Download Pharmacokinetics & Pharmacodynamics

Principles of
Pharmacology
Pharmacokinetics
&
Pharmacodynamics
Pharmacokinetics
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Movement of drugs in the body
Four Processes
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Absorption
Distribution
Metabolism
Excretion
Drug concentration at sites of action
influenced by several factors, such as:
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Route of administration
Dose
Characteristics of drug molecules (e.g., lipid
solubility)
Drug Absorption
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Routes of Drug Administration
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Oral (per os, p.o.)
Inhalation
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Mucous membranes
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intranasal (sniffing)
sublingual
rectal suppositories
Injection (parenteral)
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vapors, gases, smoke
intravenous (IV)
intramuscular (IM)
subcutaneous (SC)
intraperitoneal (IP; nonhumans only)
Transdermal
DRUG ABSORPTION
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Lipid solubility
pKa = pH at which 50% of
drug molecules are ionized
(charged)
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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
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e.g., stomach: 3-4, intestines: 8-9
pKa and Lipid Solubility
Image from McKim, 2007, p. 14
Routes of Drug Administration
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Oral Drug Administration
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Advantages:
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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.
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Routes of Drug Administration
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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
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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
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Cell Membranes
Capillaries
 Drug affinities for plasma proteins
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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
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Biotransformation (metabolism)
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Liver microsomal enzymes in
hepatocytes transform drug molecules
into less lipid soluble by-products.
Cytochrome P450 enzyme family
Termination of Drug Action
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Elimination
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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
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Kidney Actions
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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
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Factors Influencing Biotransformation
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Genetic
Environmental (e.g., diet, nutrition)
Physiological differences (e.g., age, gender
differences in microsomal enzyme systems)
Drug Interactions
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Some drugs increase or decrease enzyme
activity
e.g., carbamazepine stimulates CYP-3A3/4
 e.g., SSRIs inhibit CYP-1A2, CYP-2C
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Drug Time Course
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Time Course Studies important for
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predicting dosages/dosing intervals
maintaining therapeutic levels
determining time to elimination
Elimination Half-Life
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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
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TDM important for clinical decisions
Plasma levels rough approximation of
tissue/receptor concentrations
TDM goals
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assess medication compliance
avoid toxicity
enhance therapeutic response
Tolerance & Dependence
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Mechanisms of Tolerance
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Metabolic (Pharmacokinetic, Dispositional)
Cellular-Adaptive (Pharmacodynamic)
Behavioral Conditioning
Dependence
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Abstinence Syndrome
Not all addictive drugs produce physical
dependence.
Some nonaddictive therapeutic drugs (e.g.
SSRIs) can produce physical dependence.
Pharmacodynamics
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Drug actions at receptor sites and the
physiological/chemical/behavioral effects
produced by these actions
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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
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Receptors found on membrane spanning proteins
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Ligands (neurotransmitters, drugs) attach inside
spaces between coils, held by ionic attractions
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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
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Drug/Receptor Binding
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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
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Ion Channel Receptors
Carrier Proteins
G Protein-Coupled Receptors
Enzymes
Drug-Receptor Specificity
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Alterations to a drug’s chemical structure
may influence potency
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e.g., amphetamine vs. methamphetamine
Many drugs have multiple sites of action
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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
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100
100
Death
Percent of Subjects Dead
Percent of Subjects Sedated
Sedation
75
50
25
0
75
50
25
0
0.01
0.1
1
Dose (mg/kg)
10
100
10
100
1000
Dose (mg/kg)
10000