BASIC BIOPHARMACEUTICSCHAPTER 10

CHAPTER OUTLINE

• How Drugs Work• Concentration & Effect• ADME Processes & Diffusion• Absorption• Distribution• Metabolism• Excretion• Bioavailability• Bioequivalence• Review

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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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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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 …

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.

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.

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. Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission

from the publisher.

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

ADME PROCESSES AND BLOOD CONCENTRATION – TIME CURVES

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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.

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.

ABSORPTION

• 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

largeintestine

smallintestine

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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

DRUG MOLECULES PENETRATING A CELL MEMBRANE

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PROTEIN BINDING

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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.

METABOLISM

• Enzyme induction– 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

EXCRETION

• Kidney

– 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.

EXCRETION

• The three processes of nephrons*– glomerular filtration– secretion– reabsorption

*total drug excreted = amount filtered + amount secreted – amount reabsorbed.

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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

ABSOLUTE BIOAVAILABILITY

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Relative Bioavailability

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BIOAVAILABILITY

• F =drug product AUC

standard product AUC

Drug Name Bioavailability %

Alprazolam 88

Digoxin 70

Oxycodone 42

Quetiapine 9

Warfarin 93

BIOEQUIVALENCE

• Bioequivalent– 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

BIOEQUIVALENCE

• Pharmaceutical alternative– 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

BIOEQUIVALENCE

• Approved Drug Products with Therapeutic Equivalence Evaluations

– called the “Orange Book” because of cover color– published yearly– available online

(www.fda.gov/cder/ob/default.htm)