1. BASIC BIOPHARMACEUTICS
CHAPTER 10

2. CHAPTER OUTLINE How Drugs Work Concentration & Effect
ADME Processes & Diffusion
Absorption
Distribution
Metabolism
Excretion
Bioavailability
Bioequivalence
Review

3. HOW DRUGS WORK
Site of Action: the location where the drug causes an effect to occur
Drugs produce both desired and undesired effects.
Receptor: cellular material directly involved with the drug to cause the effect
Described as a lock into which the drug molecule fits like a key.
Specific cells respond only to certain drugs.
Drugs act only at specific receptors.
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4. AGONISTS VS. ANTAGONISTS
Agonists - produce a response that will either accelerate or slow normal cellular processes
epinephrine causes increased heart rate
acetylcholine like drugs cause decreased heart rate
Antagonists - block action by preventing other drugs from interacting with the receptor
Number of available receptors is important:
minimum # of receptors must be occupied by drug
extended stimulation with agonist can reduce #
extended inhibition with antagonist can increase #
sensitivity can also change with extended stimulation/inhibition
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5. HOW DRUGS WORK When drugs interact with the site of action, they can:
act through physical action
act chemically
modify metabolism
change osmolarity
incorporate into cellular material
form complexes
modify biochemical processes in cells
affect ion transport
influence production/release of hormones
and many others …

6. CONCENTRATION AND EFFECT
Cannot measure the amount of drug at the site of action to predict an effect
must measure the amount of drug in body
correlate that measurement to effect
One way to correlate amount of drug in the body and its effect is a dose-response curve.

7. DOSE RESPONSE CURVE
A specific dose is administered to many subjects and the effect is measured.
Some people respond to lower doses while others require a higher dose to get an equal response.
Makes dose response curve less than ideal.

8. CONCENTRATION AND EFFECT
A better way to relate the amount of drug in the body and its effect is to use a blood concentration-time profile.
Blood is generally used because of its rapid equilibrium between the site of administration and the site of action.
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9. BLOOD CONCENTRATION – TIME PROFILES
Minimum Effective Concentration (MEC)
Smallest concentration of drug to cause an effect
Minimum Toxic Concentration (MTC)
Largest concentration beyond which there are undesirable or toxic effects
Therapeutic window
Concentration range between MEC and MTC
Duration of action
Time drug concentrations are between the onset of action and the MEC reached by the declining blood concentrations

10. ADME PROCESSES AND BLOOD CONCENTRATION – TIME CURVES
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11. ADME PROCESSES AND HALF-LIFE
Blood concentrations are the result of four simultaneously occurring processes.
ADME – primarily driven by passive diffusion
absorption
distribution
metabolism
excretion
Half-life
Amount of time for the blood concentration of a drug to decline to one-half an initial value
Five times the half-life is used to estimate how long it takes to essentially remove the drug from the body.

12. ADME PROCESSES AND DIFFUSION
Movement through biological membranes
Primarily driven by passive diffusion
Lipid nature of the drug and membrane
Drugs are more lipid soluble if unionized.
Membranes tend to be lipoidal, but water-filled pores may be important in some membranes.
Active transport may play a major role with some drugs and/or membranes.

13. ABSORPTION Absorption Factors affecting oral absorption
the process transfers drug from the site of administration to the blood stream
Factors affecting oral absorption
gastric emptying time
stomach acid
movement through the small intestine
bile salts
intestinal enzymes
stomach
large
intestine
small
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14. DISTRIBUTION Blood flow rates to organs
high flow rates to heart, liver, kidneys
slow flow rates to muscle, fat, skin
Tissue membrane permeability
Protein binding
plasma protein bound drug produces no activity
can be considered a “depot” for inactive drug
free, or unbound, drug produces activity
drug can be displaced from protein binding sites by other substances or drugs

15. DRUG MOLECULES PENETRATING A CELL MEMBRANE
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16. PROTEIN BINDING
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17. METABOLISM
Transformation of drug into other chemicals (i.e., metabolite), some of which are active
Enterohepatic Cycling
The transfer of drugs and their metabolites from the liver to the bile in the gall bladder, then into the intestine, and then back into circulation
First-Pass Metabolism
In oral administration, the drug goes through the liver before it reaches the circulatory system. The liver’s enzymes can substantially degrade or destroy the drug.

18. METABOLISM Enzyme induction Enzyme inhibition
the increase in hepatic enzyme activity that results in greater metabolism of drugs
Enzyme inhibition
the decrease in hepatic enzyme activity that results in reduced metabolism of drugs

19. EXCRETION Kidney Fecal excretion can take one or two days.
Glomerular filtration is the process where plasma water, waste products, drugs, and metabolites are filtered into the kidney.
Some of these materials are secreted into the nephron.
Some of these materials are reabsorbed out of the nephron.
Fecal excretion can take one or two days.

20. EXCRETION The three processes of nephrons* glomerular filtration
secretion
reabsorption
*total drug excreted = amount filtered + amount secreted – amount reabsorbed.
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21. BIOAVAILABILITY
Amount of drug delivered to the site of action (extent) and the rate at which it becomes available
Information obtained from single blood concentration-time profile
rate of absorption
cannot determine the extent of absorption
Extent of absorption derived from a comparison of blood concentration-time profiles
absolute bioavailability – standard is rapidly administered IV solution
relative bioavailability – standard is any other standard dosage form

22. ABSOLUTE BIOAVAILABILITY
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23. Relative Bioavailability
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24. BIOAVAILABILITY F = drug product AUC standard product AUC Drug Name
Alprazolam 88
Digoxin 70
Oxycodone 42
Quetiapine 9
Warfarin 93

25. BIOEQUIVALENCE Bioequivalent Pharmaceutical equivalent
drug products that have the same bioavailability
Pharmaceutical equivalent
same active ingredient (same salt form)
same amount of active ingredient
same dosage form
inactive ingredients can be different

26. BIOEQUIVALENCE Pharmaceutical alternative Therapeutic equivalents
same active ingredient (salt form can be different)
amount of active ingredient can be different
dosage form can be different
inactive ingredients can be different
Therapeutic equivalents
pharmaceutical equivalents that produce the same effects in patients

27. BIOEQUIVALENCE
Approved Drug Products with Therapeutic Equivalence Evaluations
called the “Orange Book” because of cover color
published yearly
available online (