Week 1 - Orientation and Introduction to Biopharmaceutics and Pharmacokinetics.pdf

P HA R MA  OLFU VISION: A premier inclusive university of choice aspiring to improve man as man by developing The Our...

P HA R MA  OLFU VISION: A premier inclusive university of choice aspiring to improve man as man by developing The Our Lady of Fatima University, together with Fatima Medical Science Foundation, Inc., is dedicated to the individuals through a legacy of improvement of man as man through the holistic excellent education and formation of individuals imbued with knowledge, skills, and virtues. To achieve this end, the university aims to: compassionate value formation. Commit itself to the service of society through quality education; Develop the capabilities of individuals in order to maximize their potentials; Nurture future professionals with the requisite academic foundation and conventional skills so as to mold them into highly-respected leaders and members of society; Respond effectively to the changing needs and conditions of the times through continuing professional education and research Inculcate social awareness through community outreach program; Instill and apply environmental awareness in order to protect our national and global resources; Imbue a deep sense of nationalism and pride in our Filipino heritage; Uphold virtues of truth, justice integrity, compassion and faith in God  ASPIRATIONAL COMPASSIONATE HONORABLE INSPIRING ETHICAL VISIONARY EFFICIENT RESPONSIBLE RESPECT INTEGRITY SERVICE EXCELLENCE COURSE DETAILS Course Code: PHBP 221 Credit units: 3 units lecture Prerequisite/Co-requisite: Physical Pharmacy Course Placement: Second year, 1st Semester Class schedule: COURSE DESCRIPTION This course deals with the study of the intrinsic, formulation, physiologic, and pathologic factor affecting bioavailability of drugs from drug products This course focuses on drug absorption, distribution, metabolism, excretion and how these processes are modified by the different factors affecting the presence and action of the drug in the biologic system.  Prelim Exam – 20% Midterm Exam – 20% Final Exam – 20% GRADING SYSTEM Quizzes – 30% Assignments – 5% Attendance – 5% INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS UNIT OUTCOMES At the end of this module, the students are expected to: 1. Define Biopharmaceutics & Pharmacokinetics 2. Define LADMER system 3. Describe the pharmacotechnical parameters affecting liberation and discuss its clinical significance  Definition of terms Overview of LADMER System UNIT Measurement of drug concentration and OUTLINE its importance Physicochemical properties affecting drug absorption Liberation process BIOPHARMACEUTCS The science that examines the interrelationship of the physicochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption. The study of the chemical and physical properties of drugs, their components, and their activities in living organisms. PHARMACOKINETICS The study of the time course of drug movement in the body during absorption, distribution, and elimination. PHARMACOLOGY AND ITS DIVISIONS  L – Liberation A – Absorption LADMER D – Distribution SYSTEM M – Metabolism E – Excretion R - Response LIBERATION delivery of the active Aka: Drug release ingredient from a dosage process form into solution.  a state in which any residue of the tablet, except fragments of insoluble LIBERATION coating, remaining on the screen of the test apparatus in the soft mass have no palpably firm core. a process by which a chemical or drug becomes dissolved in a solvent DOSAGE FORMS IN WHICH LIBERATION IS ALTERED Modified release dosage forms – Parenteral injections Sublingual and (Extended-release, – (IV, IM, ID, SC) Buccal tablets Delayed-release, Targeted release ABSORPTION The process of uptake The movement of the of the compound from drug from the site of the site of application to the administration into the bloodstream. systemic circulation.  Bioavailability A measurement of the rate and extent of ABSORPTION systemic absorption of therapeutically active drug ABSORPTION First-pass effect a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation DISTRIBUTION transfer of the drug from the blood to extravascular fluids and tissues the amount of blood perfusion in an area of the body also affects the rate at which the drug could be distributed there. METABOLISM ► Detoxification/Biotransformation ► enzymatic or biochemical transformation of the drug substance to (usually less toxic) metabolic products, which may be eliminated more readily from the body ► Xenobiotics – foreign chemicals EXCRETION final loss of the drug substance or its metabolites from the body polar metabolites -> through the kidney non-polar drugs -> through the bile  Refers to the therapeutic effect, subtherapeutic effect, RESPONSE side effect and toxic effect. IMPORTANT TERMS AND CONCEPTS CLINICAL PHARMACOKINETICS ► application of pharmacokinetic methods to drug therapy. ► the study of the relationships between drug dosage regimens and concentration–time profiles  Three fundamental parameters: 1. Clearance volume of fluid completely cleared of drug per unit time Clinical 2. Volume of distribution Pharmacokinetics apparent volume into which the drug has distributed to produce the measured concentration 3. Elimination half life time taken for 50% of the drug to be eliminated CLINICAL PHARMACOKINETICS TDM ( Therapeutic Drug Monitoring) Employed for very potent drug to optimize efficacy and to prevent any adverse toxicity branch of clinical pharmacology that specializes in the measurement of medication levels in blood CPKS ( Clinical Pharmacokinetic Service) Provides pharmacokinetic and drug analysis services for safe drug monitoring CLINICAL Drugs with Narrow Therapeutic Range: PHARMACOKINETICS Drug Therapeutic range mg/L Digoxin 0.5 - 2.1 Amiodarone 1.0 - 2.5 Salicylate 150 - 300 Theophylline 10 - 20 Phenytoin 10 - 20 Carbamazepine 5.0 - 12 Population Pharmacokinetics Study of pharmacokinetics differences of drugs in various population Experimental Pharmacokinetics ► Development of biologic sampling techniques, analytical methods for the measurement of drugs and metabolites and procedure that facilitates data collection and manipulation ► In vivo- involves human subjects/ laboratory animals ► In vitro – employs test apparatus and equipment without involving human subjects/ laboratory animals Theoretical Pharmacokinetics Development of pharmacokinetics models that predict drug disposition after administration PHARMACKINETIC MODELS Model – a hypothesis using mathematical terms to describe quantitative relationship concisely. ► Empirical – a model in which the plasma conc. and time data are given and an equation is derived from the given data ► Physiological – describes drug movement in the body based on organ blood flow and organ spaces penetrated by the drug ► Compartmentally based – a model in which organs with the same blood flow and drug affinity are grouped together  COMPARTMENT MODELS ► Hypothetical space bound by an unspecified membrane across which drugs are transferred Three types of compartment models: Catenary Mamillary Physiologic  Compartment Models ► Mamillary Model ⮚One or more peripheral compartments connected to a central compartment ⮚Central compartment: Represent plasma and HIGHLY perfused tissues which RAPIDLY equilibrate with the drug ► Catenary Model ⮚ Consists of compartments joined to one another like the compartments of a train ► Physiologic Pharmacokinetic Model (Flow Model) ⮚ Considers that BLOOD FLOW is responsible for distributing drugs to various parts of the body COMPARTMENT MODELS PHARMACODYNAMICS The study of the relation of the drug concentration or amount at the site of action and its pharmacologic response. CLINICAL TOXICOLOGY The study of the adverse effects of drugs and toxic substances in the body “All things are poison and nothing is without poison; only the dose makes a thing not a poison.” MEASUREMENT OF DRUG CONCENTRATION Sampling of biologic specimen: ► Invasive Method ► Requires surgical/ parenteral intervention ► Sampling of blood, spinal fluid, synovial fluid, tissue biopsy ► Non- invasive method ► Without surgical/ parenteral intervention ► Feces, Urine, saliva  MEASUREMENT OF DRUG CONCENTRATION ► Blood ► Highly specialized tissue composed of many different kinds of components ► Whole blood ⮚ clot ⮚ centrifuge ⮚ supernatant = SERUM ► Whole blood ⮚ (+) heparin ⮚ centrifuge ⮚ supernatant = PLASMA Importance of measuring plasma drug concentration Adjustment of the drug dosage in order to individualize and optimize therapeutic drug regimen Provides guide to the progress of disease state Enable to modify the drug dosage accordingly PLASMA CONC. VS TIME CURVE PLASMA CONC VS. TIME CURVE Parts of Plasma Conc. Vs. Time Curve: Minimum Effective Concentration (MEC) –minimum conc. Needed to produce the desired pharmacologic effect. Minimum Toxic Concentration (MTC) – concentration needed to just barely produce toxic effects. Onset time – time required to reach MEC Peak time - time of maximum drug conc in the plasma and a rough marker of average rate of drug absorption PLASMA CONC VS. TIME CURVE Parts of Plasma Conc. Vs. Time Curve: Peak concentration – maximum drug concentration Duration of Drug Action – difference between the onset of time and time for the drug to decline back to MEC AUC (Area Under the Curve) – total amount of drug absorbed systematically; Total area found under the plasma concentration vs time curve from the initial dose to final elimination of the drug from the body BIOPHARMACEUTICS BIOPHARMACEUTICS Biopharmaceutics focuses on factors the influence: a. Design of drug product b. Stability of drug within the drug product c. Release of the drug from the drug product d. Rate of dissolution/ release of the drug from at the absorption site e. Delivery of drug to the site of action PHYSICOCHEMICAL PROPERTIES Partition Drug dissolution Particle Size and Coefficient and Salt formation and solubility Surface Area Extent of Ionization Complex Polymorphism Chirality Hydrates Fomration  Drug Dissolution ► the rate at which the solid drug enters into solution is often the rate limiting step in bioavailabilty. ► The Noyes-Whitney equation describes the diffusion controlled rate of drug dissolution ► The type and amount of excipients of drugs can affect its solubility and dissolution rate. Binders Lubricant Disintegrant Drug Solubility in a saturated solution is a static (equilibrium) property. The dissolution rate of a drug is a dynamic property related to the rate of absorption. Particle Size and Surface Area inversely related As solid drug particle size decreases, particle surface area increases. ↓PS ⮚ ↑ SA Partition Coefficient The partition coefficient of a drug is the ratio of the solubility of the drug, at equilibrium, in a non- aqueous solvent Increase in the no. of Carbon = Decrease water-solubility Extent of Ionization Drugs that are weak electrolytes (acids or bases) exist in both an ionized form and a nonionized form in solution. The extent of ionization depends on the pKa of the weak electrolyte and the pH of the solution. The ionized form is ____________, and therefore more _____________, than the nonionized form  EXTENT OF IONIZATION The Henderson-Hasselbalch equation describes the relation between the ionized and the nonionized forms of a drug as a function of pH and pKa pH = pKa ⮚ Drug is 50% ionized and 50% unionized SALT FORMATION WEAKLY ACIDIC DRUGS form WEEKLY BASIC DRUGS form potassium and sodium salts hydrochloride, sulfate, citrate, gluconate, estolate, napsylate or stearate salts Polymorphism the ability of a drug to exist in more than one crystalline form Amorphous, or noncrystalline, forms of a drug have faster dissolution rates than do crystalline forms. Same DIFFERENT CHEMICAL PHYSICAL STRUCTURE PROPERTIES Chirality the ability of a drug to exist as optically active stereoisomers or enantiomers Individual enantiomers may not have the same pharmacokinetic and pharmacodynamic activity. For example, ibuprofen exists as the R- and S-enantiomers; only the S- enantiomer is pharmacologically active. Hydrates Drugs may exist in a hydrated, or solvated form or as an anhydrous molecule Dissolution rates differ for hydrated and anhydrous forms. Complex Formation A complex is a species formed by the reversible or irreversible association of two or more interacting molecules or ions. Chelates are complexes that typically involve a ring-like structure formed by the interaction between a partial ring of atoms and a metal Ex. hemoglobin, insulin, cyanocobalamin Complex Formation Complex formation usually alters the physical and chemical characteristics of the drug. Large drug complexes, such as drug-protein complexes, do not cross cell membranes easily. For example: The chelate of tetracycline with calcium is less water soluble and is poorly absorbed. L ADMER Liberation  delivery of the active Liberation ingredient from a dosage form into solution.  the first step which determines onset of action, rate of absorption, availability, etc., which is true for all drug products by all routes of administration (except intravenous and the peroral use of true Liberation solutions) controlled by the characteristics of the drug product. Involves two important process: disintegration and dissolution Disintegration ► state in which any residue of the tablet, except fragments of insoluble coating, remaining on the screen of the test apparatus in the soft mass have no palpable firm core. Dissolution ►the process by which a chemical or drug becomes dissolved in a solvent. Rate Limiting Step ►the process with the slowest rate constant in a system of simultaneous kinetic processes. END OF DISCUSSION