Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics - Key Terms

Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics — Study Notes

Learning objectives (topic overview)

  • Differentiate among pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics/pharmacogenomics.
  • Discuss diagnostic labs related to liver and kidney function: AST, ALT, ALP for liver; creatinine and BUN for kidneys.
  • Utilize dimensional analysis for dosage calculations (refer to Topic 1 for practice).
  • Identify genetic considerations that may affect pharmacotherapy.
  • Discuss cultural implications of pharmacogenetics.
  • Understand drug phases and how they influence drug action (ADME) and responses.

Pharmacokinetics (PK): movement of drugs through the body (ADME)

  • PK components: Absorption, Distribution, Metabolism (biotransformation), Excretion.
  • Goals: predict how quickly and how much drug reaches systemic circulation and site of action.
Absorption (drug movement from GI tract into bloodstream)
  • Definition: movement from the GI tract into the bloodstream.
  • Routes vary in speed to the site of action:
    • PO (by mouth): must traverse GI tract; slower to bloodstream.
    • Subcutaneous (subQ), intramuscular (IM), and IV: typically faster entry into bloodstream.
  • Terminology:
    • Disintegration: breakdown of an oral drug into smaller particles.
    • Dissolution: small drug particles dissolve in liquid to form a solution.
  • Absorption mechanisms (passive vs active):
    • Passive transport: diffusion and facilitated diffusion.
    • Active transport: requires energy and a carrier substance (e.g., enzymes).
    • Pinocytosis: cell engulfs drug particles to transport them across membrane.
  • Factors affecting absorption:
    • Blood circulation: poor circulation slows absorption.
    • Pain or stress: can alter absorption rate.
    • Food texture, fat content, and temperature.
    • pH and route of administration.
  • Portal circulation and first-pass metabolism:
    • Drug movement from GI tract to liver via the portal vein.
    • First-pass effect (hepatic first-pass): some drugs are extensively metabolized in the liver before reaching systemic circulation.
  • Bioavailability (F): fraction of administered dose that reaches systemic circulation.
    • PO route: bioavailability is typically < 100% due to first-pass metabolism and other factors.
    • IV route: bioavailability ~100% (bypasses first-pass metabolism).
    • Factors influencing bioavailability: drug form, route, gastric mucosa/motility, food or drug interactions, and changes in liver metabolism.
  • Practical takeaway: PO vs IV differences illustrate how much drug makes it into bloodstream and can reach target tissues.
Drug distribution
  • Concepts to know: protein binding, free (unbound) drug, and volume of distribution (V_d).
  • Protein binding and competition:
    • Highly protein-bound drugs compete for albumin binding sites.
    • Higher-bound drugs can displace others, increasing free drug for the one with lower binding percentage, raising toxicity risk.
    • Example given: Drug A at 98% protein-bound vs Drug B at 94% protein-bound. A binds more tightly, occupying more sites; B has more free drug circulating, increasing risk of toxicity if free levels rise.
    • Analogy: albumin as a UPS truck; drugs load onto albumin for transport. If the truck is full (binding sites taken), some drugs remain free in the bloodstream, potentially causing toxicity.
  • Consequences of altered protein binding:
    • Low albumin levels reduce available binding sites, increasing free drug fraction and risk of toxicity.
  • Blood-brain barrier and placenta: distribution barriers discussed with illustrations in the source material.
  • Distribution visuals (from the slides): depictions of how drugs cross the blood-brain barrier and how drugs can cross the placenta.
  • Key variables: V_d (volume of distribution) and factors such as tissue binding, capillary permeability, and lipid solubility.
Drug metabolism (biotransformation)
  • Primary site: liver; drugs can also be metabolized in the GI tract.
  • Liver enzymes and liver function tests (A’s): AST, ALT, ALP. Elevated levels indicate potential liver dysfunction; must be within safe range prior to starting certain medications.
  • Concept of half-life (T_{1/2}): time required for drug concentration to decrease by half.
  • Loading dose: a large initial dose given to rapidly achieve minimum effective concentration in plasma so therapeutic effect begins quickly.
  • Interplay with excretion: metabolism prepares drugs for excretion; sometimes metabolites are excreted via bile into the intestinal tract.
Drug excretion
  • Primary route: kidneys (urine).
  • Other routes: bile (feces), and excretion via lungs, saliva, sweat, and breast milk.
  • Renal function labs:
    • BUN (blood urea nitrogen) and creatinine: elevated in kidney dysfunction.
    • Creatinine clearance: decreases with kidney dysfunction; important measure of renal excretory function. Often, creatinine clearance is the more accurate assessment of renal function than creatinine alone.
  • Factors affecting excretion:
    • Drugs that affect renal excretion (e.g., diuretics).
    • Cardiac output: decreased CO reduces renal blood flow, impairing excretion.
    • Drugs that compete for the same excretion pathways.
    • Urine pH changes; renal or hepatic dysfunction.
  • Clinical implication: monitor BUN/creatinine and, when applicable, creatinine clearance to assess renal excretion capacity.
Summary of PK concepts to connect (ADME)
  • Absorption: route, bioavailability, first-pass effect.
  • Distribution: protein binding, free drug, V_d, barriers (BBB and placenta).
  • Metabolism: liver-centric, liver enzymes, assessed by AST/ALT/ALP.
  • Excretion: primarily renal, plus alternate routes; influenced by renal function and urine pH.

Pharmacodynamics (PD): how drugs affect the body

  • Definition: study of the biological and physiological effects of drugs and their mechanisms of action.
  • Primary vs secondary effects:
    • Primary effect: desired therapeutic response.
    • Secondary effects: can be desirable or undesirable (e.g., a pulmonary hypertension drug later found to improve other circulations—Viagra example).
  • Drug response relationship:
    • Dose-response relationship: how minimal vs maximal dose yields a desired response; influenced by potency.
    • Potency: strength of a drug at a given dose.
    • Therapeutic index (TI): safety window of a drug; a graphical representation includes a minimum effective concentration (MEC) and a higher concentration that may produce toxicity.
    • Formal definition (typical pharmacology): TI=TD<em>50ED</em>50TI = \frac{TD<em>{50}}{ED</em>{50}} where TD{50} is the toxic dose for 50% of subjects and ED{50} is the effective dose for 50% of subjects.
  • Therapeutic range and monitoring:
    • Therapeutic drug monitoring may include peak and trough levels:
    • Peak level: highest plasma concentration at a specific time.
    • Trough level: lowest plasma concentration, just before the next dose.
    • These help ensure efficacy while avoiding toxicity.
  • Onset, peak, and duration:
    • Onset: time to reach minimum effective concentration (MEC).
    • Peak: highest drug concentration in plasma; often associated with the maximum effect and possibly more side effects.
    • Duration: length of time the drug exerts therapeutic effect.
  • Receptor theory and drug targeting:
    • Drugs bind to receptors to activate (agonist) or inhibit/block (antagonist) responses.
    • Specificity vs non-specificity: non-specific drugs affect multiple receptors/sites, potentially increasing side effects.
  • Terms related to receptor interactions:
    • Agonist: activates a receptor to produce a response.
    • Antagonist: blocks receptor activation.
    • Non-specific/non-selective: affects various receptors/body systems (eye, heart, vessels, GI tract, bronchi, bladder).
    • Mechanisms of action can include stimulation, depression, blocking, irritation, replacement of electrolytes, cytotoxic actions, antimicrobial actions, and immune modulation.
  • Side effects, adverse effects, and toxicity:
    • Side effects: secondary, often predictable; not necessarily harmful; can be tolerated.
    • Adverse effects: undesirable and potentially harmful; range from mild to severe (e.g., anaphylaxis).
    • Drug toxicity: when drug levels exceed the therapeutic range and cause harm.
  • Biological variation and pharmacogenetics:
    • Genetic factors influence individual drug responses; leads into pharmacogenetics and pharmacogenomics.
    • Concepts of tolerance (decreased response over time) and tachyphylaxis (rapid loss of response, possibly early).
    • Placebo effect: drug response not due to chemical properties but to psychological factors; important in research and clinical interpretation.
  • Drug interactions (broad overview):
    • Drug-drug interactions can enhance or diminish effects; include pharmacokinetic (absorption, distribution, metabolism, excretion) and pharmacodynamic interactions.
    • Additive effect: combined effect equals the sum of individual effects.
    • Synergistic effect: combined effect greater than the sum of individual effects (one plus one is more than two).
    • Drug-nutrient interactions: certain foods or beverages can alter absorption or metabolism.
    • Drug-laboratory interactions: some drugs alter lab values, impacting interpretation.
    • Drug-induced photosensitivity: increased sensitivity to sunlight; protect skin with lotion, clothing, hats, etc.

Pharmacogenetics and pharmacogenomics

  • Genetics: the study of an individual's genes; genomics: study of all genes and their interactions with each other, environment, and social-cultural factors.
  • Historical milestone: mapping/sequencing of the human genome completed in 2003 (02/2003, as noted in the transcript).
  • Genetic testing applications:
    • Identification of traits, diagnosis of genetic disorders, and detection of predispositions to diseases (e.g., cancer, heart disease).
    • Availability of testing for > 1,600 genetic disorders;
    • Carrier testing: determines if a person carries a gene variant that could cause disease in offspring.
    • Diagnostic testing: identifies genetic variation causing or potentially causing a condition.
  • Pharmacogenetics (pharmacogenomics):
    • Field that studies how genetic variations affect individual drug responses (therapeutic response, toxicity, and drug interactions).
    • Goal: tailor drug choice and dosing to the individual patient for optimized therapeutic benefit and reduced adverse events.
    • Direct correlations exist between genetic makeup and drug response, drug-drug interactions, and adverse drug events.
    • Genetic markers influence drug response; some drugs have varying effects in biologic subgroups based on genotype.
    • Potential outcomes:
    • More personalized treatment plans.
    • Development of new drugs tailored to genetic profiles.
  • Practical and ethical/cultural implications (cultural implications are part of the topic):
    • Equity in access to genetic testing and pharmacogenetic-guided therapy.
    • Privacy and consent issues around genetic information.
    • Cultural beliefs and trust in genetics-informed medical decisions.
    • Implications for informed consent, potential discrimination, and data sharing.

Practice questions and key takeaways (from the transcript)

  • Question 1: A patient with liver and kidney disease is given a drug with half-life $T_{1/2} = 30$ hours. The nurse expects the duration of this medication to:

    • a) increase
    • b) decrease
    • c) remain unchanged
    • d) dissipate
    • Answer: a) increase
    • Rationale: Metabolism and elimination are impaired, prolonging the half-life and overall duration of drug action.

  • Question 2: In older adults with renal dysfunction, creatinine clearance is usually:

    • a) substantially increased
    • b) slightly increased
    • c) decreased
    • d) in the normal range
    • Answer: c) decreased
    • Rationale: Age-related changes and kidney dysfunction reduce clearance; GFR declines with age.
    • Additional note: Creatinine clearance is the most accurate test to determine renal function; creatinine is a metabolic byproduct of muscle, and clearance varies with age and gender due to muscle mass.

  • Question 3: Which nursing action is most appropriate to ensure safety with a medication that has a low therapeutic index (TI)?

    • a) monitoring urine output
    • b) assessing vital signs hourly
    • c) maintaining strict isolation precautions
    • d) monitoring serum peak and trough level
    • Answer: d) monitoring serum peak and trough level
    • Rationale: Peak and trough monitoring helps ensure the drug remains within the therapeutic window and avoids toxicity or lack of efficacy.

  • Question 4: Most drugs are metabolized in the:

    • a) kidney
    • b) small intestine
    • c) liver
    • d) brain
    • Answer: c) liver

  • Note on calculations: Additional drug calculation practice is available in the posted PowerPoint. If questions arise, review Dimensional Analysis content from Topic 1 and complete the posted practice problems independently.

Quick connections to foundational principles and real-world relevance

  • PK/PD integration:
    • PK describes how the body handles a drug (ADME).
    • PD describes how the drug affects the body (receptors, signaling, and downstream effects).
    • Together, PK/PD guides dosing strategies to achieve efficacy with minimal toxicity.
  • Clinical relevance:
    • Liver and kidney function tests (AST/ALT/ALP and BUN/creatinine, respectively) guide safe drug choices and dosing, especially for medications with narrow therapeutic windows.
    • Understanding protein binding helps anticipate drug-drug interactions and potential toxicity when patients receive multiple highly bound drugs.
    • Therapeutic drug monitoring (peak/trough) is critical for drugs with narrow TI to prevent toxicity or subtherapeutic effects.
  • Pharmacogenetics in practice:
    • Genetic variations influence how patients metabolize and respond to drugs, enabling personalized medicine.
    • Broad ethical considerations include privacy, consent, and potential disparities in access to pharmacogenetic testing.

Key terms recap (glossary)

  • Absorption, Bioavailability ($F$), First-pass effect, Portal circulation
  • Distribution, Volume of Distribution ($V_d$), Protein binding, Free drug
  • Blood-brain barrier, Placental transfer
  • Metabolism (Biotransformation), Liver enzymes (AST, ALT, ALP)
  • Excretion, Creatinine clearance, BUN, Glomerular filtration rate (GFR)
  • Half-life ($T_{1/2}$), Loading dose
  • Pharmacodynamics (PD): Onset, Peak, Duration, Therapeutic drug monitoring, Peak/trough levels
  • Receptor theory, Agonist, Antagonist, Specificity vs non-specificity
  • Side effects vs Adverse drug reactions, Toxicity, Tolerance, Tachyphylaxis, Placebo effect
  • Drug interactions: Drug-Drug, Pharmacokinetic (PK), Additive, Synergistic, Drug-Nutrient, Drug-Laboratory, Photosensitivity
  • Pharmacogenetics/Pharmacogenomics, Genomics, Carrier testing, Diagnostic testing
  • Therapeutic index ($TI$) and its clinical significance

Notes on formatting and math usage in this set

  • Key quantitative concepts are expressed with LaTeX notation for clarity:
    • Therapeutic index: TI=TD<em>50ED</em>50TI = \frac{TD<em>{50}}{ED</em>{50}}
    • Minimum effective concentration denoted as MECMEC in discussions of onset and dosing windows.
    • Peak and trough levels can be conceptually represented as C<em>peakC<em>{peak} and C</em>troughC</em>{trough} for plasma concentrations.
    • Half-life represented as T1/2T_{1/2} (time for concentration to fall to half).
    • Bioavailability is denoted as FF (fraction of administered drug reaching systemic circulation).
  • All other concepts are described in bullet form to match the lecture content and to facilitate quick review before exams.