PHA 337 - Intro to PK and IV Bolus L6

Pharmacokinetics

The study of what the body does to a drug, including absorption, distribution, metabolism, and elimination.

ADME

Absorption, Distribution, Metabolism, and Elimination.

Absorption

Transfer of a drug from the site of administration to the bloodstream.

Characteristics of absorption

Rapid and not reversible.

Disposition

The fate of a drug after absorption; includes distribution and elimination.

Distribution

Transfer of drug from the blood to tissues, extravascular fluids, plasma proteins, or other body fluids.

Characteristics of distribution

Rapid, reversible, and usually occurs faster than elimination.

Factors affecting distribution

Blood flow (perfusion) and drug characteristics such as lipophilicity and hydrophilicity.

Examples of distribution sites

Blood, tissues, saliva, cerebrospinal fluid, bronchial secretions, and pericardial fluid.

Elimination

The removal of drug from the body through metabolism and excretion.

Metabolism

Chemical conversion of a drug into metabolites, primarily by the liver.

Sites of metabolism

Liver, kidney, and skin.

Renal excretion

Removal of drug through the kidneys into urine.

Biliary excretion

Removal of drug through bile into feces.

Goal of pharmacokinetics: pharmacology and toxicology

Relate drug effects and toxicity to plasma concentrations of the drug and metabolites.

Goal of pharmacokinetics: accumulation

Determine drug accumulation characteristics for evaluation of chronic toxicity.

Goal of pharmacokinetics: individualized therapy

Optimize therapeutic management for individual patients.

Goal of pharmacokinetics: compliance

Determine patient adherence to therapy.

Goal of pharmacokinetics: disease states

Evaluate the effect of disease states on drug elimination.

Dosage regimen questions

Which route, how much, how often, and how long?

Therapeutic window

The plasma concentration range between minimum effective concentration and maximum safe concentration.

Minimum concentration

The lowest concentration needed to produce a therapeutic effect.

Maximum concentration

The highest concentration before toxicity may occur.

IV bolus administration

A rapid intravenous injection in which the entire dose enters the bloodstream immediately.

Drug absorption in IV bolus

Considered instantaneous.

One-compartment model

A pharmacokinetic model assuming instantaneous distribution of drug throughout the body.

Assumption of one-compartment model

The drug distributes rapidly and uniformly throughout the body.

Concentration differences in tissues

Tissue concentrations may differ even though elimination rates are the same.

Elimination rate in one-compartment model

The rate of decrease of drug is the same from all tissues.

Blood sampling duration in one-compartment model

At least 5.5 half-lives.

Purpose of semilog plots

Convert curved concentration-time data into a straight line for easier analysis.

Why extrapolate to the y-axis?

To estimate Cp0 because actual sampling does not occur at time zero.

Cp0

Initial plasma drug concentration immediately after administration.

First-order elimination

A process in which the rate of drug elimination is proportional to the amount of drug present.

Elimination rate constant (K)

A first-order rate constant describing drug elimination.

Units of K

Time⁻¹ (e.g., hr⁻¹).

Equation for total elimination rate constant

K = km + ke

km

First-order rate constant for metabolism.

ke

First-order rate constant for excretion.

K for antibiotics

Because many antibiotics are not metabolized, K = ke.

Equation for K using two concentrations

K = ln(C1/C2) ÷ Δt

Half-life (t½)

The time required for the amount or concentration of a drug to decrease by one-half.

Equation for half-life

t½ = 0.693 ÷ K

Half-life in first-order kinetics

Constant regardless of drug concentration.

Relationship between K and half-life

Higher K results in a shorter half-life.

Apparent volume of distribution (V)

The apparent volume in which a drug appears to be dissolved.

Physiologic meaning of V

Does not represent a true anatomic space.

Equation for volume of distribution

V = Dose ÷ Cp0

Dose (D) in the V equation

Amount of drug administered.

Effect of small Cp0 on V

A smaller Cp0 results in a larger volume of distribution.

Large V indicates

The drug is extensively distributed into tissues.

Small V indicates

The drug remains primarily in the bloodstream.

Lipophilic drugs and V

Lipophilic drugs generally have a large volume of distribution.

Plasma protein binding and V

Highly protein-bound drugs have a smaller volume of distribution.

Volume of distribution in disease states

May change if distribution changes.

Total body water in a 70-kg adult

Approximately 42 L.

Interpretation of V ≈ 10 L

Drug is primarily confined to vascular and extracellular fluids.

Interpretation of V ≈ 440 L

Drug is extensively distributed into tissues.

Clearance (CL)

A measure of the body's ability to eliminate a drug.

Definition of clearance

The volume of plasma cleared of drug per unit time.

Components of total clearance

CL = CLr + CLnr

CLr

Renal clearance.

CLnr

Nonrenal clearance.

Equation relating clearance to V and K

CL = V × K

Noncompartmental clearance equation

CL = Dose ÷ AUC

AUC

Area under the plasma concentration versus time curve.

Units of clearance

L/hr or mL/min.

Relationship between clearance and elimination

Higher clearance results in faster drug removal.

Volume of distribution and clearance

Independent pharmacokinetic parameters.

Protein drugs and V

Protein drugs typically have smaller V because they cannot easily cross cell membranes.

Examples of protein drugs

Infliximab and adalimumab.

One-compartment model assumption

Instantaneous drug distribution throughout the body.

Two-compartment model assumption

Drug distribution between central and peripheral compartments occurs with a delay.

Central compartment

Well-perfused tissues and blood.

Examples of central compartment tissues

Heart, lungs, brain, liver, and kidneys.

Peripheral compartment

Poorly perfused tissues.

Examples of peripheral compartment tissues

Muscle, adipose tissue, bone, and cartilage.

Intercompartmental clearance (Q)

The movement of drug between central and peripheral compartments.

Importance of V and CL

Together determine drug concentration, elimination rate, and half-life.

One-compartment concentration-time curve

A straight line on a semilog plot.

Two-compartment concentration-time curve

Shows a distribution phase followed by an elimination phase.

Clinical significance of kidney failure

Can decrease elimination and cause drug accumulation.

Effect of increased perfusion on distribution

Increases the rate of drug distribution.

Effect of lipophilicity on distribution

Increases tissue penetration and volume of distribution.

Main pharmacokinetic parameters reported for IV bolus studies

K, t½, V, and CL.