1. Principles of Pharmacology Pharmacokinetics & Pharmacodynamics

2. 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)

3. 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

4. DRUG ABSORPTION Lipid solubility
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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

5. pKa and Lipid Solubility
Image from McKim, 2007, p. 14

6. Routes of Drug Administration
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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.

7. Routes of Drug Administration
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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.

8. Routes of Drug Administration
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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.

9. 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.

10. Termination of Drug Action
Biotransformation (metabolism)
Liver microsomal enzymes in hepatocytes transform drug molecules into less lipid soluble by-products.
Cytochrome P450 enzyme family

11. 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

12. 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.

13. 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

14. 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

15. 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

16. 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.

17. 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

18. 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.

19. 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)

20. Receptor Structures Ion Channel Receptors Carrier Proteins
G Protein-Coupled Receptors
Enzymes

21. 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

22. Dose-Response Relationships
Potency
Efficacy

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