Define the terms biopharmaceutics and bioavailability.

Transcription

1 Pharmaceutics Reading Notes Define the terms biopharmaceutics and bioavailability. Biopharmaceutics: the area of study concerning the relationship between the physical, chemical, and biological sciences as they apply to drugs, dosage forms, and drug action What do the terms absorption, distribution, metabolism and elimination (ADME) mean? Absorption: the diffusion of drug from the gastrointestinal tract to the bloodstream Distribution: the diffusion of drug throughout the circulatory system and to the various body tissues and organs Metabolism: the process by which drugs are biotransformed into pharmacologically active or inactive products Elimination: the removal of drug/metabolites from the body via metabolism and excretion to urine or feces What events occur following the administration of a drug? A drug must: 1) dissolve in the stomach and small intestine 2) cross the intestinal epithelium 3) cross the capillary epithelium to enter circulation 4) move through the bloodstream 5) cross the capillary endothelium to enter target site 6) and/or cross the capillary endothelium to enter the liver for metabolism 7) and/or cross the capillary endothelium to enter the kidney for excretion What are the different processes or mechanisms by which compounds can cross a membrane? - Paracellular transport (between cells) - Transcellular transport (through cells) o Passive diffusion: proceeds as long as there is a concentration gradient Through hydrophilic channels Through the lipid bilayer o Facilitated diffusion o Active transport o Transcytosis What is Fick s First Law and what to the terms of the equation mean? Fick s First Law: the rate of diffusion or transport across a membrane is proportional to the difference in drug concentration on both sides of the membrane.

2 dc dt = P A D(C! C! ) h Where P is the partition coefficient (higher = more hydrophobic), A is the membrane surface area, D is the solute diffusion coefficient (denotes how rapidly a molecule can diffuse through the liquid medium), C 1 and C 2 are the drug concentrations on each side of the membrane (C 1 à C 2 ), and h is the thickness of the cell membrane. Diffusion coefficients of most small molecule drugs are similar, and cell membrane thickness is relatively constant. Also, when C 2 is the bloodstream, it is negligibly small due to rapid diffusion/dilution, and can thus be taken as zero. The equation can therefore be simplified as: dc dt = P(C!) Gastrointestinal absorption of most drugs follows first-order kinetics; the rate depends directly on drug concentration. How does ph affect ionization of a drug molecule; how can you estimate the percent of a molecule ionized/unionized? The degree of ionization for a drug depends on both the ph of solution and on the pk a of the drug. Estimation of drug ionization can be accomplished using the Henderson-Hasselbalch equation. ph = pk! + log A! HA or pk! ph = log!! What effect does ionization have on movement through a membrane? The ionized forms drugs cross membranes less readily than their un-ionized forms due to decreased lipid solubility and the highly charged nature of the cell membrane. Therefore, the driving force for diffusion of weak acids and bases is the concentration gradient of the un-ionized form. When there is a ph difference between the intracellular and extracellular environment, the concentration of ionized solute is different at equilibrium; the total solute concentration is higher on the side where the ph favors greater ionization (ion trapping). What are the types of carrier-mediated transport across membranes? Facilitated diffusion: the solute is not transported against a concentration gradient Uniporter: moves one solute molecule at a time in one direction Active transport: the solute is transported against a concentration gradient Antiporter: moves two solute molecules in opposite directions!"

3 Symporter: moves two solute molecules in one direction Multidrug efflux transporters: binds many dissimilar molecules as they cross the membrane and transports them out of the cell (examples: p-glycoprotein, multidrug resistance protein) Transcytosis: probably does not play a significant role in small molecular transport; may, however, be important for protein-based drugs Endocytosis (e.g., pinocytosis, phagocytosis) Exocytosis Define pharmacokinetics. Pharmacokinetics: the quantitative description of the time course and pattern of drug absorption and disposition Why and how is the plasma concentration of a drug important? Plasma drug concentrations are related to tissue drug concentrations, which in turn are correlated with pharmacological effect. What is the general shape of the plasma level curve following intravenous administration and oral administration of a drug? Following IV administration, the plasma levels begins at C max and falls in an exponential fashion. Following oral administration, plasma levels rise until they reach C max, after which they fall in an exponential fashion. Describe the following parameters of the plasma level curve: C max, t max, AUC. C max : the highest point of plasma drug concentration; where the rate of absorption equals the rate of elimination T max : the time after drug administration at which C max is reached AUC: a measure of the total amount of drug in the circulation over time Define the following terms: minimum effective concentration, minimum toxic concentration, therapeutic range, onset of action, duration of action, intensity of effect. Minimum effective concentration (MEC): the lowest plasma concentration needed for therapeutic effect Minimum toxic concentration (MTC): aka maximum safe concentration; the plasma concentration above which toxic effects are seen Therapeutic range: aka therapeutic window; plasma concentrations between the MEC and MTC Onset of action: the time required after administration of the drug for therapeutic effects to appear Duration of action: the length of time plasma concentrations remain above the MEC

4 Intensity of effect: generally depends on how high the plasma concentration is above the MEC What is the composition of the plasma membrane and what purpose does each component serve? The primary components of the plasma membrane are lipids (mostly phospholipids) and proteins, as well as carbohydrates attached thereto. Phospholipids form a double-layer barrier that limits movement of large molecules into and out of the cell. Other lipids, such as cholesterol and fatty acids, are also dispersed in the lipid bilayer and serve various structural and functional purposes. What is the fluid-mosaic model? In the fluid-mosaic model, that cell membrane is composed of a fluid-like bilayer of phospholipids, in which protein components float freely. Why is the membrane fluid? The membrane is fluid due to the weak hydrophobic bonds between adjacent phospholipids. Double bonds within these phospholipids create kinks which decrease the strength of these bonds, allowing for a looser, more malleable structure. What is the purpose of glycosylation of the membrane? Carbohydrate groups attached to lipids (glycolipids) and proteins (glycoproteins) mediate cell-to-cell interactions, such as recognition by the immune system. Differentiate between the terms systemic administration and local administration. Systemic administration: drug travels through the circulatory system to reach the site of action. Local administration: drug is administered directly to the site of action (e.g., topical cream) What are factors that affect the rate of absorption of a drug? Dissolved drug molecules must cross the epithelial tissue at the absorption site and the capillary endothelium to enter the bloodstream. The latter occurs readily for most drugs. The former tends to occur more slowly and is thus the rate-limiting step in absorption. Rate of absorption into the bloodstream depends on: - The physicochemical properties of the drug - The permeability of the epithelial membrane at the absorption site - The surface area of the membrane exposed to drug at the absorption site - The concentration gradient of the drug between the absorption site and the bloodstream The equation for the rate of absorption is given by: absorption rate = P A D (C! C! ) h where P is the partition coefficient of the drug, A is the surface area of the membrane, D is the diffusion coefficient of the drug, Ca and Cp are the drug concentrations at the site of absorption and in the plasma, respectively, and h is the thickness of the epithelial membrane at the absorption site.

5 If we assume Cp is negligible due to blood flow, and combine P, A, D, and h to give a constant k, the equation becomes: absorption rate = k C! This is a first-order expression (directly dependent on the concentration of drug) and k is the first-order permeation rate constant. Note that the actual rate of absorption is often less than predicted by this equation, due in part to drug efflux pumps. Why is the stomach not the optimal site for drug absorption? 1) Due to the low ph of the stomach, most weak bases are completely ionized, which increases solubility but decreases absorption across membranes 2) Drugs spend relatively little time in the stomach after dissolution 3) The surface area of the stomach is relatively small What anatomical structure causes the large membrane surface area of the small intestine? The intestinal mucosa is bent into folds called the folds of Kerckring that increase intestinal surface area by a factor of 3. These folds are composed of finger-like protrusions called villi that increase surface area by another factor of 10. Villi are composed of endothelial cells, each of which features brush-like projections called microvilli that increase the surface area by a further factor of 20. Explain passive transcellular diffusion of drug molecules, especially related to degree of ionization. In the small intestine, where most drug absorption occurs, a dissolved drug that exists predominantly in its un-ionized form will be absorbed faster than one that exists predominantly in its ionized form. The dissolution and absorption of nonionizable drugs will not be influenced by ph in the GI tract. What is intestinal drug efflux? Non-specific multidrug resistance (MDR) transporters move certain drugs unidirectionally from the epithelial cell back into the intestinal lumen, thereby slowing or preventing absorption. However, these can be saturated with high enough concentration of drug. What are some factors that affect gastric emptying? Anticholinergic drugs slow gastric emptying. Laxatives can increase the rate of gastrointestinal motility, while age generally decreases it. How may the size of a solid drug particle influence absorption? When the surface area of drug particles is increased, the rate of dissolution is proportionally increased. If dissolution of the drug is otherwise slow, using smaller particle sizes can increase the rate/extent of absorption. What can be done to change particle surface area?

6 Drugs can be made into micronized powders to increase surface area. Conversely, drug powder can be blended with a water-soluble polymer, forming a dispersion. If this dispersion is then solidified, a highlysoluble powder is formed. What do the terms crystalline and amorphous mean and how would you expect the form to affect absorption? Solid drug materials may occur as pure crystalline substances of definite identifiable shape or as amorphous particles without definite structure. Amorphous forms are usually more soluble than crystalline forms (which means faster absorption), but crystalline forms may have higher stability. What is a polymorph and what is the affect of polymorphic form on drug absorption? A polymorph is a drug that can exist in more than one crystalline form. Only one form of a pure drug substance is stable at a given temperature and pressure; the others, known as metastable forms, convert gradually over time to the stable crystalline form. Once dissolved, different crystalline forms are indistinguishable. Describe how the salt form of a weak acid or weak base drug may affect absorption. Sodium and potassium salts of weak organic acids and hydrochloride salts of weak organic bases dissolve much more readily then their respective free acids or bases. What is bioavailability and bioequivalence? Bioavailability: describes the rate and extent to which an active drug ingredient is absorbed from a drug product and becomes available at the site of action Bioequivalence: refers to the comparison of bioavailabilities of different formulations, drug products, or batches of the same drug product How is bioavailability determined? Bioavailability is determined by studying the pharmacokinetic profile of the drug and/or its metabolite(s) over time in the appropriate biological system (blood, plasma, urine, etc). What do the terms pharmaceutical equivalents, pharmaceutical alternatives, bioequivalents, and therapeutic equivalents mean? Pharmaceutical equivalents: drug products that contain identical amounts of the identical active drug ingredient in identical dosage forms (though not necessary containing the same inactive ingredients) that meet identical standards for identity, strength, quality, purity, etc. Pharmaceutical alternatives: drug products that contain the identical therapeutic moiety or its precursor but not necessarily in the same amount or dosage form or as the same salt or ester. Bioequivalents: pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions

7 Note: some pharmaceutical equivalents or alternatives may be considered bioequivalent despite differences in extent or rate of absorption if such differences are intentional or therapeutically irrelevant Therapeutic equivalents: pharmaceutical equivalents that provide essentially the same therapeutic effect when administered to the same individuals using the same dosing regimens What is the FDA publication, Approved Drug Products with Therapeutic Equivalent Evaluations? What is a crossover design study and how is it used in bioavailability studies? Summarize the factors that influence the bioavailability of orally administered drugs.