BioPhar - PRELIMS.pdf

PhChem 3107: BIOPHARMACEUTICS & PHARMACOKINETICS 1st SEMESTER | S.Y. 2023 – 2024 | LECTURE | PALOMO, R.Y. MODULE 1: INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS BIOPHARMACE...

PhChem 3107: BIOPHARMACEUTICS & PHARMACOKINETICS 1st SEMESTER | S.Y. 2023 – 2024 | LECTURE | PALOMO, R.Y. MODULE 1: INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS BIOPHARMACEUTICS ¨ The study of the relationship of the physical and chemical properties of a drug to its bioavailability, pharmacokinetics, and pharmacodynamic and toxicologic effects. Thus, biopharmaceutics involves factors that influence the; 1. Design of the drug product 2. Stability of the drug within the drug product 3. Manufacture of the drug product 4. The release of the drug from the drug product 5. The rate of dissolution/release of the drug at the absorption site 6. Delivery of drug to the site of action, which may TOXICOKINETICS involve targeting localized area. is an application of the pharmacokinetic principles to the design, conduct, and interpretation of drug safety evaluation studies and in validating dose-related exposure PHARMACOKINETICS in animals. Is defined as the study of the time course of drug ¨ Which Are performed in animals during preclinical movement in the body during absorption, distribution, and drug development and may continue after the elimination (excretion and biotransformation). drug has been tested in clinical trials. ¨ “What the body DOES to the drug” ¨ Clinical Toxicology Study of adverse effects of ¨ which can be perform In vivo in the living body of a drugs and toxic substances in the body. plant or animal or In vitro outside the living body ¨ The pharmacokinetics of a drug in an and in an artificial environment. overmedicated patient may be very different from the pharmacokinetics of the same drug given in PHARMACODYNAMICS lower therapeutic doses. ¨ refers to the relationship between the drug concentration at the site of action and TERMINOLOGIES: pharmacologic response, including biochemical DRUG EXPOSURE and physiologic effects that influence the refers to the dose and various measures of acute or interaction of drug with the receptor. integrated drug concentrations in plasma and other ¨ “What the drug DOES to the body” biological fluid. Drugs are substances intended for use in the diagnosis, DRUG RESPONSE cure, mitigation, treatment, or prevention of disease. While refers to a direct a direct measure of the pharmacologic Drug product is the finished dosage form that contains the effect of the drug. active drug ingredient “excipients” vehicle or formulation matrix. BILIARY RECYCLING (ENTEROHEPATIC RECIRCULATION) The phenomenon that drugs emptied via bile into the small RECEPTOR intestine can be reabsorbed from the intestinal lumen into is a site in the biophase to which drug molecules can be systemic circulation. bound (protein or proteinaceous material). CENTRAL COMPARTMENT BIOPHASE is the sum of all body regions (organs or tissue) in which the is the actual site of action of drugs in the body. The drug concentration is in instantaneous equilibrium with that biophase may be surface of a cell or within the cell (one of in blood or plasma. the organelles BIOAVAILABILITY the relative amount of drug from an administered dosage form which enters the systemic circulation and the rate at which the drug appears in the blood stream. PAGE 1 1st SEMESTER |Phchem 3107 |lecture| PALOMO, R.Y. FIRST PASS EFFECT must pass membranes which act as lipid barriers. is the term used for hepatic metabolism of drug when ¨ Different transport mechanisms are employed to absorbed and delivered through portal blood. penetrate into and to permeate through these ¨ Greater the first pass effect, less amounts of the membranes. drug reach the systemic circulation. ¨ Most of the drugs are absorbed or transported by passive diffusion, which depends on the pka value of the drug, the pH of the solution and the lipid solubility of the unionized form. ¨ Drugs passing through the lipid barrier may directly enter the central compartment. ¨ First, the drug in its dosage form is taken by the patient by an oral, intravenous, subcutaneous, transdermal, etc, route of administration. ¨ Next, the drug is released from the dosage form in a predictable and characterizable manner. Then, some fraction of the drug is absorbed from the site of administration into either the surrounding tissue for local action or into the body (as with oral dosage forms) or both. ¨ Finally, the drug reaches the site of action. A pharmacodynamic response results when the drug concentration at the site of the action reaches or exceeds the minimum effective concentration (MEC). LIBERATION ¨ The suggested dosing regimen, including starting first step which determines onset of action, rate of dose, maintenance dose, dosage form, and dosing absorption, availability. (except IV administration) interval, is determined in clinical trials to provide the drug concentrations that are therapeutically ABSORPTION effective in most patients. the process of uptake of the compound from the site of administration into the systemic circulation. NEW DRUG DELIVERY SYSTEM RATE DISCIPLINE DISTRIBUTION Theoretical Pharmaceutics refers to the transfer of the drug from the blood to In vitro extravascular fluids and tissues. In vivo Biopharmaceutics ¨ Albumin – binds acidic drugs Absorption ¨ α-acid glycoprotein – binds basic drugs V and Concentration Pharmacokinetics peroral use of true solutions Distribution Metabolism METABOLISM Elimination Pharmacodynamics is an enzymatic or biochemical transformation of the drug substance to (usually less toxic) metabolic products, which Response may be eliminated more readily from the body. ¨ To supply energy for body functions and LADMER System maintenance. In order that a drug can be absorbed it must be present in ¨ It plays central role in the elimination of the drugs the form of solution, therefore dissolution becomes the first and xenobiotics (foreign compounds). and sometimes rate-limiting step. ¨ Converts drug into polar, water soluble, ionized ¨ Upon administration we find drug particles in the GI form that are readily excreted. tract, in body cavities or in tissue. ¨ After dissolution, the drug diffuses to the site of ELIMINATION absorption. is the removal of the drug substance or its metabolites from ¨ Some of the drug will already be inactivated the body, such as through the kidney (urine), intestines before it can be absorbed. (feces), skin (sweat), saliva, and/or milk. ¨ Only drugs administered intravenously in solution enter the circulatory system immediately. ¨ With all other routes of administration, the drugs PAGE 2 1st SEMESTER |Phchem 3107 |lecture| PALOMO, R.Y. RESPONSE Disadvantages: can be a therapeutic, subtherapeutic effect, side effect or (1) Less amount of drug reaches the target tissue. toxic effect (2) Some of the drug is destroyed by gastric juices e.g. adrenaline, insulin, oxytocin (3) Absorption has to take place which is slow, so is not preferred during emergency. (4) It might cause gastric irritation (5) It might be objectionable in taste. (6) It might cause discoloration of teeth e.g. iron causes staining, tetracyclines below 14 cause brown discoloration so are not advisable during pregnancy. SUBLINGUAL ROUTE involves tablets placed under the tongue or between cheeks or Gingiva. The drug should be lipid soluble and small. DRUG DELIVERY SYSTEM AND ROUTE OF ADMINISTRATION Advantages: Drug delivery system a drug formulation and the dynamic interactions among the drug, its formulation matrix, its (1) Rapid absorption takes place. container and the patient. (2) Drug is dissolved easily (3) Drug enters the blood directly Major Route of Administration (4) Less first pass effect. 1. ENTERAL ROUTE (5) Spitting out of the drug removes its effect involves absorption of the drug via the GI tract and Disadvantages: includes oral, gastric or duodenal (e.g., feeding tube), and This method is inconvenient. rectal administration. (1) Irritation of the mucous membrane might occur (2) Person may swallow the drug 2. PARENTERAL ROUTE (3) Might be unpleasant in taste. includes the subcutaneous, intramuscular, and intravenous routes. For these routes to be viable, a medication must be Examples of drugs given by this route include: water- soluble or in suspension. ¨ nitroglycerin, isoprenaline and oxytocin. ¨ Nifedipine used for the treatment of hypertension in The intravenous route of administration bypasses the emergency is given by sublingual route. absorption step, resulting in 100% bioavailability. RECTAL ADMINISTRATION Drugs in solid forms such as suppositories or in liquid forms such as enema are given by this route. This route is mostly used in old patients. Drugs may have local or systemic actions after absorption. Advantages: (1) This route is preferred in unconscious or uncooperative patients. (2) This route avoids nausea or vomiting (3) Drug cannot be destroyed by enzymes. (4) This route is preferred if drug is irritant. ENTERAL ROUTE Disadvantages: ORAL ADMINISTRATION ¨ Is the most common route of drug administration. It (1) This route is generally not acceptable by the is mostly used for the neutral drugs. patients. (2) Locally acting drugs include glycerin and Bisacodyl ¨ It may be in the form of tablets, capsules, syrup, emulsions or powders. suppository (3) Systemic-acting drugs include Indomethacin (anti- Advantages: inflammatory) and aminophylline (bronchodilator) (1) It is convenient (4) Retention enema is diagnostic and is used for (2) It is the cheapest available route finding the pathology of lower intestines. (3) It is easy to use (5) Drugs given by rectal route have 50% first pass (4) It is safe and acceptable. metabolism. PAGE 3 1st SEMESTER |Phchem 3107 |lecture| PALOMO, R.Y. PARENTERAL ROUTE INCLUDES: INJECTIONS INTRAPLEURAL PENICILLIN INTRAMUSCULAR ROUTE It may be injected in cases of lung empyema by ¨ might be applied to the buttock, thigh and deltoid. intrapleural route. ¨ The volume used is 3 ml. Advantages: INTRAPERITONEAL (1) Absorption is rapid than subcutaneous route. It may be used for peritoneal dialysis. (2) Oily preparations can be used. (3) Irritative substances might be given INTRA-ARTICULAR ROUTE (4) Slow releasing drugs can be given by this route. It involves injection into the joint cavity. Corticosteroids may Disadvantages be injected by this route in acute arthritis. (1) Using this route might cause nerve or vein damage. INTRADERMAL (INTRACUTANEOUS) This route is mostly used for diagnostic purposes and is INTRA VENOUS MIGHT BE APPLIED TO THE CUBITAL, BASILIC involved in: AND CEPHALIC VEINS Advantages: (a) Schick test for Diphtheria (1) Immediate action takes place (b) Dick test for Scarlet fever (2) This route is preferred in emergency situations (c) Vaccines include DBT, BCG and polio (3) This route is preferred for unconscious patients. (d) Sensitivity is to penicillin (4) Titration of dose is possible. (5) Large volume of fluids might be injected by this SUBCUTANEOUS ROUTE route ¨ Hypodermic Subcutaneous route might be used for (6) Diluted irritant might be injected the arm, forearm, thigh and subscapular space. ¨ The volume used is 2 ml. (7) Absorption is not required (8) No first pass effect takes place. ¨ Insoluble suspensions like insulin and solids might be applied by this route. (9) Blood plasma or fluids might be injected. Advantages: Disadvantages: (1) Absorption is slow and constant (1) There is no retreat (2) It is hygienic (2) This method is more risky (3) Disadvantages: (3) Sepsis-Infection might occur (4) It might lead to abscess formation (4) Phlebitis (Inflammation of the blood vessel) might (5) Absorption is limited by blood flow occur (5) Infiltration of surrounding tissues might result. Examples of drugs given by subcutaneous route include (6) This method is not suitable for oily preparations insulin, adrenaline and Norplant. (7) This method is not suitable for insoluble preparations INHALATION Advantages: INTRA-ARTERIAL This method is used for chemotherapy in cases of malignant (1) Parenteral route is rapid. tumors and in angiography. (2) It is useful for uncooperative patients (3) It is useful for unconscious patients INTRA-CARDIAC INJECTION (4) Inactivation by GIT enzymes is avoided It can be applied to the left ventricle in case of cardiac (5) First pass effect is avoided arrest. (6) Bioavailability is 100% Disadvantages: INTRA-THECAL ROUTE (1) Skill is required It involves the subarachnoid space. Injection may be (2) It is painful applied for the lumbar puncture, for spinal anesthesia and (3) This method is expensive for diagnostic purposes. This technique requires special precautions. (4) It is less safe. INTRAOSSEOUS Into bone marrow PAGE 4 1st SEMESTER |Phchem 3107 |lecture| PALOMO, R.Y. TOPICAL ROUTE DRUG METABOLISM AND ADMINISTRATION Drugs may be applied to the external surfaces, the skin and the mucous membranes. ENEPIDERMIC ROUTE ¨ When the drug is applied to the outer skin, it is called enepidermic route of drug administration. ¨ Examples include poultices, plasters, creams and ointments. EPIDERMIC ROUTE (INNUNITION) ¨ When the drug is rubbed into the skin, it is known as epidermic route. ¨ Examples include different oils. INSUFFLATIONS ¨ When drug in finely powdered form is blown into the body cavities or spaces with special nebulizer, the method is known as insufflations. INSTILLATION ¨ Liquids may be poured into the body by a dropper into the conjunctival sac, ear, nose and wounds. Solids may also be administered. IRRIGATION OR DOUCHING ¨ This method is used for washing a cavity e.g. urinary bladder, uterus, vagina and urethra. ¨ It is also used for application of antiseptic drugs. PAINTING/SWABBING ¨ Drugs are simply applied in the form of lotion on cutaneous or mucosal surfaces of buccal, nasal cavity and other internal organs. ROUTES OF ADMINISTRATION PAGE 5 PhChem 3107: BIOPHARMACEUTICS & PHARMACOKINETICS 1st SEMESTER | S.Y. 2023 – 2024 | LECTURE | PALOMO, R.Y. MODULE 2: MEASUREMENTS OF DRUG CONCENTRATION ESTIMATION AND THE USE OF CALCULATORS AND Curve Fitting is the process of constructing a curve, or COMPUTERS mathematical function, that has the best fit to a series of ¨ A scientific calculator or computer software data points, possibly subject to constraints. It is a statistical program with logarithmic and exponential technique use to drive coefficient values for equations that functions will make the calculations less tedious. express the value of one (dependent) variable as a ¨ Computer software is a tool that allows one to solve function of another (independent variable). more complex pharmacokinetic problems rapidly, but efficient use requires a thorough understanding REGRESSION EQUATION of the subject. ¨ response= intercept + slope x predictor ¨ Calculation accuracy is important ¨ Y= βo+ β1X1 (notice this is the equation of straight ¨ Calculators with exponential and logarithmic line y = mx + b) functions. ¨ Additional function: mean, standard deviation, and linear regression analysis. APPROXIMATION ¨ A useful process for checking whether the answer to a given set of calculations is probably correctly. ¨ To estimate a series of computations, round the numbers and write the numbers using scientific notation. PROBLEMS OF FITTING POINTS TO A GRAPH Consider the law of parsimony- “keep it simple”. That is, if a choice between two hypotheses is available, choose the EXPONENTIAL AND LOGARITHMIC FUNCTIONS simpler relationship. Exponent: is the power to which a number, symbol, or ¨ Interpolation – filling the gap between the expression is to be raised. observed data on a graph, is usually safe and ¨ For example, the 3 in x3. assumes that the trend between the observed ¨ Logarithm: The logarithm of a number is the data is consistent and predictable. exponent by which another fixed value, the base, ¨ Extrapolation – predicting new data beyond the has to be raised to produce that number. Log – observed data, and assumes that the same trend logarithmic to base 10 ln (natural log) - logarithmic obtained between two data points will extend in to base e Graphs Visualizing the relationship either direction beyond the last observed data between variables. points. ¨ Computer software is a tool that allows one to solve more complex pharmacokinetic problems rapidly, DRUG CONCENTRATION AND ITS SIGNIFICANCE but efficient use requires a thorough understanding ¨ Drug concentrations are measured in biologic of the subject. Calculation accuracy is important! samples, such as milk, saliva, plasma, and urine. Such measurement is generally validated so that GRAPHS accurate information is generated for Visualizing the relationship between variables. pharmacokinetic and clinical monitoring. TYPES OF GRAPHS ¨ Measurements of drugs in biological fluids ¨ Cartesian or Rectangular Coordinate Graph Paper o General methods use measure drug concentrations by means of ¨ Semi-log graph paper chromatographic which separates drugs Trapezoidal Rule is a numerical method frequently used in the drug from other related materials that pharmacokinetics to calculate the area under the plasma may cause assay interference and mass drug concentration-versus time curve, called area under spectrometric allows detection of the curve (AUC). molecules or molecule fragments based on their mass-to charge ratio. Least square method a useful procedure for obtaining the line of best fit through a set of data points by minimizing the SAMPLING OF BIOLOGIC SPECIMENS deviation between the experimental and the theoretical ¨ Invasive methods- include sampling blood, spinal line. fluid, synovial fluid, tissue biopsy, or any biologic y = mx + b material that requires parenteral or surgical Where: intervention in the patient. y – the dependent variable ¨ Noninvasive methods- include sampling of urine, saliva, feces, expired air, or any biologic material x – the independent variable that can be obtained without parenteral or m – slope surgical intervention. b – y intercept PAGE 6 1st SEMESTER |Phchem 3107 |lecture| PALOMO, R.Y. DRUG CONCENTRATION IN BLOO D, PLASMA, OR SERUM DRUG PRODUCT PER FORM ANCE PARAMETERS: ¨ In general, serum or plasma is most commonly used ¨ MEC - a minimum effective concentration of drug for drug measurement to obtain serum, whole needed to produce the desired pharmacologic blood is allowed to clot and the serum is collected effect. from the supernatant after centrifugation. ¨ MTC - minimum toxic concentration represents the ¨ Plasma is obtained from the supernatant of drug concentration needed to produce toxic centrifuged whole blood to which an effect. anticoagulant, such as heparin has been added. ¨ Onset time - the time required to reach the MEC. ¨ Therefore, the protein content of serum and Duration of Drug Action – the difference between plasma is not the same. Plasma perfuses all the the onset time and the time for the drug to decline tissues of the body, including the cellular elements back to the MEC. in the blood. ¨ Therapeutic Window – concentrations between the ¨ Assuming that a drug in the plasma is in dynamic MEC and the MTC (therapeutic index). equilibrium with the tissues, then changes in the drug concentration in plasma will reflect changes DRUG CONCENTRATION IN TISSUES in tissue drug concentrations. ¨ For many tissues, blood flow to one part of the ¨ Drugs in the plasma are often bound to plasma tissues need not be the same as the blood flow to proteins are filtered from the plasma before drug another part of the same tissue. concentrations are measured. This is the unbound ¨ The measurement of the drug concentration in drug. tissue biopsy material may be used to ascertain if ¨ Alternatively, drug concentration may be the drug reached the tissues and reached the measured from unfiltered plasma; this is the total proper concentration within the tissue. plasma drug concentration. DRUG CONCENTRATION IN URINE AND FECES PLASMA DRUG CONCENTRATION -TIME RELATIONSHIP ¨ Drug in urine is an indirect method. Generated by obtaining the drug concentration in plasma ¨ The extent of drug excreted in the urine reflects the samples taken at various time intervals after a drug product rate and extent of systemic drug absorption. is administered. ¨ While drug in feces may reflect drug that not been ¨ The concentration of drug in each plasma sample absorbed after an oral dose or may reflect drug is plotted on rectangular-coordinate graph paper that has been expelled by biliary secretion after against the corresponding time at which the systemic absorption. plasma sample was removed. ¨ As the drug reaches the general circulation, plasma drug concentrations will rise up to a DRUG CONCENTRATION IN SALIVA maximum if the drug was given by an extravascular ¨ Only free drug diffuses into the saliva, saliva drug route. levels tend to approximate free drug rather than total plasma drug concentration. ¨ Usually, absorption of a drug is more rapid than elimination. ¨ Mostly influenced by the pka of the drug and the pH of the saliva. ¨ Elimination of a drug can proceed by excretion, biotransformation, or a combination of both. ¨ The used of salivary drug concentrations as a therapeutic indicator should be used with caution and preferably as a second indicator. FORENSIC DRUG MEASUREMENT ¨ Forensic drug measurement is the application of science to personal injury, murder, and other legal proceedings. ¨ Drug measurement in tissues obtained at autopsy or in other bodily fluids such as saliva, urine, and blood may be useful if a suspect or victim has taken an overdose of a legal medication, has been poisoned, or has been using drugs of abuse. SIGNIFICANCE OF MONITORING PLASMA DRUG CONCENTRATIONS (1) The intensity of the pharmacologic or toxic effect of a drug is often related to the concentration of the drug at the receptor site, usually located in the tissue cells. PAGE 7 1st SEMESTER |Phchem 3107 |lecture| PALOMO, R.Y. (2) Measuring the plasma drug level is a responsive ORDER OF REACTION method of monitoring the course of therapy. Refers to the way in which the concentration of a drug or a (3) Ascertains that the calculated dose actually reactant influences the rate of a chemical reaction or delivers the plasma level required for therapeutic process effect. (4) Monitoring of plasma levels is needed to distinguish A. ZERO-ORDER REACTIONS the patient who is receiving too much of a drug the drug concentration changes with respect to time at a from the patient who is supersensitive to the drug. constant rate (5) The patient’s physiologic functions may be C = -k0t + C0 affected by disease, nutrition, environment, Where: concurrent drug therapy, and other factors. ¨ C = drug concentration at any time (6) Allows for the adjustment of the drug dosage in order to individualize and optimize therapeutic ¨ K0 = zero-order rate constant (units of drug regimens. concentration per time) is the slope of the line (7) Provide a guide to the progress of the disease state ¨ C0 = is the y intercept drug concentration, when and enable the investigator to modify the drug time (t) equals zero dosage accordingly. ¨ Negative sign = indicates that the slope is (8) Therapeutic decisions should not be based solely decreasing on plasma drug concentrations. (9) Pharmacodynamic response to the drug is more B. FIRST-ORDER REACTIONS important to measure than just the plasma The Cp vs Time profile during the elimination phase is linear concentration. ¨ Example: 1.2 mg are eliminated every hour, independently of the drug concentration in the RATES AND ORDERS OF RE ACTIONS body. ¨ The RATE of a chemical reaction- velocity with The drug concentration changes with respect to time equal which it occurs to the product of the rate constant and the concentration ¨ The ORDER of a reaction- the way in which the of drug remaining. concentration of a drug or reactant in a chemical reaction affects the rate. Refers to the way in A first order process is where the amount of drug eliminated which the concentration of a drug or reactants may change with the amount of drug in the body, but the influences the rate of a chemical reaction or fraction of a drug in the body eliminated over a given time process remains constant UNITS IN PHARMACOKENITICS Fraction or percent of drug being removed is the same with PARAMETER SYMBOL UNIT EXAMPLE a high or a low drug concentration RATE dD Mass/time mg/h dt dC Conc./time µ/ml h dt Zero-order ko Conc./time µ/l h rate constant Mass/time mg/h Where: First-order k 1/time 1/h or h-1 ¨ C = drug concentration at any time rate constant ¨ k = first-order rate constant (units of reciprocal time, Drug dose Do Mass mg or time-1) Concentration C Mass/vol µg/ml ¨ -k/2.3 = is the slope of the line Plasma drug Cp Drug/vol µg.ml ¨ C0 = is the y intercept = drug concentration, when concentration time (t) equals zero Volume v Volume ml or L FIRST ORDER PROCESS Area under AUC Conc. X µg h/ml ¨ First order kinetics means that the rate of change of the curve time drug concentration by any process is directly Fraction of the F No units 0 to 1 proportional to the drug concentration remaining drug to undertake that process. absorbed o In first-order elimination the amount of drug Clearance Cl Vol/time ml/h eliminated in a set of time is directly Half-life T½ Time h proportional to the amount of drug in the body ¨ Zero Order elimination is rare mostly occurring PAGE 8 1st SEMESTER |Phchem 3107 |lecture| PALOMO, R.Y. when the elimination system is saturated. An FIRST-ORDER ELIMINATION KINETICS example is the elimination of Ethanol. a linear process ¨ amount of drug eliminated may change with the ¨ rate of elimination is amount of drug in the body, but the fraction of a proportional to the drug drug in the body eliminated over a given time concentration remain constant ¨ the elimination processes are ¨ fraction or percent of drug being removed is the not saturated and can adapt same with a high or low drug concentration ¨ to the needs of the body, to Time after drug Amount of Amount of Fraction of reduce accumulation of the administration drug in the drug drug drug body (mg) eliminated eliminated over over ¨ 95% of the drugs in use at preceding preceding therapeutic concentrations hour hour are eliminated by first-order 0 1000 - - kinetics. 1 850 150 0.15 ELIMINATION FIRST ORDER ZERO ORDER 2 723 127 0.15 KINETICS 3 614 109 0.15 Curve in the log Linear Nonlinear 4 522 92 0.15 plasma concentration vs. 5 444 78 0.15 time plot after IV 6 377 67 0.15 bolus 7 320 57 0.15 Relation between Elimination rate is Elimination rate elimination rate and proportional to saturates with higher drug concentration drug drug concentration SIGNIFICANCE OF RATE CONSTANTS concentration Characterize the change of drug concentration in a Term in clinical Linear kinetics Nonlinear kinetics particular reference region. pharmacology ¨ Give the speed at which a drug: concerns 95% of drugs, at The remaining 5% ¨ Enters the compartment (absorption rate constant, therapeutic and ethanol ka) concentrations ¨ Distributes between a central and peripheral compartment (distribution rate constant) FIRST-ORDER HALF-LIFE ¨ Is eliminated from the systemic circulation ¨ constant for a first-order process (elimination rate constant, k) ¨ related to the first-order rate constant o no matter what the initial amount or HALF-LIFE (T½) UNITS: TIME concentration of the drug is, the time ¨ Expresses the period of time required for the required for the amount to decrease by concentration of a drug to decrease by one half one half Is constant Also define as the time required to decrease the o - t1/2 = 0.693/k initial dose of drug by 50% (one half of original value). unit: time SIGNIFICANCE OF HALF-LIFE ¨ Determine the dosing interval necessary to obtain the desired CP of the drug o Generally, the dosing interval is the same as t½ ¨ Predict how long it will take a drug to reach steady-state levels ¨ Predict the accumulation of a drug in the body for a specific dosing interval ZERO-ORDER HALF-LIFE not constant for a zero-order process o During multiple dosing or continuous IV infusion it takes approximately 4-5 half-lives ¨ proportional to the initial amount or concentration to reach steady-state levels of the drug and is inversely proportional to the zero- order rate constant ko ¨ Predict how long it will take a drug concentration to decrease to a lower concentration All drugs are ¨ T1/2 = 0.5Ao/ko decreased by 96% after 4 half-lives o where: § Ao = Cpo § ko= zero -rate constant PAGE 9