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
 vapors, gases, smoke
 Mucous membranes
 intranasal (sniffing)
 sublingual
 rectal suppositories
 Injection (parenteral)
 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 can’t 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 by-products.
 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, steady-state
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
 Continuous series of amino acid loops
 Ligands (neurotransmitters, drugs) attach inside
spaces between coils, held by ionic attractions
 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 drug’s 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
Sedation Death
Percent of Subjects Sedated

75

Percent of Subjects Dead

75

50 50

25 25

0 0

0.01 0.1 1 10 100 10 100 1000 10000

Dose (mg/kg) Dose (mg/kg)