Principles of

Pharmacology
Pharmacokinetics
&
Pharmacodynamics

Pharmacokinetics

Movement of drugs in the body

Four Processes

Absorption
Distribution
Metabolism
Excretion

Drug concentration at sites of action

influenced by several factors, such as:

Route of administration
Dose
Characteristics of drug molecules (e.g., lipid
solubility)

Drug Absorption

Routes of Drug Administration

Oral (per os, p.o.)

Inhalation

Mucous membranes

intranasal (sniffing)
sublingual
rectal suppositories

Injection (parenteral)

vapors, gases, smoke

intravenous (IV)
intramuscular (IM)
subcutaneous (SC)
intraperitoneal (IP; nonhumans
only)

Transdermal

DRUG ABSORPTION
Lipid solubility
pKa = pH at which 50%
of drug molecules are
ionized (charged)

Only uncharged molecules are

lipid soluble.
The pKa of a molecule
influences its rate of absorption
through tissues into the
bloodstream.
pH varies among tissue sites

e.g., stomach: 3-4, intestines: 8-9

pKa and Lipid Solubility

Image from McKim, 2007, p. 14

Routes of Drug
Administration

Oral Drug Administration

Advantages:

relatively safe, economical, convenient,

practical

Disadvantages:
Blood levels are difficult to predict due to
multiple factors that limit absorption.
Some drugs are destroyed by stomach
acids.
Some drugs irritate the GI system.

Routes of Drug
Administration
Advantages of Injection Routes
Absorption is more rapid than with
oral administration.
Rate of absorption depends on blood
flow to particular tissue site (I.P. >
I.M. > S.C.).
Advantages specific to I.V. injection
No absorption involved (inject directly
into blood).
Rate of infusion can be controlled.
A more accurate prediction of dose is
obtained.

Routes of Drug
Administration

Disadvantages/Risks of Injection
A rapid onset of action can be
dangerous in overdosing occurs.
If administered too fast, heart and
respiratory function could collapse.
Drugs insoluble in water or
dissolved in oily liquids can not be
given I.V.
Sterile techniques are necessary to
avoid the risk of infection.

Drug Distribution

Cell Membranes
Capillaries
Drug affinities for plasma proteins

Bound molecules cant cross capillary walls

Blood Brain Barrier

Tight junctions in capillaries
Less developed in infants
Weaker in certain areas, e.g. area
postrema in brain stem
Cerebral trauma can decrease integrity
Placenta
Not a barrier to lipid soluble substances.

Termination of Drug Action

Biotransformation (metabolism)

Liver microsomal enzymes in

hepatocytes transform drug
molecules into less lipid soluble byproducts.
Cytochrome P450 enzyme family

Termination of Drug Action

Elimination

Two-stage kidney process (filter,

absorption)
Metabolites that are poorly reabsorbed by
kidney are excreted in urine.
Some drugs have active (lipid soluble)
metabolites that are reabsorbed into
circulation (e.g., pro-drugs)
Other routes of elimination: lungs, bile,
skin

Termination of Drug Action

Kidney Actions

excretes products of body metabolism

closely regulates body fluids and
electrolytes
The human adult kidney filters approx. 1
liter of plasma per minute, 99.9% of
fluid is reabsorbed.
Lipid soluble drugs are reabsorbed with
the water.

Termination of Drug Action

Factors Influencing Biotransformation

Genetic
Environmental (e.g., diet, nutrition)
Physiological differences (e.g., age,
gender differences in microsomal
enzyme systems)

Drug Interactions

Some drugs increase or decrease

enzyme activity
e.g., carbamazepine stimulates CYP-3A3/4
e.g., SSRIs inhibit CYP-1A2, CYP-2C

Drug Time Course

Time Course Studies important for

predicting dosages/dosing intervals

maintaining therapeutic levels
determining time to elimination

Elimination Half-Life

time required for drug blood levels to be reduced

by 50%
Approx. 6 half-lives to eliminate drug from body
With repeated regular interval dosing, steadystate concentration reached in approx. 6 x half-life

Therapeutic Drug Monitoring

TDM important for clinical decisions

Plasma levels rough approximation of
tissue/receptor concentrations
TDM goals

assess medication compliance

avoid toxicity
enhance therapeutic response

Tolerance & Dependence

Mechanisms of Tolerance

Metabolic (Pharmacokinetic, Dispositional)

Cellular-Adaptive (Pharmacodynamic)
Behavioral Conditioning

Dependence

Abstinence Syndrome
Not all addictive drugs produce physical
dependence.
Some nonaddictive therapeutic drugs (e.g.
SSRIs) can produce physical dependence.

Pharmacodynamics

Drug actions at receptor sites and

the physiological/chemical/behavioral
effects produced by these actions

Studies of drug mechanisms of action at

the molecular level
Provides basis for rational therapeutic
uses and the design of new, superior
therapeutic agents

Drug-Receptor Interactions

Receptors found on membrane spanning

proteins

Ligands (neurotransmitters, drugs) attach

inside spaces between coils, held by ionic
attractions

Continuous series of amino acid loops

Reversible ionic binding of ligand activates receptor

by changing protein structure.
Intensity of transmembrane signal is determined by
percentage of receptors occupied.

Drugs may influence transmembrane signal by

binding to neurotransmitter receptor or to
nearby site.

Drug-Receptor Interactions

Drug/Receptor Binding

Mimic actions of neurotransmitter at

same site (agonist)
Bind to nearby site and facilitate
neurotransmitter binding (agonist)
Block actions of neurotransmitter at
same site (antagonist)

Receptor Structures

Ion Channel Receptors

Carrier Proteins
G Protein-Coupled Receptors
Enzymes

Drug-Receptor Specificity

Alterations to a drugs chemical

structure may influence potency

e.g., amphetamine vs. methamphetamine

Many drugs have multiple sites of

action

Some sites of action are responsible for

side effects
e.g., tricyclic antidepressants: sedation,
dry mouth, blurred vision

Dose-Response Relationships
Potency
Efficacy

Dose-Response Functions
Efficacy (ED50 = median effective
dose)
Lethality (LD50 = median lethal dose)
Therapeutic Index = LD 50 /ED 50

100

100

Death

75

P e r c e n t o f S u b je c ts D e a d

P e rc e n t o f S u b je c ts S e d a te d

Sedation

50

25

75

50

25

0.01

0.1

Dose (mg/kg)

10

100

10

100

1000

Dose (mg/kg)

10000