Fundamentals Of Pharmacology PK Principles PDF

▶ Absorption is the transfer of a drug from the site of administration to the bloodstream. ▶ The rate and extent of absorption depend on the environment where the drug is absorbed, chemical characteristics of the drug, and the route of administration (which influ...

▶ Absorption is the transfer of a drug from the site of administration to the bloodstream. ▶ The rate and extent of absorption depend on the environment where the drug is absorbed, chemical characteristics of the drug, and the route of administration (which influences bioavailability). ▶ Routes of administration other than intravenous may result in partial absorption and lower bioavailability. 1. Effect of pH on drug absorption 2. Blood flow to the absorption site 3. Total surface area available for absorption 4.Contact time at the absorption surface 5. Expression of P- ▶ Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. FACTORS THAT INFLUENCE BIOAVAILABILITY 1. First-pass hepatic metabolism 2. Solubility of the drug 3. Chemical instability 4. Nature of the drug formulation ▶ particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients ▶ Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues. 1. Blood flow 2. Capillary permeability 3. Binding of drugs to plasma proteins and tissues 4. Lipophilicity 5. Volume of distribution ▶ Drug elimination is described in terms of hypothetical clearance well-stirred from compartment a containing uniform drug distribution. ▶ METABOLISM ▶ EXCRETION ▶ The term clearance describes the process of drug elimination from the body or from a single organ without identifying the individual processes involved. ▶ Clearance may be defined as the volume of fluid removed of the drug from the body per unit of time. ▶ First-order Elimination  First order kinetics means that the rate of change of drug concentration by any process is directly proportional to the drug concentration remaining to undertake that process.  The rate of drug metabolism and elimination is directly proportional to the concentration of free drug  First-order kinetics is also referred to as linear kinetics. Zero-order Elimination  Aspirin, ethanol, and phenytoin  The amount of drug eliminated does not change with the amount or concentration of drug in the body, but the fraction removed varies.  The enzyme is saturated by a high free drug concentration, and the rate of metabolism remains constant over time.  Also called nonlinear or saturation kinetics ▶ Biotransformation ▶ Metabolism leads to production of products with increased polarity, which allows the drug to be eliminated.  Prodrugs are inactive and must be biotransformed in the body to metabolites that have pharmacologic activity. ▶ Clearance (CL) estimates the amount of drug cleared from the body per unit of time. ▶ Pathways of drug biotransformation may be divided into two major groups of reactions, phase I and phase II reactions.  Phase I, or asynthetic reactions, include oxidation, reduction, and hydrolysis.  Phase II, or synthetic reactions, include conjugations. ▶ Phase I biotransformation reactions occur first and introduce or expose a functional group on the ▶ drug molecules. Phase I reactions convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group, such as –OH or – NH2. ▶ Oxidation – catalyzed by monooxygenase (cytochrome P-450) ▶ Reduction ▶ Hydrolysis  Phase II consists of conjugation reactions. Many phase I metabolites are still too lipophilic to be excreted. A subsequent conjugation reaction with an endogenous substrates results in polar, usually more water- soluble compounds that are often therapeutically inactive. Conjugation reactions - combine the parent drug (or its metabolites) with certain endogenous constituents: glucuronic acid, glycine, glutamine, sulfate, glutathione, two-carbon acetyl fragment, or one-carbon methyl fragment ▶ Drug excretion is the removal of the intact drug. ▶ The kidney is the main excretory organ for the removal of metabolic waste products and plays a major role in maintaining the normal fluid volume and electrolyte composition in the body. ▶ The processes by which a drug is excreted via the kidneys may include any combination of the following:  Glomerular filtration  Active tubular secretion  Tubular reabsorption ▶ Half- life The most useful in designing drug dosage regimens.  The time required to change the amount of drug in the body by one- half during elimination ▶ Maintenance dose  Drugs are generally administered to maintain a steady state concentration (Css) within the therapeutic window. ▶ Loading dose  Drug is administered to achieve the desired plasma level rapidly, followed by a maintenance dose to maintain the steady state