FOUNDATIONS OF PHARMACOLOGY

Pharmacokinetics

Absorption and Bioavailability

• Absorption moves a medication from its administration site into systemic circulation. The route and site of administration influence the onset and amount absorbed (Ernstmeyer & Christman, 2023).
• Bioavailability is the fraction or percentage of an administered dose that reaches systemic circulation. Intravenous medications have complete bioavailability, while oral medications may have lower bioavailability because absorption is incomplete or some of the dose is metabolized before reaching systemic circulation (Ernstmeyer & Christman, 2023; Peterson & Randazzo, 2022).
• The first-pass effect occurs when an orally or enterally administered medication passes through the intestinal wall and liver before entering systemic circulation. Metabolism during this passage can reduce bioavailability (Ernstmeyer & Christman, 2023).
• Transdermal, nasal, inhaled, and injected routes bypass the gastrointestinal first-pass pathway. Route selection should account for the desired onset, duration, administration needs, and patient factors (Ernstmeyer & Christman, 2023).

Distribution

• Distribution is the movement of absorbed drug through body fluids to target tissues. Blood flow, water or lipid solubility, molecular size, acid-base characteristics, protein binding, transporters, and volume of distribution affect this process (Woo & Robinson, 2019).
• Highly perfused tissues receive drug earlier than tissues with lower blood flow. Adipose tissue can store lipid-soluble drugs, and some drugs have an affinity for bone (Woo & Robinson, 2019).
• Volume of distribution is an apparent volume that relates the amount of drug in the body to its measured plasma concentration. A larger volume of distribution generally indicates more extensive movement into tissues and is an important determinant of loading-dose calculations (Peterson & Randazzo, 2022).
• Drugs circulate in bound and unbound forms. Unbound drug crosses membranes and is available for receptor binding, metabolism, and filtration. Changes in the free fraction are especially important for highly protein-bound drugs with a narrow therapeutic index and may also alter elimination (Ernstmeyer & Christman, 2023; Peterson & Randazzo, 2022).
• The blood-brain barrier limits entry into the central nervous system, while many drugs can cross the placental barrier. Lipid solubility and molecular size influence distribution across these barriers (Ernstmeyer & Christman, 2023).

Metabolism

• Metabolism chemically transforms a drug. The process may inactivate an active drug, activate a prodrug, or form active or toxic metabolites, often while making the compound easier to eliminate. The liver is the primary site for many drug-metabolizing reactions (Ernstmeyer & Christman, 2023; Peterson & Randazzo, 2022).
• Phase I metabolism commonly involves oxidation, hydrolysis, or reduction. Phase II metabolism conjugates the drug or metabolite with a water-soluble substance (Ernstmeyer & Christman, 2023; Woo & Robinson, 2019).
• Cytochrome P450 enzymes mediate much of hepatic Phase I metabolism. Clinically important families include CYP1, CYP2, and CYP3, with common isoenzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Ernstmeyer & Christman, 2023; Woo & Robinson, 2019).
• A prodrug is administered in an inactive or less active form and is metabolized into an active compound (Ernstmeyer & Christman, 2023).
• Enzyme inhibitors can slow metabolism and generally increase the effect of an active substrate. Enzyme inducers can increase metabolism and generally decrease its effect. The expected result must be reconsidered when the medication is a prodrug that requires activation (Ernstmeyer & Christman, 2023).

Excretion and Clearance

• Excretion removes drug and metabolites from the body. Most drugs are eliminated through the kidneys, although elimination can also occur through the gastrointestinal tract, lungs, sweat, saliva, and breast milk (Ernstmeyer & Christman, 2023; Woo & Robinson, 2019).
• Renal elimination involves glomerular filtration, active tubular secretion, and tubular reabsorption. Drug must be free, unbound, and water soluble to undergo glomerular filtration (Ernstmeyer & Christman, 2023; Woo & Robinson, 2019).
• Kidney function, age, hydration, and cardiac output can alter renal excretion. Reduced excretion can prolong drug exposure and increase the risk of accumulation or toxicity (Ernstmeyer & Christman, 2023; Woo & Robinson, 2019).
• Biliary excretion can be followed by intestinal reabsorption, creating an enterohepatic cycle that extends the time a drug remains in the body (Ernstmeyer & Christman, 2023; Woo & Robinson, 2019).
• Clearance is the volume of plasma from which drug is completely removed per unit of time. Total clearance integrates renal, hepatic, and other elimination pathways and is a principal determinant of maintenance dosing (Peterson & Randazzo, 2022).

Applying Renal Function to Dosing

Because many drugs are cleared at least partly by the kidney, estimated creatinine clearance is commonly used as a surrogate for renal drug-elimination capacity. A reduced estimated creatinine clearance should prompt review of the medication’s indication-specific renal dosing recommendations. Whether the dose, interval, or medication should change depends on the drug’s renal clearance, therapeutic index, labeling, and the patient’s clinical status. Older age or an elevated serum creatinine should prompt renal function assessment before starting a renally cleared medication (Peterson & Randazzo, 2022).

The Cockcroft-Gault equation estimates creatinine clearance from age, weight, sex, and serum creatinine: CrCl (mL/min) = [(140 – age) × weight in kg] ÷ (72 × serum creatinine in mg/dL), multiplied by 0.85 for female patients (Peterson & Randazzo, 2022).

Applied example: a 75-year-old, 60-kg woman with a serum creatinine of 1.8 mg/dL has an estimated CrCl of [(140 – 75) × 60] ÷ (72 × 1.8) × 0.85, approximately 26 mL/min. This degree of impairment may meaningfully delay elimination of a renally cleared drug. If she is taking digoxin and the measured concentration is above the treatment target, reduced renal clearance is one possible contributor. Interpretation should also consider when the level was drawn, the prescribed dose, drug interactions, adherence, and recent changes in kidney function. Dose or interval changes should follow this integrated assessment rather than the concentration or an assumption about adherence alone (Peterson & Randazzo, 2022).

Time, Concentration, and Dosing

• Half-life is the time required for the amount or concentration of a drug in the body to decline by 50%. Shorter half-lives often require more frequent dosing, while longer half-lives may permit less frequent dosing (Ernstmeyer & Christman, 2023; Peterson & Randazzo, 2022).
• With intermittent dosing, steady state is a stable, repeating peak-trough pattern in which the amount administered over a dosing interval equals the amount eliminated. Under first-order kinetics, most drugs approach steady state after approximately four to five half-lives (Peterson & Randazzo, 2022).
• A loading dose is used when a therapeutic concentration is needed promptly and is determined mainly by the target concentration, volume of distribution, and bioavailability. A maintenance dose replaces the amount eliminated over time and is determined mainly by clearance, target concentration, dosing interval, and bioavailability (Peterson & Randazzo, 2022). Loading dose = (target concentration × volume of distribution) ÷ bioavailability (F). Maintenance dose = (target concentration × clearance × dosing interval) ÷ F. Assuming complete bioavailability (F = 1), such as with intravenous administration, a hypothetical drug with a volume of distribution of 0.5 L/kg and a target concentration of 20 mg/L in a 70-kg patient requires a loading dose of approximately 700 mg. If clearance is 5 L/hr and the dosing interval is 8 hours, the maintenance dose is approximately 800 mg per dose, replacing the amount eliminated between doses at steady state (Peterson & Randazzo, 2022).
• Onset describes when a clinically meaningful effect begins. Peak identifies the highest concentration or greatest effect, depending on context. Duration describes how long the clinically meaningful effect persists (Ernstmeyer & Christman, 2023).
• Peak and trough levels are timed measurements used for selected medications. The results help determine whether concentrations remain within the therapeutic window and whether the dose or interval may need adjustment (Ernstmeyer & Christman, 2023).

Patient-Specific Considerations

• Neonates and young children may have reduced hepatic enzyme activity and immature renal elimination. Older children may metabolize some medications more rapidly after hepatic enzymes mature (Ernstmeyer & Christman, 2023).
• Older adults may have reduced hepatic metabolism, reduced renal elimination, and decreased first-pass metabolism. These changes can increase circulating drug concentrations and the risk of adverse effects or toxicity (Ernstmeyer & Christman, 2023).
• Pregnancy, liver disease, genetic variation, time of day, diet, alcohol use, environmental exposures, and drug interactions can change metabolism (Woo & Robinson, 2019).
• Kidney function, age, hydration, and cardiac output can change excretion (Ernstmeyer & Christman, 2023; Woo & Robinson, 2019).
• Low albumin or displacement from protein-binding sites can increase the free fraction of highly bound drugs. The clinical effect depends on the drug’s therapeutic index, distribution, and whether unbound drug is cleared more rapidly (Ernstmeyer & Christman, 2023; Peterson & Randazzo, 2022).
• Critical illness and major changes in fluid status or body composition can alter distribution and clearance, making prior dose requirements less reliable (Peterson & Randazzo, 2022).

Clinical Application and Monitoring

• Confirm the route, formulation, dose, interval, indication, and expected time to effect before judging whether a medication has failed.
• Review kidney and liver function, albumin, age, pregnancy status when relevant, hydration, cardiac output, medication interactions, alcohol use, diet, and recent changes in clinical condition.
• Use therapeutic drug monitoring when concentration data meaningfully guide efficacy or toxicity. Interpret the value in relation to sampling time, dose history, adherence, albumin, kidney function, and clinical findings.
• Reassess after a dose change at a time that reflects the medication’s half-life, onset, peak, duration, and the clinical urgency.

Common Interpretation Errors

• Assuming that every inhibitor increases effect. Inhibition can reduce the effect of a prodrug that requires activation.
• Treating a total serum concentration as equivalent to active exposure when protein binding has changed.
• Declaring treatment failure before enough time has passed for absorption, distribution, or the expected onset of effect.
• Ignoring the timing of a peak or trough level when interpreting the result.

Related YourDNP Resources

• Pharmacodynamics
• Pharmacogenomics
• Rational Drug Selection
• Quiz: Foundations of Pharmacology

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References

Ernstmeyer, K., & Christman, E. (Eds.). (2023). Pharmacokinetics and pharmacodynamics. In Nursing pharmacology (2nd ed.). Chippewa Valley Technical College. https://www.ncbi.nlm.nih.gov/books/NBK595006/

Peterson, A. M., & Randazzo, A. M. (2022). Pharmacokinetic basis of therapeutics and pharmacodynamic principles. In V. P. Arcangelo, A. M. Peterson, V. F. Wilbur, & T. M. Kang (Eds.), Pharmacotherapeutics for advanced practice: A practical approach (5th ed.). Wolters Kluwer.

Woo, T. M., & Robinson, M. V. (2019). Review of basic principles of pharmacology [PowerPoint slides]. F. A. Davis.