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Pharmacology Review: Pharmacokinetics, Pharmacodynamics, and Therapeutic Index (Ch 1-9)

Absorption

  • Absorption definition: the movement of a drug from the site of administration into the bloodstream.

  • Why absorption matters: barriers at each phase can affect how much drug gets into systemic circulation and ultimately to its site of action.

  • Major factors affecting absorption:

    • Route of administration: IV, IM, Subcutaneous (SubQ), PO (oral), rectal/vaginal, buccal/sublingual, aerosol. Each route has different barriers before reaching the bloodstream.
    • Drug formulation and dosage form:
    • Liquid vs tablet: liquids often absorb faster than pills because they don’t need dissolution.
    • Enteric coating: delays absorption, absorbs in the small intestine to avoid stomach irritation.
    • Delayed/extended release: designed for slower, longer absorption.
    • Dose size relative to absorption: larger doses may take longer to absorb.
    • Absorption surface area: larger surface areas (e.g., stomach lining vs smaller surface areas) affect how much is absorbed.
    • Digestive motility: slowed motility (e.g., with PEG tubes or GI disorders) slows absorption.
    • Blood flow to absorption site: poor perfusion (e.g., in obesity, vascular disease) slows absorption at the site.
    • Molecular size: smaller molecules absorb more readily; large molecules are absorbed more slowly.
    • Lipid solubility: more lipid-soluble drugs cross membranes more easily.
    • Food and pH:
    • Food in the stomach can delay absorption; empty stomach often preferred for faster absorption.
    • pH and acid in the stomach affect ionization and dissolution; some drugs are better absorbed in acidic vs. basic environments.
    • Drug interactions affecting absorption:
    • Drug-drug interactions can compete for absorption or alter GI environment.
    • Drug-food interactions (e.g., grapefruit juice) can alter absorption by changing stomach pH or transporters.
    • Grapefruit juice is a notable interaction that can alter pH and absorption of various meds.
    • Drug and drug interactions: competition at absorption sites can delay absorption if one drug absorbs much faster than another.
    • Drug and food/herbal supplements: various substances can alter absorption; grapefuit juice often cited as problematic.
    • PEG/nasogastric/tube medications: in patients with PEG/J/G-tubes, GI motility and residuals affect absorption; a stomach that’s not moving effectively can lead to poor absorption.

  • Fastest vs slowest absorption (conceptual):

    • IV: fastest absorption (absorption is effectively instantaneous since the drug is in the bloodstream).
    • IM: relatively fast but slower than IV; in general, many injections show effect within 15–30 minutes depending on blood flow.
    • Buccal/Sublingual: faster than SubQ for many drugs because mucosal absorption can bypass first-pass metabolism.
    • SubQ: slower due to adipose tissue having relatively less blood flow; may be slower for large fat deposits.
    • PO: slowest among many routes; liquids absorb faster than tablets; absorption may be slowed by food, GI motility, pH, and first-pass effect.

  • Intuition examples from lecture:

    • Liquid Benadryl absorbed faster than tablet form, explaining quicker symptomatic relief with liquids.
    • Enteric coating prevents stomach absorption; designed to protect drug from gastric acid and release in small intestine.
    • An antacid can neutralize stomach acid and alter drug dissolution/absorption, potentially reducing absorption of certain medications.
    • PEG tubes: residuals and stomach emptying influence whether a medication reaches systemic circulation when given via tube.
    • Alcohol and acid-base balance can alter absorption and drug ionization.

  • First-pass effect (oral medications):

    • Definition: oral drugs absorbed from the GI tract enter the hepatic portal circulation and are inactivated by hepatic enzymes before reaching systemic circulation.
    • Consequence: reduced bioavailability for affected drugs; explained by F (bioavailability) decreasing due to hepatic metabolism.
    • Ways to overcome: use alternative routes (IV, buccal, sublingual) or adjust dosing to compensate for first-pass metabolism.
    • Related chemistry: acid in the stomach can cause extensive ionization of some drugs, affecting dissolution and absorption; enteric coating helps drugs reach sites with more favorable pH for absorption.

  • Practical absorption considerations in nursing:

    • Take some medications on an empty stomach to favor faster absorption (unless specific GI irritation or instructions call for taking with food).
    • Consider food interactions and timing for specific medications.
    • Monitor for residuals in patients with GI tubes; ensure stomach is moving and not overly full before administering oral meds.

  • Key formulas related to absorption/PK:

    • Bioavailability (oral vs IV):
      F = rac{AUC{ ext{oral}}}{AUC{ ext{IV}}}
    • First-pass implications: higher first-pass metabolism lowers F; alternative routes bypass first-pass.

Distribution

  • Distribution definition: the process of drug transportation throughout the body via the bloodstream to tissues and organs.

  • Primary barrier: blood flow; if blood flow is poor (e.g., atherosclerosis, diabetes-related vascular changes), drug delivery to target tissues is impaired.

  • Factors affecting distribution:

    • Blood flow to tissues and organ perfusion; decreased cardiac output reduces distribution speed.
    • Capillary permeability and tissue barriers; some tissues have tight barriers that limit entry (e.g., blood-brain barrier).
    • Size of the drug molecule relative to capillary pores; very large molecules may be unable to pass into certain tissues.
    • Plasma protein binding: drugs bound to albumin or other proteins are inactive; only unbound (free) drug can distribute to tissues and exert effects. Competition for binding sites can cause displacement and alter free drug levels.
    • Drug-drug interactions (competition for receptor binding sites or transporters) can alter distribution and cause displacement or enhanced effects.
    • Displacement concept: when one drug displaces another from protein-binding sites, the free concentration of the displaced drug may rise, increasing toxicity risk.
    • Synergism and antagonism in distribution/pharmacodynamics:
    • Synergism: combined drugs produce greater effect (e.g., two analgesics providing more pain relief than additive effect).
    • Antagonism: one drug blocks the effect of another at receptor sites.
    • Displacers example: Narcan (naloxone) displaces morphine at opioid receptors, reversing opioid effects.
    • Helpful interactions: certain combinations can enhance effect (e.g., combination analgesia) but require monitoring for toxicity.

  • Receptors and distribution:

    • Specific drugs have known receptor targets (e.g., morphine on mu and kappa opioid receptors) and predictable effects.
    • Nonspecific drugs (e.g., some chemotherapies) can kill rapidly dividing cells non-selectively, causing broad toxicity.

  • Barriers and selective permeability:

    • Blood-brain barrier: protects brain but can hinder CNS-penetrant drugs; some cancers require drugs that cross this barrier.
    • Placental barrier: restricts fetal exposure; some drugs cross and affect the fetus; pregnancy adds complexity to distribution.

  • Examples from the lecture:

    • Morphine and fentanyl competing for the same receptor sites can lead to overdose risk if displaced or if receptors become saturated.
    • Beta blockers act on adrenergic receptors as antagonists, reducing sympathetic effects (e.g., heart rate) by blocking receptor activity.

  • Key concept in equations:

    • Receptor occupancy model (simplified):
      ext{Occupancy} = rac{[D]}{K_d + [D]}
    • Synergistic interactions can be conceptualized as multiplicative increases in effect beyond simple additivity.

  • Practical distribution considerations in nursing:

    • Monitor organ perfusion and conditions that impair blood flow (e.g., cardiovascular disease) as part of drug therapy planning.
    • Be aware that changes in protein binding (e.g., hypoalbuminemia) alter free drug concentrations and potential toxicity.

Metabolism

  • Metabolism definition: chemical modification of drugs, primarily to prepare them for excretion; main organ is the liver.

  • Primary site: liver; hepatic enzymes metabolize drugs, often rendering them inactive or more water-soluble for excretion.

  • Enzyme roles and types:

    • Hepatic enzymes (e.g., CYP450 family) are central to drug metabolism.
    • Enzyme inhibitors: drugs that decrease metabolic activity of hepatic enzymes, leading to slower drug breakdown and higher systemic exposure; risk of toxicity.
    • Example discussed: ketoconazole as a strong enzyme inhibitor; can raise levels of concomitant drugs like warfarin.
    • Enzyme inducers: drugs that increase metabolism, leading to faster clearance and reduced effect.

  • Clinical implications of metabolism:

    • Infants have immature liver and kidney function, leading to slower metabolism and excretion; dosing must be adjusted.
    • Older adults often have reduced hepatic metabolic capacity; may require dose reductions.
    • Severe liver disease (cirrhosis, hepatitis, alcoholism) impairs metabolism; risk of drug accumulation and toxicity.
    • Genetic factors (pharmacogenetics) influence how individuals metabolize certain drugs; genetics can affect enzyme activity and drug response.
    • First-pass metabolism reduces bioavailability of oral drugs; alternative routes can bypass first-pass (e.g., IV, buccal, sublingual).

  • Important clinical relationships:

    • When hepatic metabolism is impaired, drug levels can accumulate, increasing toxicity risk; adjust doses downward.
    • The liver’s metabolic capacity determines how quickly a drug is deactivated and cleared from the body.

  • Age-related changes in metabolism:

    • Infants: immature liver enzymes; slower metabolism.
    • Elderly: decreased metabolic activity, leading to longer drug half-lives and potential accumulation.

  • First-pass effect (detailed):

    • Oral drugs are absorbed in the GI tract, enter hepatic circulation, and may be inactivated by the liver before reaching systemic circulation.
    • Overcoming strategies: use non-oral routes (IV, buccal, sublingual) or adjust dosing to account for hepatic metabolism.

  • Important formulas and concepts:

    • Half-life relationship (see below) ties to metabolism and clearance:
      t{1/2} = rac{0.693 imes Vd}{CL}
    • Pharmacogenetics concept: genetic variations affect enzyme activity and thus metabolism rates.

  • Practical metabolism considerations in nursing:

    • Assess liver function tests (AST/ALT) and consider genetic factors when selecting drug regimens.
    • Be cautious with drugs that have narrow therapeutic indices when hepatic function is impaired.
    • In liver disease, reduce doses or choose drugs with safer metabolic profiles.

Excretion

  • Excretion definition: removal of drugs and metabolites from the body.
  • Primary organ for excretion: kidneys (urine) is the dominant route.
  • Other elimination routes: respiratory (e.g., volatile substances), glands (sweat, saliva), biliary system (bile/feces).
  • What the kidneys can excrete: only free (unbound) drug that is water-soluble and small enough to pass through glomerular filtration; high molecular weight or highly protein-bound drugs are not readily excreted.
  • Implications of excretion in different populations:
    • If kidneys are impaired (e.g., chronic kidney disease, dialysis), drug clearance decreases, increasing risk of toxicity; lower doses are often required.
    • In liver disease, excretion can also be affected since metabolism helps prepare drugs for renal excretion; both metabolism and excretion can be impaired.
  • Labs to monitor excretion/metabolism:
    • Kidney function: BUN, creatinine, and glomerular filtration rate (GFR).
    • Liver function: AST, ALT (and other enzymes as needed).
  • Alternate excretion pathways:
    • Biliary excretion increases fecal elimination; some drugs are excreted in bile and reabsorbed (enterohepatic recirculation) affecting duration of action.
  • Clinical anecdotes and implications from lecture:
    • Patients with kidney disease require careful dosing to avoid accumulation and toxicity.
    • The lecture referenced that certain odors and physical signs (e.g., sweat or breath changes) may occur as drugs are excreted via glands or lungs; e.g., anesthetic excretion and unusual odors.

Pharmacokinetic-Pharmacodynamic Concepts (Biomethododynamics)

  • PK vs PD:
    • Pharmacokinetics (PK): what the body does to the drug (absorption, distribution, metabolism, excretion).
    • Pharmacodynamics (PD): what the drug does to the body (receptor interactions, resulting effects).
  • Drug concentration measures:
    • Minimum Effective Concentration (MEC): the lowest plasma concentration needed to produce a therapeutic effect.
    • Therapeutic range: plasma concentrations between MEC and toxic concentration where effects are optimal without adverse effects.
    • Toxic concentrations: concentrations that produce unacceptable toxicity.
    • Therapeutic Index (TI): safety margin of a drug; typically TI = TD50/ED50 or LD50/ED50 (historic definitions; in practice, ED50 and toxic dose metrics are used to assess safety).
    • Wide therapeutic index: larger margin between therapeutic and toxic doses → safer.
    • Narrow therapeutic index: small margin, requires careful monitoring (e.g., vancomycin with peaks and troughs).
  • Peak, trough, onset, duration, and half-life definitions:
    • Onset: time to first observed effect after administration.
    • Peak: time of maximum effect or maximum plasma concentration.
    • Duration: how long the drug’s effect lasts.
    • Half-life ($t_{1/2}$): time for plasma concentration to fall by half; determines dosing interval and time to redose.
    • Trough: lowest concentration just before the next dose.
  • Dosing strategies:
    • Loading dose: a higher initial dose used to rapidly achieve therapeutic concentrations.
    • Maintenance dose: dose given to maintain drug levels within the therapeutic window.
    • Bolus: a rapid administration of a dose to quickly reach target concentration.
    • Dosing frequency depends on half-life and desired steady-state; aim is to keep levels within the therapeutic range.
  • Peak and trough monitoring (example use):
    • Vancomycin often requires peaks and troughs due to narrow therapeutic index; troughs guide next dosing to avoid toxicity; peaks assess efficacy.
    • For IV meds with short half-lives, monitoring shortly after administration helps assess onset and peak to adjust dosing.
  • Receptor interactions and drug action:
    • Agonists: bind to receptors and activate them, producing a physiological response (e.g., morphine binding to mu and kappa receptors to produce analgesia and euphoria).
    • Partial agonists: bind to the receptor and produce a partial response, weaker than a full agonist.
    • Antagonists: bind receptor without activating it, blocking agonist binding and action (e.g., naloxone displacing opioid effects).
    • Antagonists can also block endogenous substances or other exogenous drugs.
    • Nonspecific drugs (e.g., many chemotherapies): lack precise receptor targets and can cause broad cytotoxic effects.
  • Agonist vs antagonist example questions:
    • An agonist binds and produces the effect.
    • An antagonist blocks receptor sites and prevents activation by agonists.
    • Partial agonists bind and activate but produce a smaller effect than full agonists.
  • Potency vs efficacy:
    • Potency: how much drug is required to produce a given effect; a more potent drug El = lower dose to achieve the same effect (e.g., fentanyl more potent than morphine).
    • Efficacy: the maximum effect a drug can produce (magnitude of response).
    • A drug with high potency does not necessarily have higher efficacy.
  • Special consideration in elderly patients (age-related pharmacokinetics):
    • Absorption: often slower due to decreased GI motility; increased gastric acidity; higher fat stores; dehydration can further slow GI transit.
    • Distribution: decreased total body water and lean mass; increased fat storage; decreased cardiac output affecting tissue perfusion.
    • Metabolism: reduced hepatic metabolism; lower first-pass effect; potential for prolonged half-life.
    • Excretion: decreased renal function; lower GFR; risk of drug accumulation.
    • Dosing in elderly often requires lower or more frequent adjustments; watch for polypharmacy and individual variability.
  • Practical considerations for elderly care:
    • Use pill organizers and reminders; ensure someone is filling and understanding the schedule.
    • Monitor for dehydration and constipation, which can affect drug absorption and distribution.
    • Consider monitoring labs (AST/ALT, BUN/creatinine) to guide dosing and avoid toxicity.

Special Topics: Practice Questions and Exam Tips (from lecture)

  • Absorption factors (select all that apply):
    • pH level in the stomach (true).
    • Presence of food in the stomach (true).
    • Body surface area (false for oral absorption; more relevant to unrelated routes like subcutaneous in some contexts, but the instructor indicated false here).
    • Drug formulation (true).
    • Liver function (true; indirectly affects absorption via metabolism and first-pass effects).
  • PK/PD concept questions: a P450 enzyme inhibitor delays metabolism and increases risk of drug toxicity due to slower clearance.
  • Route of elimination: primary route for most drugs is urine (kidneys).
  • Narrow therapeutic index (NTI) questions: a drug with NTI requires close monitoring to avoid toxicity; safety margin is small, not large.
  • Agonist vs antagonist: a drug that binds receptor and produces effect is an agonist; a drug that blocks receptor and prevents activation is an antagonist.
  • Elderly pharmacokinetics question: among options, the statement that best reflects aging is decreased rate of hepatic metabolism; renal clearance is typically decreased, not increased.
  • Absorption rate influence question: correct factors include pH of GI tract, presence of food, drug formulation; surface area and GI absorption context may be route-specific.
  • Practical reminder: consider first-pass effect and alternative routes to bypass it; monitor for interactions like grapefruit juice; ensure dosing is adjusted for patients with organ impairment.

Quick Reference: Key Formulas and Terms

  • Half-life:
    t{1/2} = rac{0.693 imes Vd}{CL}
  • Bioavailability (oral vs IV):
    F = rac{AUC{ ext{oral}}}{AUC{ ext{IV}}}
  • Therapeutic index (TI):
    TI = rac{TD{50}}{ED{50}} ext{ or } TI = rac{LD{50}}{ED{50}}
  • Receptor occupancy (simplified):
    ext{Occupancy} = rac{[D]}{K_d + [D]}
  • Efficacy model (Emax):
    E = rac{E{max} imes [D]}{EC{50} + [D]}
  • Loading dose (illustrative concept):
    DL ext{ approximately } C{target} imes V_d / F

This set of notes consolidates the major and many minor points covered in the transcript on pharmacokinetics and pharmacodynamics, including routes of administration, distribution, metabolism, excretion, drug interactions, aging considerations, and core dosing concepts (onset, peak, trough, half-life, loading/maintenance dosing, and therapeutic index). The content also integrates practical nursing considerations, real-world anecdotes from the lecture, and example questions to help reinforce exam-ready understanding.