Pharm 4: ADME/Pharmacokinetics Part 2

Distribution

The transfer and equilibration of drug from plasma to other locations in the body

Drug protein binding

Important factor which may influence the distribution of a drug

Reversible phenomenon

Unbound (free) drug

Only the ___ is thought to be capable of diffusing out of the vascular system to the sites of pharmacologic activity as well as to sites of biotransformation and elimination

Equilibrium

The ratio of bound to unbound drug is in constant ___ (varies for each drug).

Acidic

What kind of drugs commonly bind to albumin? (Acidic or basic?)

Basic

What kind of drugs bind to alpha-one acid glycoprotein? (Acidic or basic?)

High-affinity hormone transport proteins

Present for corticosteroids, thyroxin, and testosterone

Bound, unbound

At equilibrium, there is a constant relative concentration of ___ and ___ (free) drug.

Displace, increase

If a highly protein-bound drug is co-administered with a drug that uses the same protein-binding site, it can ___ the first drug from the plasma protein and thus [increase/decrease] the amount (unbound plasma conc.) of the first drug available for pharmacological action.

90

The degree of protein-binding and subsequent interactions is only clinically significant for those drugs that are more than __% protein-bound.

Lipid

Distribution into the brain is usually reserved for highly ___-soluble drugs.

Water

Distribution of ___-soluble drugs is impaired.

Blood-brain barrier

1. Tight junctions between capillary endothelial cells

2. Tight junctions between epithelial cells of the choroid plexus

3. Astrocytic (glial) sheaths surround the capillary endothelium

Transplacental distribution

1. Primarily occurs by simple diffusion

2. Most drugs given to the mother reach the fetus to some extent

Prostate, testicles, globe of the eye, high

The ___, ___, and ___ contain barriers that prevent drug penetration. Under normal physiologic conditions, most drugs do not attain [low/high] concentrations in these tissues.

Drug redistribution

Redistribution of a drug from its site of action to other tissues where it’s not pharmacologically active can terminate the drug response (Thiopental)

Effective drug concentration

___ = concentration of free (not protein-bound) drug at receptor site

Plasma, topical

At equilibrium, the concentration at the receptor is usually proportional to the concentration in ___ (except for ___ drugs).

Plasma drug concentration

We usually only measure plasma concentration of drug, so the whole field of pharmacokinetics is related to ___.

Plasma drug concentration

A function of:

1) Rate of input of drug (absorption)

2) Rate of distribution, and

3) Rate of elimination

Input

How much drug given and absorbed (i.e., bioavailability)

Rate of distribution

___ = volume of distribution

Rate of elimination

___ = clearance

t_1/2

Time for plasma concentration of drug to decrease by ½ after a single dose

Volume of distribution

How much of a single dose stays in plasma at equilibrium (after distribution phase)

Clearance

Amount of drug from single dose cleared from plasma per hour

Oral fraction

Fraction of single oral dose that gets to plasma

C₀

Plasma concentration right at equilibrium = time 0

Blood, total body water, body fat, other body tissues and organs

Areas for distribution

Small, high

Drugs with high water solubility have a [small / large] volume of distribution and [low / high] blood concentrations.

Large, low

Drugs with high lipid solubility have a [small / large] volume of distribution and [low / high] blood concentrations.

One-compartment model

1. Depicts body as a single, kinetically homogenous unit

   1. Simplest model

Instantaneously, same

1. In a one-compartment model, distribution is assumed to occur ___ between the blood and other body fluids and tissues

2. However, this does not mean that drug concentrations are the ___ throughout the body

Equal

Drug concentrations in the plasma/serum rarely ___ drug concentrations in other body fluids and tissues.

Proportional, 1/2

1. The underlying assumption in pharmacokinetics is that rate of change of drug concentrations in the plasma is ___ to the rate of change of concentration in the tissue (i.e., at the drug receptor)

2. In other words, if over a period of time plasma drug concentration goes down by ½, then concentration of drug at tissue decreases by ___

L

Units of volume of distribution (Vd)

Biologic half-life (t1/2)

Time for plasma concentration of drug to decrease by ½ after giving a single dose

1. Specific value for each drug

1st order

Are the majority of drugs eliminated through 1st order or 0 order kinetic rate?

Proportional

A first order process is one in which the rate of elimination of drug from the body at any time is ___ to the amount of drug in the body at that time (C)

Kel

Rate elimination constant for each drug

C

Concentration of drug

n

Kinetic order of process

Either equals 1 (first-order) or 0 (zero-order)

Five

It takes approximately ___ half-lives to reach steady-state concentration

First-order kinetic rate

1. A constant fraction of the drug present is eliminated per unit time

2. The rate of elimination is proportional to the amount of drug in the body

3. The rate of drug decay changes with concentration, but the rate constant (K) does not

4. The majority of drugs are eliminated in this way

Zero-order kinetic rate

1. If elimination mechanisms become saturated, the kinetics follow this process (nonlinear kinetics)

2. A constant quantity of drug is eliminated per unit of time

3. This form of kinetics occurs with several important drugs at high dosage concentrations: aspirin, ethanol, phenytoin, and is initially the case in large intoxications

Shorter

The faster the drug is eliminated, the [longer/shorter] the half-life.

Plasma clearance (Clp)

Amount of drug from single dose cleared from plasma per hour

Clearance

Rate of elimination times the total volume that needs to be cleared

Faster

The faster the rate of elimination, the [slower/faster] the clearance.

Faster

The larger the volume of distribution (indication of the total drug in body plasma is drawing from), the [slower/faster] the clearance.

Bioavailability of oral fraction

1. Fraction of oral dose given that gets to plasma

2. Can be measured by dividing the area under the concentration vs. time curve of an oral dose of the drug (AUCoral) by the area under the concentration vs. time curve for an IV dose of the drug (AUCi.v.)

Steady-state

1. Concentration of drug in plasma remains stable and from dose to dose (rate in = rate out during a dosing interval)

   1. Replacing drug by dosing at same rate as drug is being eliminated/metabolized

Two-compartment model

1. Often, drugs entering the body do not instantly and equally distribute (equilibrate) into all tissues

2. Highly-perfused organs and tissues such as the liver and kidney should be in rapid distribution and equilibrium with the blood

3. May be treated kinetically as a common homogenous unit generally referred to as the central compartment

4. Drug concentrations in poorly perfused tissues (e.g., muscle, lean tissue, fat, etc.) are referred to as the peripheral compartment and equilibrate more slowly than the central compartment

5. Most all drugs actually distribute in this model

Middle

Where in the therapeutic range should one aim if toxicity is not a major issue?

Top

Where in the therapeutic range should one aim if there is no major toxicity and efficacy is an issue?

Bottom (monitor response and adjust the dose upward as necessary)

Where in the therapeutic range should one aim if toxicity is an issue or is unknown?