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Chapter 3: Pharmacokinetics & Pharmacodynamics — Rational Dosing & the Time Course of Drug
Action
This chapter explores the fundamental principles of pharmacokinetics and pharmacodynamics as
they relate to determining rational drug dosing regimens and understanding the time course of
drug action. It emphasizes the integration of dose, concentration, and effect relationships to
optimize therapeutic outcomes and minimize toxicity.
Introduction
The goal of therapeutics is to attain a beneficial effect with minimal adverse effects.
Rational dosing combines pharmacokinetics (dose-concentration) and pharmacodynamics
(concentration-effect) principles.
Pharmacodynamics includes concepts like maximum response (Emax) and sensitivity (C50 or
EC50).
Pharmacokinetics involves the processes of drug input, distribution, and elimination, which
determine the drug exposure at target sites.
Individual patient physiological and pathological variations affect pharmacokinetic and
pharmacodynamic parameters, requiring dose adjustments.
1. Pharmacokinetics
1.1 Overview
The standard dose is based on trials in average patients.
Volume of Distribution (V) and Clearance (CL) are key pharmacokinetic parameters.
Volume of Distribution describes the apparent space the drug occupies in the body related to
concentration.
Clearance measures the body's ability to eliminate the drug.
1.2 Volume of Distribution (V)
Defined as V = CA where A is amount of drug in body and C is drug concentration
(blood/plasma).
It is an "apparent" volume, often exceeding physical volumes because of drug distribution in
extravascular tissues.
Examples:
Drugs limited to plasma have low V (~0.04 L/kg).
Drugs highly distributed in tissues (e.g., digoxin) have large V values (up to thousands of liters).
1.3 Clearance (CL)
Clearance predicts elimination rate relative to concentration:
Rate of elimination = CL × C
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Clearance can be additive across several organs (kidney, liver, lungs).
Total systemic clearance is the sum of organ clearances.
Renal clearance is often measured via urinary excretion; hepatic clearance includes metabolism
and biliary excretion.
1.4 Drug Elimination Kinetics
A. Capacity-Limited (Nonlinear) Elimination
Clearance varies with concentration, e.g., phenytoin, ethanol.
Elimination rate follows Michaelis-Menten kinetics:
Vmax × C
Rate =
Km + C
At high C, elimination approaches saturation (zero-order kinetics).
Clearance calculation and AUC-based estimation are invalid for saturable elimination.
B. Flow-Dependent (High-Extraction) Elimination
Elimination depends on blood flow to organ.
Highly extracted drugs are cleared nearly completely on first pass (e.g., morphine, propranolol).
Hepatic blood flow thus limits clearance.
C. Large Molecules
Therapeutic proteins typically show long half-lives (weeks).
Target-mediated drug disposition occurs when drug clearance depends on binding to target (e.g.,
T cells).
This can shorten half-life and affect pharmacokinetics.
1.5 Half-Life
The half-life (t1/2 ) is time to reduce drug amount in body by 50%.
For one-compartment model:
0.7 × V
t1/2 =
CL
Half-life governs time to reach steady state and washout after dosing changes.
Disease states can alter volume and clearance, changing half-life (e.g., chronic renal failure
decreasing digoxin clearance and V).
1.6 Multicompartment Kinetics
Drugs may distribute between compartments causing complex elimination patterns.
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Observed half-life may be longer than predicted by simple models.
1.7 Drug Accumulation
With repeated dosing, drug accumulates until elimination equals input.
Accumulation Factor (AF) relates steady-state concentration (Css ) to concentration after first dose:
1
AF =
1 − e−kt
For dosing interval equal to one half-life, AF is 2.
1.8 Routes of Administration and Bioavailability
Routes differ in onset, bioavailability (fraction of dose reaching systemic circulation), and
characteristics.
Oral bioavailability may be reduced by incomplete absorption or first-pass metabolism.
Bioavailability calculations:
Extent of absorption (f ) and hepatic extraction ratio (ER):
F = f × (1 − ER)
First-pass metabolism mainly occurs in liver; some in gut wall or portal blood.
1.9 Rate and Extent of Absorption
Drug effect depends on both rate and extent of absorption.
Zero-order absorption: constant rate independent of concentration.
First-order absorption: rate proportional to concentration.
Changes in absorption affect concentration-time curve shape and clinical effect.
1.10 Avoiding First-Pass Metabolism
Alternative routes (sublingual, transdermal, rectal) bypass hepatic first pass to varying extents.
Drugs like lidocaine have low oral bioavailability due to high first-pass metabolism.
2. The Time Course of Drug Effect
2.1 Instantaneous Effects
Some drug effects closely follow plasma concentration (e.g., ACE inhibitors like enalapril).
Relationship between concentration and effect is nonlinear (Emax model).
Drugs with plasma concentration much greater than C50 show sustained effects despite declining
concentration.
2.2 Delayed Effects
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Effects may lag behind concentration changes due to:
Distribution delay from plasma to site of action (short delay).
Slow receptor binding/dissociation kinetics (e.g., digoxin).
Slow turnover of physiological mediators (e.g., warfarin inhibits clotting factor synthesis leading to
delayed INR response tied to half-life of clotting factors).
2.3 Schedule-Dependent Effects
Toxicity or effect can depend on dosing schedule and not just concentration.
Example: Gentamicin renal toxicity higher with continuous infusion due to saturable uptake
mechanisms.
2.4 Cumulative Effects
Some drugs exhibit irreversible or cumulative binding (e.g., anticancer drugs binding DNA).
Area under the curve (AUC) is a useful measure of cumulative exposure.
3. Designing a Rational Dosage Regimen: The Target Concentration Approach
3.1 Concept
Assume a target plasma concentration that produces therapeutic effect.
Use pharmacokinetic parameters to individualize dose to reach this concentration.
3.2 Maintenance Dose Calculation
At steady state, input rate equals elimination rate:
Dose Rate = CL × TC
where TC is the target concentration.
For oral dosing with bioavailability F :
CL × TC
Dose Rate =
F
For intermittent dosing with dosing interval τ :
CL × TC × τ
Dose = Dose Rate × τ =
F
3.3 Practical Considerations
Volume of distribution and half-life influence peak and trough concentrations but not average
steady-state concentration.
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Clinicians should adjust doses based on individual clearance to achieve target concentrations,
balancing efficacy and toxicity.
Summary
This chapter provides an essential framework linking pharmacokinetics and pharmacodynamics,
focusing on rational drug dosing by targeting specific plasma concentrations. It discusses key
pharmacokinetic parameters such as volume of distribution and clearance, explains different
elimination kinetics, and illustrates how dosing routes and absorption rates influence
bioavailability and effect. The time course of drug action includes immediate, delayed, schedule-
dependent, and cumulative effects with real clinical examples. Finally, the target concentration
approach provides a practical tool for individualizing maintenance doses to optimize therapeutic
outcomes.
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