BASIC BIOPHARMACEUTICS CHAPTER 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. 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.

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 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.

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 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.

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 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 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.

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 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.

PROTEIN BINDING 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.

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 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

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.

EXCRETION The three processes of nephrons* glomerular filtration secretion reabsorption *total drug excreted = amount filtered + amount secreted – amount reabsorbed. 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.

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 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.

Relative Bioavailability 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.

BIOAVAILABILITY F = drug product AUC standard product AUC Drug Name Alprazolam 88 Digoxin 70 Oxycodone 42 Quetiapine 9 Warfarin 93

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

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

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)