9.1 Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics
Key Takeaways
- Steady state and washout each take about four to five half-lives — do not call a long-half-life drug a failure on day three, and do not assume it is gone the day after the last dose.
- Codeine and tramadol are CYP2D6 prodrugs: poor metabolizers get little analgesia; ultrarapid metabolizers can produce toxic morphine, especially in children and in breastfed infants.
- Test HLA-B*5701 before abacavir and never rechallenge a positive result; screen HLA-B*1502 before carbamazepine in at-risk East and South Asian ancestry because of SJS/TEN.
- Clopidogrel needs CYP2C19 to become active — a known poor metabolizer needs an alternative P2Y12 plan with cardiology, not a silent default prescription.
- Low albumin in older or malnourished adults raises the free fraction of highly bound drugs such as warfarin and phenytoin; a 'normal' total level can still be toxic.
The current FNP-BC Test Content Outline places pharmacotherapeutics, pharmacokinetics, pharmacodynamics, and pharmacogenetics in Domain III Planning. Implementation then tests pharmacotherapeutic intervention — interactions and contraindications (Section 9.2). This is the mechanism chapter. Cardiovascular, endocrine, and infection chapters later assume you can already predict what a CYP isoform, a falling eGFR, or a 2D6 phenotype will do to a named drug.
Pharmacokinetics is what the body does to the drug
Absorption is how a dose reaches blood. Food, gastric pH, chelation, gut edema, and first-pass extraction all change it. Doxycycline and fluoroquinolones bind divalent cations — calcium, iron, magnesium, sucralfate, and many antacids — so a casual "take it with milk" instruction can convert a working anti-infective into a subtherapeutic one. Separate those doses by several hours. First-pass metabolism is why sublingual nitroglycerin exists: an oral nitrate would be extracted by the liver before it reached the coronaries. Drugs with high first-pass (propranolol, oral morphine) have much larger oral than intravenous doses. Switching route without converting the dose is an Implementation error, not a rounding issue.
Distribution is where the drug goes after it is in plasma. Highly protein-bound drugs — warfarin, phenytoin, diazepam, valproate — ride on albumin. Older adults, people with malnutrition, nephrotic syndrome, or decompensated cirrhosis run low albumin. Total phenytoin can look "in range" while the free fraction is already toxic. Do not increase a highly bound drug just because a total level is low until you know the albumin or a free level. Volume of distribution also rises in pregnancy (more plasma volume) and in obesity; some loading doses scale with weight and some maintenance doses do not. Read the label for that molecule instead of inventing a universal milligram-per-kilogram rule for adults.
Metabolism is mostly hepatic cytochrome P450. Three isoforms carry almost every FNP genetics item:
| CYP / pathway | High-yield substrates | What the FNP does |
|---|---|---|
| CYP3A4 (most common isoform) | Simvastatin, lovastatin, many dihydropyridine calcium-channel blockers, midazolam | Do not stack with strong inhibitors: clarithromycin, itraconazole, ketoconazole, ritonavir, large-volume grapefruit |
| CYP2D6 | Codeine, tramadol, tamoxifen, many antidepressants, metoprolol | Phenotype changes prodrug activation and parent-drug clearance |
| CYP2C19 | Clopidogrel (needs activation), some PPIs | Poor metabolizers form less active clopidogrel |
Inducers — rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort — speed clearance and drop substrate levels, including combined oral contraceptives. Inhibitors raise substrate levels. Azithromycin is a weak 3A4 player compared with clarithromycin or erythromycin; if the stem offers both a macrolide and an azole, the strong inhibitor is the one that wrecks the statin.
Excretion is largely renal for many ACE inhibitors, metformin, gabapentin, lithium, and a long list of antibiotics. eGFR, not a "normal" creatinine in an 82-year-old with almost no muscle, is the dosing number. A creatinine of 0.7 mg/dL in a frail 48-kg woman is not proof of a youthful kidney. If the label uses creatinine clearance, calculate it. Dose-adjust or choose another agent when clearance falls; do not copy the middle-aged eGFR-90 dose into the frail-elderly box (Section 9.3).
Half-life and steady state
Elimination half-life is the time for plasma concentration to fall by half after distribution is finished. Steady state on a regular schedule arrives in about four to five half-lives. That is why levothyroxine is rechecked around six weeks, why lithium or an SSRI is not declared a failure on day three, and why missing a week of fluoxetine is not the same as missing a week of paroxetine or venlafaxine (short-half-life withdrawal). After you stop a drug it also takes about four to five half-lives to clear. Plan washouts and "when will this be gone?" answers with that clock, not with a calendar guess.
Pharmacodynamics is what the drug does to the body
An agonist binds a receptor and activates it (a mu-opioid agonist; albuterol at beta-2). A partial agonist activates less than a full agonist and can blunt a full agonist already on board (buprenorphine at mu receptors). An antagonist occupies the receptor and blocks the agonist: naloxone, beta blockers, ondansetron at 5-HT3. Competitive antagonists can be overcome by more agonist; noncompetitive ones cannot. Exam stems that ask why naloxone must sometimes be redosed are asking you to compare half-lives (the agonist may outlast the antagonist), not to recite a brand name.
Therapeutic index is the gap between a helpful concentration and a toxic one. Narrow-index drugs — warfarin, lithium, digoxin, phenytoin, carbamazepine, theophylline — need a level or a close surrogate (INR) and a low threshold to recheck after any new inhibitor, inducer, or change in albumin or eGFR. A wide-index drug can still harm; it just tolerates a small dose change more often.
Pharmacogenetics the FNP must act on
Codeine is a prodrug. CYP2D6 O-demethylates it to morphine. A poor metabolizer makes little morphine and gets no analgesia — do not "just give more codeine." An ultrarapid metabolizer makes excess morphine: respiratory depression, deaths in children after tonsillectomy, and toxicity in breastfed infants of ultrarapid mothers. FDA contraindicates codeine after pediatric tonsillectomy or adenoidectomy and warns against use while breastfeeding. Tramadol is also 2D6-activated. When the phenotype is unknown and the patient is a child, pick a non-prodrug analgesic.
Clopidogrel is a prodrug that CYP2C19 must activate. Poor metabolizers form less of the active thiol metabolite and have more stent thrombosis and recurrent ischemic events. If 2C19 poor-metabolizer status is already on the chart, do not leave the visit on default clopidogrel. Arrange an alternative P2Y12 inhibitor that does not depend on 2C19 activation, with cardiology — not a silent dose increase as your only move.
HLA-B*5701 predicts abacavir hypersensitivity: fever, rash, and respiratory or gastrointestinal symptoms that worsen on rechallenge and can kill. Screen before the first dose. A positive result is an absolute never-start and never-rechallenge.
HLA-B*1502 is linked to carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis, with higher prevalence in some Han Chinese, Thai, and other East and South Asian ancestry groups. FDA labeling recommends screening at-risk ancestry before carbamazepine. A positive allele means do not start. Do not use ancestry as a stereotype in place of the test when the label calls for the allele, and do not skip the question in a patient whose family origin is in a high-prevalence group. Related aromatic anticonvulsants can share risk; if the stem is carbamazepine plus ancestry, the allele is the Planning step.
| Gene / pathway | Drug | FNP action |
|---|---|---|
| CYP2D6 ultrarapid | Codeine, tramadol | Avoid — morphine/opioid toxicity, including in a breastfed infant |
| CYP2D6 poor | Codeine, tramadol | Little analgesia; choose a different agent |
| CYP2C19 poor | Clopidogrel | Reduced activation; alternative P2Y12 with cardiology |
| HLA-B*5701 | Abacavir | Test before first dose; never start or rechallenge if positive |
| HLA-B*1502 | Carbamazepine | Screen at-risk ancestry; do not start if positive (SJS/TEN) |
| CYP3A4 strong inhibition | Simvastatin, lovastatin | Hold or switch the statin if the inhibitor is unavoidable |
Vignette. A 34-year-old woman of Han Chinese ancestry presents with new trigeminal neuralgia. The correct Planning step before carbamazepine is HLA-B*1502 (or a drug that does not carry this allele risk), not "start low and see whether a rash appears." A 62-year-old week after coronary stent who is a documented CYP2C19 poor metabolizer should not leave primary care on default clopidogrel without a written cardiology plan.
Exam trap. PK/PD items hide in ordinary stems. "Why is this older adult sedated on a usual diazepam dose?" is low albumin plus a long-half-life benzodiazepine. "Why no pain relief from codeine?" is 2D6 poor metabolism. "Why did simvastatin myopathy start the day clarithromycin began?" is CYP3A4 inhibition. Planning chooses the molecule and the monitoring clock from the mechanism. Implementation is refusing the pair the mechanism predicts will harm.
A 4-year-old is still in severe pain after a weight-based codeine dose. The child's parent had the same experience with codeine. Which mechanism best explains the lack of analgesia?
Before the first dose of abacavir, which test must be completed, and what does a positive result require?
An FNP starts levothyroxine in an adult with new hypothyroidism. When is a TSH most likely to reflect steady state on the current dose?
A 68-year-old with hypoalbuminemia has a total phenytoin concentration in the usual reference range but new nystagmus and ataxia. Which pharmacokinetic fact best explains the exam finding?