contraceptive exposure | Non-oral method or barrier backup for 4 weeks after starting and each dose increase |
| Non-rifamycin antibiotics | No reduction in effectiveness | Category 1; no backup needed |
Interactions Caused by Hormonal Contraception
- Lamotrigine: Estrogen induces glucuronidation and cuts lamotrigine levels about 50%, which can cause seizures; levels rebound during the hormone-free week, which can cause toxicity. US MEC rates combined methods Category 3 with lamotrigine monotherapy; progestin-only methods and IUDs avoid the interaction.
- Drospirenone plus potassium-raising drugs (ACE inhibitors, ARBs, spironolactone, potassium supplements, daily NSAIDs): Check potassium.
- Levothyroxine: Estrogen raises thyroxine-binding globulin, so women may need a higher dose after starting oral estrogen.
Other High-Yield Interactions
| Combination | Risk |
|---|---|
| Warfarin with TMP-SMX, metronidazole, fluconazole, or fluoroquinolones | INR rises, causing bleeding |
| SSRIs or SNRIs with tramadol, linezolid, triptans, St. John's wort, or MAOIs | Serotonin syndrome (agitation, hyperthermia, clonus) |
| QT-prolonging drugs (ondansetron, azithromycin, fluoroquinolones, citalopram, methadone, antipsychotics) | Torsades de pointes, especially with low potassium or magnesium |
| Clarithromycin or strong azoles with simvastatin or lovastatin | Rhabdomyolysis |
| Methotrexate with TMP-SMX or NSAIDs | Bone marrow and renal toxicity |
| PDE5 inhibitors with nitrates | Severe hypotension |
| Paroxetine or fluoxetine with tamoxifen | Less endoxifen, which may reduce efficacy |
| Calcium, iron, PPIs, or soy with levothyroxine | Reduced absorption; separate by 4 hours |
| Grapefruit juice with CYP3A4 substrates (some statins and calcium channel blockers) | Higher drug levels |
Patient Education and Safe Prescribing
- Reconcile medications at every visit, including OTC drugs, herbs, and supplements.
- Use teach-back to confirm understanding of dosing, side effects, and warning signs.
- Check interactions with a reliable database before adding any drug, especially for patients on anticoagulants, antiseizure drugs, antiretrovirals, or transplant medications.
- Counsel on reproductive implications (teratogenicity, contraception needs, and lactation compatibility) whenever prescribing to a person who could become pregnant.
A 25-year-old with tuberculosis infection will take rifampin for 4 months. She currently uses a combined oral contraceptive and wants to avoid pregnancy. What is the best recommendation?
Continue the pill, because rifampin affects only progestin-only pills and not combined pills.
Switch to the vaginal ring, which avoids the interaction by bypassing first-pass liver metabolism.
Double the daily pill dose for the duration of rifampin therapy and for 28 days after it ends.
Switch to DMPA or an IUD, because rifampin lowers both combined and progestin-only pill levels.
A breastfeeding mother 5 days postpartum is prescribed acetaminophen with codeine for perineal pain. Her newborn becomes excessively sleepy and feeds poorly. Which pharmacogenetic explanation is most likely?
The mother is a CYP2D6 ultrarapid metabolizer whose codeine becomes excess morphine in breast milk.
The mother is a CYP2C19 poor metabolizer, so unconverted codeine accumulates in her breast milk.
The infant has G6PD deficiency, so acetaminophen in breast milk causes hemolysis and lethargy.
The mother has TPMT deficiency, which slows acetaminophen clearance and concentrates it in milk.
A 29-year-old with epilepsy controlled on lamotrigine monotherapy starts a combined oral contraceptive with a 7-day placebo week. Two months later she has a breakthrough seizure. What is the most likely explanation?
Lamotrigine induces liver enzymes that inactivate ethinyl estradiol and cause irregular bleeding.
Ethinyl estradiol speeds lamotrigine glucuronidation, cutting levels about in half on active pills.
The progestin component directly lowers the seizure threshold in women with epilepsy.
Combined pills have no interaction with lamotrigine, so the seizure is unrelated to the pill.
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