Bioavailability & Drug Distribution PDF

Bioavailability Windows is not genuine Click this message to learn how to get genuine. Bioavailability: Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. (chemically unchanged form). For example, if 100 mg of a drug is...

Bioavailability Windows is not genuine Click this message to learn how to get genuine. Bioavailability: Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. (chemically unchanged form). For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 or 70%. Determining bioavailability is important for calculating drug dosages for intravenous routes of administration. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after oral administration with plasma levels achieved by IV administration. After IV administration, 100% of the drug rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC)can be measured.  Bloavallability = AUC oral x 100 AUC IV drug of concentration Drug IVgiven Plasma AUC (IV) Drug glven oraily AUC (oral) H Time Drug administered Factors that influence bioavailability: 1. First - pass hepatic metabolism: When drug is absorbed across the GI tract. It enters the portal circulation before entering the systemic circulation. If the is rapidly metabolized by the liver, the amount of unchanged reach to systemic circulation is decreased (lidocaine, propranolol). 2. Solubility of the drugs: Hydrophilic drug are poorly absorbed because of their inability to cross the lipid - rich cell membrane.  3. Chemical instability: Some drug such as penicillin G, are unstable in the pH of the gastric contents, insulin are destroyed in the GI tract by digestive enzymes. 4. Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, enteric coatings, and the presence of excipients can influence the ease of dissolution and, therefore, alter the rate of absorption. Drug Distribution Drug Distribution: Drug distribution is the process by which a drug reversibly leaves the blood stream and enter the extracellular fluid and tissues This process depend on: A. Blood flow B. Capillary permeability. C. Binding of drug toproteins (plasma protein) D. Lipophilicity E. Volume of distribution A. Blood flow: The rate of blood flow to the tissue capillaries varies widcly. For instance, blood flow to "vessel-rich organs" (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. B. Capillary permeability: is determined by: Capillary structure Chemical nature of the drug. Capillary structure in the brain is continuous, and no slit junction ( pore between the endothelial cell) in the basement membrane. But in liver and spleen discontinuous capillaries a arge plasma protein can pass.  Structure of a brain A Structure of liver B capillary capillary Astrocyte foot processes Large fenestratlons allow drugsto move between blood and Interstitlum In the lIver. Basement membrane Braln endothellal cell Drug Endothellal At tight junctlons, two adjoining cells merge so that the cells are slit Junctlons physlcally Jolned and form a continuous wall that prevents many Basement substances from entering the braln. Tight Junction membrane  C. Binding of drug to proteins: 1. Drug bind to plasma protein: non diffusible and slow transfer out of the vascular compartment. Plasma albumin is the major drug binding protein and may act as a drug reservoir, the free drug concentration is decreased. (phenytoin) The extent of binding to proteins is dependent on several factors such as: Affinity. number of binding sites. drug concentrations at the site. 2. Binding to tissue proteins: Many drugs accumulate in tissues, leading to higher concentrations in tissues than in interstitial fluid and blood. Drugs may accumulate because of binding to lipids, proteins, or nucleic acids. (cyclophosphamide) D. Lipophilicity The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic menmbranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. E. Volume of distribution The apparent volume of distribution, Và, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma.  Total body wator Plasmna Interstitlal volume Intracellular volume 42 llters Intracellular volume Extracelular volume 28 liters 14 iters Interstitlal volume Plasma volume 10 lters 4 Wters  Calculation of ofVd: The fact that drug clearance is usually a first-order process allows calculation of Vd. First order means that a constant fraction of the drug is eliminated per unit of time. After intravenous drug administration, the plasma drug concentration falls rapidly at first, as the drug is distributed from the central compartment to the peripheralcompartment. The Vd is calculated by dividing the dose of a drug given intravenously by the plasma drug concentration immediately after the distribution phase (a ). this drug concentration can be determined by ex trapolating the plasma drug concentration back to time zero. Dose V= Cpo  Distribution Elimination phase phase Extrapolation to time For example, if 10 mg of drug is injected into Serum 3 concentration zero gives Co the 2 hypothetical drug a patient and the plasma concentrationis concentration Co=1 predicted if the extrapolated back to time zero, and distribution had been achleved instantly. 0.5 CO = lmg/L, then Vd = 10 mg/l mg/L 0.4 0.3 = 10 L. 0.2 t1/2 0.1 Dose 1 2 Time V= -Rapid injection of drug Cp