INTRODUCTION

TO PHARMACOKINETICS
AND PHARMACODYNAMICS
 Lecture objectives
After completing this lecture, you should
be able to:
 1. Define and differentiate between
pharmacokinetics and clinical
pharmacokinetics.
 2. Define pharmacodynamics and relate
it to pharmacokinetics.
 3. Describe the concept of the
therapeutic concentration range.
 4. Identify factors that cause
interpatient variability in drug
disposition and drug response.
 5. Describe situations in which routine
clinical pharmacokinetic monitoring
would be advantageous.
 6. List the assumptions made about drug
distribution patterns in both one- and
two compartment models.
 7. Represent graphically the typical natural
log of plasma drug concentration versus time
curve for a one-compartment model after an
intravenous (IV) dose.
 8. Understand the processes that control the
dose–response relationship
 9. Appreciate in a general way how
mathematical expressions in
pharmacodynamics and pharmacokinetics can
be used for the rational determination of
optimum dosing regimens
 Pharmacokinetics is defined as the
study of the time course of drug
absorption, distribution, metabolism,
and excretion.
 Clinical pharmacokinetics is the
application of pharmacokinetic
principles to the safe and effective
use of drugs in an individual patient.
 enhancing
efficacy

Primary
assessment goals of
decreasing
of organ clinical toxicity
function pharmaco
kinetics

assessment
of
adherence
 This fig.
illustrates how
drug conc. in the
accessible tissues
reflects its conc.
At the receptor
site i.e. kinetic
homogeneity
 N.B.
 Due to: physical or chemical properties,
in some drugs plasma concentration does
not reflect tissue concentration.
 Examples:
 Digoxin: concentrates in the myocardium
 Benzodiazepines: concentrate in fat.
 Pharmacodynamics: the relationship
between drug concentration at the site
of action and the resulting effect (i.e.
the time course and intensity of
therapeutic and adverse effects).

 Therapeutic drug monitoring (TDM ): the

use of assay procedures for
determination of drug concentrations in
plasma, and the interpretation and
application of the resulting
concentration data to develop safe and
effective drug regimens.
 TDM using drug concentration data is
valuable when the following occurs:
 A good correlation exists between the
pharmacologic response and plasma
concentration.
 Wide intersubject variation in plasma
drug concentrations results from a given
dose.
 The drug has a narrow therapeutic index.
 The drug’s desired pharmacologic effects
cannot be assessed readily by simple
means.
 The value of TDM is limited in situations:
 No well-defined therapeutic Cp range.
 Pharmacologically active metabolites
complicate the application of Cp data.
 Toxic effects are not related to drug the
Cp.
 There are no significant consequences
associated with too high or too low
levels.
Aminoglycosides, anticonvulsants
and cancer chemotherapy drugs
are most commonly monitored
drugs
variability in
plasma drug
concentration
among
subjects given
the same drug
dose
 Interpatient variability is primarily attributed
to one or more of the following:
 Variations in drug absorption
 Variations in drug distribution
 Differences in drug metabolism and elimination
 Disease states (renal or hepatic insufficiency)
 Physiologic states e.g., age, obesity,
sepsis/distributive shock of critical illness ….
 Drug interactions

Examples of drugs with

interpatient variability
include:
- Theophylline
- Doxorubicin
 Relationship of pharmacokinetics
and pharmacodynamics and factors
that affect each
 DRUGS AND DOSES
 Drugs are chemicals that alter
physiological or biochemical processes in
the body, making them useful in the
treatment, prevention, or cure of
diseases.
 Drug action begins with input (dose,
frequency of administration, route of
administration) and concludes with the
biological response (onset, intensity, and
duration of therapeutic effect), with
minimized any harmful effects.
 The steps between drug input and the
emergence of the response can be
broken down into two phases:
 Pharmacokinetic (all the events between
the administration of a dose and the
achievement of drug concentrations
throughout the body and
 Pharmacodynamics (all the events
between the arrival of the drug at its site
of action and the onset, magnitude, and
duration of the biological response).
 As indicated above, pharmacodynamics
(PD) is the onset, intensity, and duration
of drug response and how these are
related to the concentration of a drug at
its site of action.
 Drug Effects at the Site of Action:
 a. Drug response is initiated by
drug/receptor interaction.
 This interaction results in a
conformational change in the receptor,
which results in the generation of a
stimulus, that leads to a biochemical or
physiological response. Most (over 95%)
receptors are proteins , but e.g. the
receptors of the alkylating agents of
cancer chemotherapy are on DNA.
 The drug–receptor interaction involves a
reversible chemical bonding.
 An equilibrium is established between
the bound and the unbound drug.
 As the drug is eliminated from the body,
it dissociates from the receptor and the
response dissipates.
 A few drugs form irreversible covalent
bonds with their receptors. For example,
aspirin inhibits the formation of
thromboxane by binding covalently to
cyclooxygenase.
 Some drugs exert their action by bringing
about physicochemical changes in the
body without binding to receptors e.g.
conventional antacids and osmotic
laxatives.
 Postreceptor Events
 i. opening or closing of an ion channel,
e.g. the interaction of acetylcholine with
its nicotinic receptor results in the
opening of the ion channel causing Na+
to move into the cell which results in the
initiation of an action potential.
 ii. activation of a G-protein, which then
initiates a series of events that
culminate in the biological response.
 iii. stimulation of a receptor-associated
enzyme.
CONCENTRATION–RESPONSE
RELATIONSHIPS

Plots of response versus drug concentration:

on a linear scale (a) and on a semilogarthmic
scale (b)
Plot of response versus log concentration
for an agonist in the absence and presence
of increasing concentrations of an
antagonist.
Plot of response versus log concentration for
a full and a partial agonist.
 Pharmacokinetics (PK)
 1. Plasma Concentration of Drugs
 Drug concentrations in the plasma are the
focus in pharmacokinetics for two reasons:
 i. blood is easily obtained for drug
concentration analysis.
 - The concentration of drug in whole
blood is not commonly used. Blood with the
cellular elements removed, either by
centrifugation (plasma) or clotting (serum),
is preferred.
 - For plasma, an anticoagulant such as
heparin is used, which can interfere with the
assay of some drugs e.g. digoxin. Serum is
 ii. another reason for focusing on plasma
concentrations is that all drug input
processes conclude when drug reaches the
plasma, and all disposition processes
begin once drug is present in the plasma.
 Many drugs can reversibly bind with the
plasma proteins. This binding may be
expressed according to the law of mass
action:


 The term plasma concentration (Cp) in

PKs refers to the bound plus the free drug.
Processes of drug
absorption,
distribution and
elimination
(metabolism and
excretion) (ADME).
 2. Processes in Pharmacokinetics
 Pharmacokinetics involves the study of
the processes that affect the plasma
concentration of a drug at any time after
the administration of a dose.
 After a tablet is swallowed by a patient,
how does the API reach the systemic
circulation?
 Drug is pumped by the heart with the
blood so it has the opportunity to reach
every where including the biophase.
 The early plasma drug concentration is
affected by:
 - the rate and extent of absorption
 - the rate and extent of distribution
 - the elimination
 The table below summarizes the
individual pharmacokinetic steps
associated with the administration of a
tablet:
 The goal of pharmacokinetics is to study each of the
ADME processes with the aim of:
 1. Identifying the drug and patient factors that
determine the rate and extent of each process with
special consideration for the following:
 - effect of drug’s lipophilicity on absorption,
distribution, and elimination
 - factors that determine a drug’s distribution
pattern
 - the portion of the dose absorbed into the body
 - tissues into which a drug distributes
 - renal drug excretion as opposed to hepatic
elimination
 - how are pharmacokinetic processes affected by
patient characteristics, e.g.: age, renal or hepatic
impairment, ethnicity, and genetics
 2. quantification of ADME process:
 i. quantification of the extent of
absorption
 ii. quantification of the distribution
to the tissues
 3. Deriving mathematical expressions for
the rate processes in ADME
 4. DOSE–RESPONSE RELATIONSHIPS
 drug concentration in the body at any
time is proportional to the dose.
 plots of response as a function of dose,
resemble the plots of response versus
concentration.
 hyperbolic on the linear scale and a
sigmoidal on the semilog scale.
 Response versus log
of dose.

NB:
-low doses produce no effect
-Higher than maximum doses produce
no further effect
- toxicity mainly occurs at higher
doses.
 5 THERAPEUTIC RANGE
 In vivo pharmacodynamic studies are
rarely used for the development of
mathematical expressions of drug
response because:
 i. for many drugs data are subjective and
based on a patient’s or a physician’s
opinion.
 ii. The mathematical expressions derived
from pharmacodynamic models are
mainly nonlinear.
 iii. summarizing the characteristics of
the concentration–response relationship
can be complex.
 iv. In many cases a drug’s response lags
behind the plasma concentration.
 Instead, PK studies are more easily used.
 Therapeutic range
 This is defined as the range of plasma
concentrations that are associated with
optimum response and minimal toxicity
in most patients. See below
 Determination of the Therapeutic
Range
 It is usually determined by studying the
effects of a drug in a large population
and noting the plasma concentrations at
which patients:
 - Experience therapeutic effects
 - Experience side effects or toxicity
 The cumulative plot of the percentage of
patients experienced a therapeutic
response is then plotted as a function of
plasma concentration. See below
Whereas 100% of pts experience toxicity if concs are
high enough, fewer than 100% experience
therapeutic effects even at high concs.
Pts who do not respond are referred to as
nonresponders.
The concentrations selected for the MEC and the
MTC will depend on the margin of safety and the
risk–benefit ratio acceptable for a given indication.
 However, the therapeutic range has
limitations, which include:
 1. Certain pts will experience
therapeutic effects at concs below the
MEC, and others experience toxicity
below the MTC. Some patients never
respond therapeutically.
 2. It does not incorporate a graded
concentration-related response.

 3. It only applies to Cps that are in
equilibrium with the drug concs at the
site of action and some drugs e.g. it takes
about 6 to 8 h for digoxin to fully
distribute to its site of action. During this
distribution period the therapeutic range
will not apply.
 Therapeutic Index (TI) or Therapeutic
Ratio
 the therapeutic index or therapeutic
ratio is a way to express the safety
margin offered by a drug.
 It is the ratio of the dose that produces
toxicity in 50% of pts to the dose that
produces therapeutic response in 50% of
pts:
Thank
You