PHARMACOKINETICS

DEVELOPMENT OF THE DOSAGE

REGIMEN

Kirsten Culver, PhD

Pharmacokinetics
Four processes of pharmacokinetics
 Absorption
 Weakly acidic drugs are absorbed in the stomach
 Weakly basic drugs are absorbed in the intestines
 Distribution
 Only drugs in a free or “unbound” state can be distributed
 Non-polar, fat soluble drugs are easily distributed
 Metabolism
 Occurs mainly in the liver
 Creates water soluble metabolites via Phase 1 (Oxidation) & Phase
2 (Conjugation) reactions
 Excretion
 Only water soluble metabolites can be excreted via the urine
Pharmacokinetics and the Dosage
Regimen
These four pathways control
 Concentration of drug present in the serum
 Therapeutic concentration of drug
 The onset, peak and duration of drug actions
 Onset of drug action - based on rate of absorption
and distribution
 Intensity of drug action - based on the amount of
drug that is absorbed
 Duration of drug action - based on the rate of drug
metabolism
 Drug dosing interval
 Drug metabolism and elimination
Bioavailability and the Dosage
Regimen
Bioavailability
Fraction (percentage) of drug that

reaches the systemic circulation in a

chemically unchanged and biologically
active form
Factors that influence bioavailability

 First pass hepatic metabolism e.g. lidocaine

 Chemical instability e.g. insulin

 Drug formulation e.g. extended release drugs

 Plasma protein binding

Distribution and the Dosage
Regimen
Distribution
 Process by which a drug reversibly leaves
the blood stream and enters body tissues
 Factors that influence drug distribution
 Blood flow
 Capillary permeability
 Plasma protein binding
 Drug structure
 Non-polar, lipophilic molecules cross cell membranes
more easily
Volume of distribution
 Theoretical volume into which a drug is
distributed in the body
 Consists of several fluid compartments
depending on whether the drug is polar
or non-polar:
 Plasma
 Interstitial fluid
 Intracellular fluid
Apparent Volume of
Distribution
 The volume into which a drug is known to distribute
within the body is referred to as the Apparent Volume
of Distribution (Vd)
 This volume is expressed in
 Liters (L)
 Liters/kilogram (L/kg)
 Every drug has its own unique apparent volume of
distribution
 Why should we care?
 Vd can be used to calculate the amount of drug required (dose)
to achieve a specified concentration of drug in the plasma
Therapeutic Concentration
 For a drug to exert a therapeutic effect,
the concentration of the drug in plasma
must fall within the therapeutic
concentration range of that drug
 The therapeutic concentration range of a
drug ([D]th) is often expressed as:
 mg/L
 ug/mL
Therapeutic Concentration
The therapeutic range of Drug A is 1–3
mg/L
 A plasma concentration of 2 mg/L falls within
this range and would be expected to produce a
therapeutic response
 A plasma concentration of 5 mg/L is above the
therapeutic range and can be expected to
cause adverse effects (toxicity)
 A plasma concentration of 0.5 mg/L is below
the therapeutic range and would be expected
to produce little effect
The therapeutic range
Loading Dose
 Used to quickly achieve a high therapeutic
plasma concentration of drug ([D]o)
 Loading dose, Vd and [D]o are related by
the equation shown below

Wd = [D]o x Vd

[D]o = Top of the therapeutic range of the drug

Wd = Weight of drug administered to patient
Vd = Apparent volume of distribution
Dosing Regimens: Not a Static
Phenomena!
 While understanding how to calculate a
loading dose is valuable, it is important to
understand that often patients are on
medications for an extended period of time
 The rate of drug elimination is not taken into
consideration when calculating a loading dose
 The rate at which a drug is metabolized
and excreted from the body plays a critical
role in determining how plasma drug
concentrations can be maintained within the
therapeutic range over time
Dosing Regimens: Not a Static
Phenomena!
 Drug Elimination
Drug Concentration (ug/mL)

0.6
Pain Drug B:
[D]th thraputic range
= 0.2 - 0.6 ug/mL
0.3 t1/2
0.2

1 2 3 4 5 6 7 8
Time (hours)

 Patient #1, the t1/2 of the drug is 5 hours. The concentration of the drug falls below
therapeutic concentrations 8 hours after the dose
 Patient #2, the t1/2 of the drug is 3 hours. The concentration of the drug falls below
therapeutic concentrations 5 hours after the dose
Repeated Dose Drug
Therapy
 Most drugs are prescribed for an
extended period of time (e.g. post-
operative pain management)
 It is important to keep the concentration
of Pain Drug B within the therapeutic
range to control the patient’s pain
 In the current example, the patient
should receive the next dose of drug
before the concentration of drug in the
plasma falls below 0.2 ug/mL
Plateau Principle
 The t1/2 life of a drug provides a useful measure
called the Plateau Principle:

95% of the steady state will be reached

after 4 half-lives
 This means that after you start, stop or change a
dosage regimen, it will take 4 half-lives for the
concentration of the drug in plasma to be stable
 Plateau Principle
Drug Concentration (ug/mL)

Peak Loading Dose: 120 mg

0.9 Maintenance Dose: 120 m
t1/2 : 5 hours
[D]th: thraputic range 0.2 – 0.6 ug
0.6

Trough

0.3
5 10 15 20 25 30 35
Time (hours)

 After 20 hours (t1/2 x 4) a plateau will be reached and there will

be no changes in the peak or trough concentrations following
subsequent doses
 Therapeutic vs. Toxic
Concentration Range
Drug Concentration (ug/mL) Loading dose is maintained
Peak [D]
0.9

0.6

Trough [D]

0.3
5 10 15 20 25 30 35
Time (hours)
 If the loading dose is always used for subsequent drug administrations, the peak
values of [D] will be well above the therapeutic range, and the patient will likely
experience toxicity/adverse events
 In the case of Pain Drug B, an overdose may lead to difficulty breathing
Maintenance Dose
 Amount of drug (dose) required to maintain the
plasma concentrations of the drug within the
therapeutic range
 This dose should always be smaller than the
loading dose
Wd = [D]pl x T x Clr

Wd = Weight of drug administered to the patient

[D]pl = Middle of the therapeutic range of the drug
T = Dose interval
Clr = Clearance
Clearance
 Volume of plasma completely cleared of a
drug per unit of time (L/hr)
 Clearance, Vd and t1/2 are related by the
equation shown below

Clr = k x Vd

Clr = Clearance
k = Elimination Rate Constant (k = 0.693/t1/2 )
Vd = Apparent Volume of Distribution of the drug
 Dosing Interval
 Amount of time between doses
 The dosing interval may be calculated using
the following equation

[D]
log - (k/2.303) x T
=
[Do]
[D] = Bottom of the therapeutic range or
Concentration of drug after a given period of time
[Do] = Top of the therapeutic range or
Concentration of drug in plasma at the start of
treatment
k = Elimination Rate Constant (k = 0.693/t1/2 )
How about some practice?
 As a nurse, you will use these equations to determine
how much drug to give your patient and to ensure that
the drug orders are correct
 On the midterm and final exam, you will be expected
use these equations to determine
 Loading dose
 Clearance
 Dose interval
 Maintenance dose
 The online learning module “Pharmacokinetics:
Calculating the Correct Dose” will provide you with
another opportunity to review these equations and
their significance
 This module also contains practice questions similar to
those you will see in practice (and in the exams)