Pharmacokinetics (PK) describes what the body does to a drug: how it is absorbed, distributed, metabolized, and excreted (ADME). Pharmacodynamics (Topic 2) describes what the drug does to the body. PK explains how fast a drug acts, how high the blood level rises, how long it lasts, and why it accumulates. Most dosing rules a nurse follows — route, interval, loading dose, hold parameters, timing of drug levels — are applied pharmacokinetics.

Key terms

Useful relationships (concepts, not bedside formulas)

• Half-life ≈ 0.693 × Vd ÷ CL — if clearance falls (kidney failure), half-life lengthens
• Loading dose ≈ target concentration × Vd ÷ F — fills the "tank" quickly
• Maintenance dose rate ≈ target concentration × CL ÷ F — replaces what is removed
• About 97% of a drug is eliminated after 5 half-lives once dosing stops; this is also why a steady state takes 4–5 half-lives to reach

When PK principles change practice

Protein binding. Only the free (unbound) drug is active and can be metabolized or excreted. Albumin binds many acidic drugs. Normal serum albumin is 3.5–5.0 g/dL (35–50 g/L). With low albumin (malnutrition, liver disease, nephrotic syndrome, older age), a highly bound drug such as phenytoin has more free drug — toxicity can occur even when the total level looks "normal." Two highly bound drugs can also displace each other.

Barriers. The blood–brain barrier limits many drugs (levodopa crosses; dopamine does not). The placenta and breast milk let small, lipid-soluble, unbound drugs through (see Topic 5).

Metabolism and the CYP450 system

Classic interactions: rifampin lowers the effect of hormonal contraceptives and warfarin; stopping smoking raises clozapine levels; grapefruit raises levels of some statins, calcium channel blockers, tacrolimus, and cyclosporine.

Genetics (pharmacogenomics). People differ in enzyme activity. CYP2D6 ultrarapid metabolizers turn codeine into morphine quickly (overdose risk); CYP2C19 poor metabolizers activate clopidogrel poorly (reduced antiplatelet effect — boxed warning).

Excretion. The kidneys filter free drug; lipid-soluble drugs are reabsorbed unless metabolized to water-soluble forms. Urine pH matters: alkalinizing the urine with sodium bicarbonate increases excretion of weak acids such as salicylates. Some drugs are excreted in bile and reabsorbed from the gut (enterohepatic recirculation), prolonging their effect.

Therapeutic drug monitoring (common narrow-range drugs)

Class-specific boxed warnings (e.g., lithium toxicity, aminoglycoside nephrotoxicity and ototoxicity) are covered in the drug-class topics.

Peak and trough timing

• Trough: drawn just before the next dose (commonly within 30 minutes before) — reflects the lowest level; high trough = accumulation and toxicity risk
• Peak: drawn when the level is highest (e.g., about 30 minutes after an IV infusion ends for aminoglycosides) — reflects effectiveness
• Record the exact dose time and the exact sampling time; a level without timing cannot be interpreted

Pharmacokinetic problems cause adverse effects mainly through accumulation (level too high) or failure (level too low).

• Accumulation: kidney impairment, liver impairment, dehydration, heart failure (reduced liver and kidney blood flow), enzyme inhibitors, older age, repeated doses of a long half-life drug
• Subtherapeutic levels: vomiting, diarrhea, rapid GI transit, enzyme inducers, missed doses, binding with food or minerals (e.g., tetracyclines and fluoroquinolones with calcium, iron, magnesium, or antacids; levothyroxine with calcium or iron)
• Delayed toxicity: drugs with long half-lives or active metabolites (e.g., meperidine's metabolite normeperidine causes seizures, especially in kidney impairment; diazepam's active metabolites build up in older adults)

• Kidney impairment: dose reduction or longer intervals for renally cleared drugs. Serum creatinine (normal about 0.6–1.2 mg/dL (53–106 µmol/L), varies by sex and lab) and eGFR or creatinine clearance guide dosing. Metformin is contraindicated when eGFR is below 30 mL/min/1.73 m², and starting it is not recommended at eGFR 30–45
• Liver impairment: reduced metabolism and albumin; caution with drugs that have high first-pass metabolism, sedatives, opioids, and acetaminophen
• Heart failure and shock: reduced perfusion slows absorption from IM and SC sites and reduces clearance — IV route is preferred in shock
• Interactions: always screen for CYP inhibitors and inducers, grapefruit, herbal products, alcohol, and mineral supplements
• Food: some drugs need an empty stomach (levothyroxine 30–60 minutes before breakfast; alendronate with plain water 30 minutes before food), others need food to improve absorption or reduce GI upset

Listed in priority order.

1. Assess organ function before and during therapy: serum creatinine, eGFR, urine output, liver tests, albumin, fluid status (edema, dehydration)
2. Time doses and levels correctly
   • Give time-critical drugs on schedule to keep levels in range
   • Coordinate peak and trough samples with the lab; record exact times
   • Hold the dose and notify the prescriber if a trough is above range or a new toxicity sign appears — do not hold narrow-range drugs just because a level is pending unless the order or protocol says so
3. Watch for signs of accumulation when kidney or liver function worsens, after a new interacting drug is started, or in older adults
4. Screen every new drug (including over-the-counter and herbal products) for enzyme inducers and inhibitors
5. Respect dosage forms: do not crush extended-release or enteric-coated products (can cause dose dumping or destroy the drug)
6. Separate binding drugs: give tetracyclines, fluoroquinolones, and levothyroxine apart from calcium, iron, magnesium, and antacids (usually 2–4 hours; follow the label)
7. Evaluate effect: a slow response to a long half-life drug is expected — do not give extra doses to "speed it up"

• Take each drug at the same times each day; do not double doses after a missed dose unless told to
• Tell every provider and pharmacist about all drugs, supplements, herbal products (especially St. John's wort), and grapefruit intake
• Stopping or starting smoking can change the level of some drugs (clozapine, theophylline) — tell the care team
• Separate mineral supplements and antacids from drugs they bind
• Keep appointments for blood levels; take the dose after the blood draw when a trough is ordered
• Report new symptoms such as nausea, confusion, dizziness, or unsteadiness, especially during illness with vomiting, diarrhea, or poor fluid intake (dehydration raises lithium and digoxin levels)

• Narrow therapeutic index drugs (digoxin, lithium, warfarin, phenytoin, theophylline, aminoglycosides, vancomycin, carbamazepine, tacrolimus) cause toxicity with small changes in level
• Accumulation signs: digoxin — anorexia, nausea, vomiting, visual changes, bradycardia, dysrhythmias (antidote digoxin immune fab); lithium — coarse tremor, vomiting, diarrhea, confusion, ataxia (hemodialysis for severe toxicity; no antidote); phenytoin — nystagmus, ataxia, slurred speech; theophylline — tachycardia, restlessness, seizures
• Overdose kinetics: in overdose, absorption may be prolonged (extended-release tablets, drug clumps) and elimination may become saturated (phenytoin, salicylates, alcohol), so levels can keep rising for hours
• Enhancing elimination: activated charcoal for selected ingestions when the airway is protected; urinary alkalinization for salicylates; hemodialysis for lithium, salicylates, methanol, and ethylene glycol
• Missed levels are a safety event: a trough drawn at the wrong time can lead to a wrong dose change

• PK = ADME: absorption, distribution, metabolism (liver), excretion (kidneys)
• IV bioavailability = 100%; oral drugs lose some to first-pass metabolism
• Sublingual, transdermal, and parenteral routes bypass first-pass metabolism
• Half-life = time for concentration to fall by half; steady state after 4–5 half-lives
• A loading dose reaches the target level quickly; maintenance doses keep it there
• Only free drug is active — low albumin raises the free fraction of highly bound drugs (phenytoin, warfarin)
• Inducers (rifampin, carbamazepine, phenytoin, St. John's wort) lower levels; inhibitors (clarithromycin, azoles, grapefruit, ritonavir) raise levels
• Kidney impairment → accumulation of renally excreted drugs; check creatinine and eGFR
• Trough just before the next dose; record exact times
• Digoxin 0.5–2.0 ng/mL (0.5–0.9 in heart failure); lithium 0.6–1.2 mEq/L; phenytoin 10–20 mcg/mL
• Dehydration and hyponatremia raise lithium levels; hypokalemia (also hypomagnesemia, hypercalcemia) increases digoxin toxicity