Pharmacology - PK Concepts (Vocabulary)

Absorption and First-Pass Effect

• Medications that bypass the first-pass effect go straight into circulation and begin exerting their effects immediately.
• This leads to greater availability of the drug in systemic circulation compared with oral administration.
• Example concept (not required to memorize exact values):
  • Bioavailability via IV: BA_{IV}=100\%
  • Bioavailability via PO: BA_{PO}\approx 75\%
  • The important takeaway: IV delivery tends to have higher and more immediate systemic availability than oral dosing.
• Implication: Dosing may need to be adjusted because the same nominal dose can produce a stronger effect when given IV versus PO.

Routes of Administration: Localized vs Systemic Effects

• Some routes deliver local effects with reduced systemic exposure:
  • Subcutaneous injections (e.g., insulin injections) target subcutaneous tissues.
  • Epinephrine given subcutaneously is a common route for certain reactions.
  • Topical hydrocortisone (and similar) applied to a bug bite or localized skin issue produces itching relief locally and may have reduced systemic exposure.
• Formulations like nitroglycerin can have a longer duration of action and, depending on formulation, can be absorbed systemically.
• Blood-brain barrier (BBB) concept: Some medications cannot cross the BBB; others can, depending on chemistry and ability to cross barriers.

Pharmacokinetics: Protein Binding and the Free Drug

• When drugs bind to plasma proteins, the bound portion is largely inactive and cannot reach the site of action; only the free (unbound) drug can exert pharmacologic effects.
• The "free" or unbound drug is the fraction available to cross membranes (including sites of action) and be eliminated.
• Drug binding varies by compound:
  • Some drugs are not highly protein-bound (they bind less to albumin).
  • Some drugs are highly protein-bound (e.g., Warfarin).
• When two highly protein-bound drugs compete for limited binding sites, displacement can occur, increasing the free drug fraction and potentially leading to toxicity. This binding competition can make outcomes unpredictable.
• Core questions addressed in class:
  • Is the therapeutic effect produced by the drug-bound form or by the free form? Answer: The free (unbound) drug is the active form.
• Clinical implications:
  • If protein binding capacity is reduced (e.g., low albumin) or if binding sites are saturated, more free drug can be present, increasing effects or toxicity.

Metabolism, Individual Variability, and Dosing in Special Populations

• Individual variability in metabolism: some people metabolize drugs faster than others; this can affect dosing frequency and amount.
• In older adults:
  • Principle: start low and go slow. Begin with the lowest dose and titrate slowly while monitoring response and tolerance.
  • This accounts for changing physiology, comorbidities, and potential organ function changes.
• Dose adjustments may be needed due to organ function:
  • If kidneys or liver function is impaired or aging affects metabolism, doses may need to be reduced.
  • Medication selection and dosing must consider individual variability and coexisting conditions.
• If a patient has a change in diet or lifestyle, drug effects can change:
  • For example, significant dietary changes (e.g., doubling protein intake, drastic diet changes) can alter drug effects, possibly by altering metabolism or distribution.
• Pharmacogenetics and enzyme activity:
  • Enzyme activity varies by person (genetics influence metabolism). Higher or lower enzyme activity can affect how quickly a drug is processed and cleared.
• Prodrug topic:
  • The term prodrug was raised as a question in class. The transcript notes that the term’s use and rationale can vary, and some people may not have explored it deeply. Pharmacogenetics and metabolism can influence whether a prodrug becomes active in a given patient.

Diet, Drug Interactions, and Metabolic Modulation

• Food and juice interactions:
  • Grapefruit juice can increase the accumulation of certain drugs by slowing their metabolism, prolonging action and increasing risk of toxicity.
  • This interaction illustrates how dietary components can affect pharmacokinetics via enzymatic pathways.
• Induction or inhibition of drug metabolism:
  • Some substances can stimulate metabolism, potentially decreasing drug efficacy or shortening duration of action.
  • Conversely, inhibition of metabolism can raise drug levels and increase adverse effects.
• Clinical takeaway: Nutritional factors, supplements, and certain foods can significantly modulate drug exposure and response; clinicians should consider potential interactions.

Excretion and Elimination: Kidneys, Liver, and Enterohepatic Circulation

• Excretion is primarily via the kidneys for the free (unbound) drug, through glomerular filtration.
• The liver can excrete drugs into bile, contributing to elimination via the biliary system.
• Enterohepatic recirculation:
  • Fat-soluble drugs (and fat-soluble vitamins) can be excreted into bile, released into the gut, reabsorbed into the bloodstream, returned to the liver, and re-excreted again.
  • This recycling prolongs the presence of certain drugs in the body and can delay complete elimination.
• The overall excretion pathway influences duration of action and potential for accumulation with repeated dosing.

Clinical Scenarios and Practical Considerations

• Infections requiring rapid, reliable drug levels:
  • Hospital admission for IV antibiotics ensures consistent and immediate drug delivery.
• Route choice influences onset and duration of effect (local vs systemic) and potential side effects.
• Baseline assessments before starting potentially hepatotoxic drugs:
  • Obtain liver function baseline (enzyme levels, overall hepatic function) to gauge potential risk and monitor changes during therapy.
  • Baseline liver health is particularly important for drugs that affect the liver or are metabolized there.
• Aging and organ function: take into account changes in metabolism and excretion with age when planning dosing schedules.
• Examples from everyday medications (to anchor concepts):
  • Subcutaneous injections like insulin for glucose control.
  • Subcutaneous epinephrine administration in an acute setting.
  • Topical hydrocortisone for skin itching or inflammation.
  • Nitroglycerin formulations that can have systemic absorption and longer action in some cases.

Summary of Key Concepts

• First-pass effect reduces oral drug bioavailability compared with non-oral routes; IV administration can circumvent this entirely.
• Bioavailability differences influence dosing and expected onset of action; IV typically yields faster and greater effect than PO.
• Local vs systemic delivery determines whether the drug acts at the site of application or throughout the body; some formulations provide both local and systemic effects.
• The BBB restricts entry of some drugs into the CNS; crossing the BBB depends on drug properties and barriers.
• Protein binding controls the balance between bound (inactive) and free (active) drug; only free drug exerts effect, and high protein binding can complicate therapy when multiple drugs compete for binding sites.
• Metabolism is highly variable among individuals; age, genetics, diet, and concomitant medications can alter metabolic rate and drug levels.
• Start low, go slow in older adults to minimize adverse effects and account for slower clearance and different sensitivity.
• Diet and drug interactions (e.g., grapefruit juice) can markedly affect drug levels and duration of action.
• Excretion occurs mainly via kidneys for free drugs and via liver/bile for others; enterohepatic recirculation can prolong drug presence, particularly for fat-soluble compounds.
• Baseline organ function assessment (especially liver) is important before initiating therapies that impact those organs.
• Prodrug concepts are influenced by genetics and enzymatic activity; individual variation can affect whether a prodrug is activated and achieves therapeutic effect.