Subject: Pharmacology Topic: Pharmacokinetics Lecturer: Dr.

Dela Cruz Date of Lecture: 06/15/2011 Transcriptionist: Kikuichimonji Pages: 7

Pharmacokinetics What the body does to the drug? How the body handles the drug? Studyof how drugs move into, through and out of the body including delivery to the target sites. Deals with dose concentration Deals with ADME: A Absorption D Distribution M Metabolism E Excretion Pharmacokinetic Processes: (ADME) A Drug suptake from the site of administration to the systemic circulation. D Drug smovement to various sites after systemic circulation M Drug sconversion to metabolites E Drug sremoval from the body Mechanism of Drug Passage across membranes 1. 2. 3. 4. Passive Diffusion Facilitated Diffusion Active Transport Pinocytosis

PASSIVE DIFFUSION Along concentration gradient (from to conc) Without the use of energy Driving force: difference in drug concentration ACTIVE TRANSPORT Against concentration gradient o From low concentration to high concentration. Carrier mediated process Energy consuming (utilize ATP) Has saturability, selectivity and storability Competitive inhibition by co-transported compounds

Remember . THE CELL MEMBRANE SEMI PERMEABLE meaning it will only allow certain molecules and ions to pass through it and PROTEIN BOUND DRUGS (macromolecules) have difficulty passing through it. Selective barrier

FACILITATED DIFFUSION Along concentration gradient Carrier mediated process Without the use of energy Carrier enhances the movement of the drug down an electrochemical gradient Example: GLUT4 enhances the permeation of glucose across a muscle cell membrane. Drug Permeation is dependent on solubility, concentration gradient and Surface area & Vascularity of drugs PINOCYTOSIS Folding over the part of the cell membrane Formation of small vesicles Molecules of extracellular contents are trapped FACTORS THAT AFFECT THE DRUG PASSAGE ACROSS MEMBRANE

NON

IONIZED drugs can easily pass

through LOW MW drugs can also easily pass though

SY 2011-2012

1. Molecular size and shape 2. Degree of ionization 3. Relative lipid solubility of its ionized and non - ionized forms 4. binding to serum and tissue protein ABSORPTION Concerns the process of entry of drug into the systemic circulation The determinants of absorption are those of drug permeation Intravascular administration (eg.IV) does not involve absorption, and there is no loss of drug. With extravascular administration (eg.oral, intramuscular, subcutaneous, inhalation) less than 100% of a dose may reach the systemic circulation because of variations in bioavailability. FACTORS THAT AFFECT THE RATE AND EXTENT OF DRUG ABSORPTION 1. Dosage form / Drug Formulation a. Liquid dosage forms are absorbed more efficiently than solid dosage forms. 2. Physical Chemical Properties a) Molecular weight must be smaller for better absorption. b) pH will determine ionization c) Lipophilic vs. Hydrophilic Partition Coefficient = measure of lipophilicity; the greater it is, the more lipid soluble the drug. Lipophilic drugs readily diffuse through the cell membrane (lipid bilayer). Hydrophilic drugs / charged drugs cannot readily diffuse through the cell membrane. 3. Physiologic Variable a) Gastric motility motility = absorption Delay transition of drug from stomach to intestine (where most of the drug absorption takes place). b) pH at absorptive site y Acidic pH Weak Acid =more unionized =more lipid soluble Weak base=less unionized=less lipid soluble y Basic pH Weak Acid=less unionized=less lipid soluble Weak Base=more unionized=more lipid soluble **Non-ionized lipid soluble;

Diffuse readily across cell membrane **Ionized - low lipid solubility c) area of absorbing surface -duodenum site of absorption because of the villi d) mesenteric blood flow e) pre systemic elimination / first pass effect - Liver, stomach, etc. - Rapid metabolism of a drug prior to reaching the general circulation. FACTORS THAT INFLUENCE ABSORPTION 1. Blood flow at the site of administration 2. Total Surface area available for absorption 3. Contact time at the site of absorption BIOAVAILABILITY (f) k The parameter of absorption k Function of Time and conc. k Measure the rate and extent by w/c a drug reaches the systemic circulation k Fraction of unchanged drug that reaches the systemic circulation k The fraction of a drug dose that reaches the bloodstream after absorption at any site of administration f = AUCPO AUC IV Bioequivalence: when two related drugs show comparable bioavailability Therapeutic Equivalence: when two similar drugs have comparable efficacy and safety **For bioequivalence to occur between two formulations of the same compound, they must have the same bioavailability and the same rate of absorption. When this occurs, the plasma levels of the two products will be super imposable if they are given at the same dose, by the same mode. Cmax and Tmax are rate dependent. The faster the rate of absorption, the smaller the Tmax and the larger the Cmax, and vice versa. ABSOLUTE VS RELATIVE BIOAVAILABILITY Absolute Bioavailability compares the bioavailability of the active drug in systemic circulation following non-intravenous administration with the bioavailability of the same drug following IV administration.

Relative Bioavailability measures the bioavailability of a formulation of a certain drug when compared with another formulation of the same drug, usually an established standard or through administration via a different route. FACTORS THAT AFFECT BIOAVAILABILITY 1. Biopharmaceutical factors Dosage form ; Physicochemical properties

**IV administration by definition has 100% bioavailability and the most rapid onset DISTRIBUTION process by which a drug reversibly leaves the systemic circulation and enters the interstitial space and/or the cells of the tissues once in the blood stream, the drug is distributed to the different tissues The process of distribution of a drug from the systemic circulation to organs and tissue involves permeation through membrane barriers and are dependent on its solubility (recall that only non ionized drugs cross biomembranes), the rate of blood flow to tissues and the binding of drug molecules to plasma proteins. FACTORS THAT INFLUENCEDRUG DISTRIBUTION 1. Plasma Protein Binding - Drugs bound to proteins are not readily distributed and are inactive - High protein binding prolongs onset and duration of action ** Many drugs bind to plasma proteins, including albumin, with equilibrium between bound and free molecules (Recall that only unbound drugs cross biomembranes). **Competition between drugs-drugs for plasma protein binding sites may increase the free fraction , possibly enhancing the effects of the drug displaced. **Remember that plasma protein binding limits the distribution, intensity of pharmacologic action and elimination rate of drugs. **Therefore: A highly protein bound drug generally has longer duration, low toxicity, and low biologic effect. PROTEIN BINDING major plasma protein component; Albumin reversible drug binding; weakly acidic drugs Alpha -1 Acidic Glycoproteins (AAG) and Globulin weakly basic drugs Lipoproteins macromolecular complexes of lipids + proteins; Binding drugs when albumin sites become saturated RBC Binding does not significantly affect distribution Free, unbound drug is the active form of the drug Drugs bound to proteins are not readily distributed and are inactive

2. Physiologic factors Gastric Motility ; Pre systemic metabolism 3. GIT Contents Foods, drugs, liquids 4. Disease State DETERMINANTS OF BIOAVAILABILITY 1. Plasma Data **Tmax **AUC time of maximum drug concentration Rate of the drug absorption Area under the curve; shaded portion Most reliable measure for bioavailability - Direct - Extent of the drug absorption - It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation

2. Urine Data  maximum urinary excretion rate  time for maximum excretion rate  cumulative amount of drug excreted in the urine 3. Pharmacologic effect

High protein binding prolongs onset and duration of action 2. Cardiac Output and Blood flow to vascular organ -highly vascular organs receive more of the drugs (heart, liver, kidneys, brain) -blood flow (perfusion) is directly proportional to the drug distribution. 3. Permeability and Perfusion of Membranes - Capillary wall structure - Drug s pKa and blood pH - Blood perfusion 4. Natural barriers - Placental Barrier most small molecular weight drugs cross this barrier, although fetal blood levels are usually lower than maternal - Blood brain barrier permeable only to lipid soluble drugs or those of very low molecular weight - Blood ocular barrier 5. Diseases - renal, cardiac failure - plasma albumin conc: in malnutrition, hepatic and renal diseases - Alpha-1-acid glycoprotein conc: in pregnancy and post MI VOLUME OF DISTRIBUTION (V) i the volume of fluid to which a drug is distributed i drugs with large volume of distribution will have a longer half-life and duration of action i The parameter of distribution i Relates the amount of a given drug in the body to the concentration to the drug in the blood. i Actually non - physiological or hypothetical volume; is concerned with extent and where a drug is distributed. i Defined with respect to blood, plasma, or water (unbound drug), depending on the concentration used in the equation i Can vastly exceed and physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or water. i Can be determined in the blood or by back extrapolation V = Total amount of drug in the body (A) Plasma drug concentration (C)

Apparent Volume of Distribution (Vd) - A kinetic parameter of a drug that correlates dose with plasma level at zero time - The higher the Vd, the lower the plasma concentration and vice versa - Vd is low when a high percentage of a drug is bound to plasma proteins used for calculating Vd by using the dose only if one knows or can calculate drug concentration. - Tissue binding and accumulation of drugs with high Vd values raises the possibility of displacement by other agents Changes in pharmacologic activity. Vd= amount of drug administered Initial drug concentration METABOLISM process by which a drug is altered chemically into another compound called metabolites which may be more active or less active than the parent drug. Aka biotransformation primarily occurs in the liver can also occur in the stomach, small intestines, plasma, kidney, lung, skin, other tissues Biotransformation is the metabolic conversion of drugs, generally to less active compounds but sometimes to isoactive or more active forms Two Phases of Metabolism: **remember xenobiotics? Phase 1 Include oxidation (especially the cytochrome P45-group of enzymes also called mixed function oxidase), reduction, deamination, and hydrolysis. Reactions that convert the parent drug to a more polar (water soluble) or more reactive product by unmasking or inserting a polar functional group such as OH, -SH, -or -NH Phase 2 synthetic reaction that involve addition (conjugation) of subgroups to OH, -NH2and SH functions on the drug molecule. The subgroups that are added include glucoronate, acetate, glutathione, glycine, sulfate, and methyl groups. Most of these groups are relatively polar and make the product less lipid soluble than the original drug molecule. - glucuronidation, sulfation, glutathione conjugation, n-acetylation, methylation SIGNIFICANCE OF METABOLISM

i defensive mechanism i increases polarity of drug molecules  restricts penetration thru membranes  reduces distribution  promotes elimination

cellular

FACTORS AFFECTING DRUG METABOLISM 1. Non Genetic  Age extremes of age: slower metabolism due to lack of enzymes, and/or reduced availability of essential co-factors.  Sex males have faster metabolism due to the effect of androgenic hormone.  Liver size / function more functional and inc size=inc enzymes=faster absorption.  Diet / Nutrition Charbroiled food: inhibit CYP 1A Grapefruit juice: inhibit CYP 3A  Environmental 2. Genetics a. Hydrolysis of esters succinylcholine b. Acetylation of amines isoniazid in slow and fast acetylators Dependent on the amount of hepatic n-acetyltransferase. Slow acetylators: at risk for toxicity. Filipinos are fast acetylators whereas Caucasians are slow acetylators. c. Oxidation debrisoquin, sparteine, phenformin, dextromethorphan, metoprolol, and some tricyclic antidepressant; poor and extensive Not dependent on enzyme availability. EXCRETION process by which a drug or its metabolites is eliminated from the body main organ of elimination is the kidneys other organ of excretion include the billiary system, GIT, skin and lungs removal of intact drug PATHWAYS **Remember physio :p 1. Biliary Excretion

 Anions, cations, non ionized molecules with lipophilic polar groups and those with MW>500  For drugs poorly absorbed in the intestines  Organic acids and organic bases active transport  Considered biliary recycling Enterohepatic Recirculation  Main organ kidney 2. Salivary Excretion - Via different transport mechanism 3. Mammary Excretion Nursing mothers should avoid taking drugs Anti-thyroid, lithium, chloramphenicol, ant icancer drugs Do not nurse Extremely narrow therapeutic index (effective dose) gentamicin, kanamycin Take special care 4. Drug Excretion into sweat k Passive diffusion of the non-ionized moiety k Non ionized compounds: Alcohol, Antipyrine, Urea k Weak Acids: Sulfonamides, salicylic acids k Weak Base: Thiamine k Metals: I, Br, Hg, Pb 5. Drug Excretion into Expired Air Less soluble anesthetics Soluble gases Other volatile compounds: Alcohol, Ethereal oils 6. Genital Excretion  Prostate secretions  Seminal fluid: anti-cancer drugs malformations 7. Intestinal Excretion Verified by the presence of drugs in the GUT lumen after IV administration Ex. Doxycycline renal failure; no need for dose adjustments; intestinal excretion is favored 8. Renal Drug Excretion Major route Non-volatile; water soluble, low MW drugs

HALF LIFE (t ) The period of time required for the amount or concentration of drug to decrease by one half. Related to its duration of action and indicates when another dose should be given often used to determine frequency of administration determines the time to attain steady-state concentration Drug needs about 4-5 half lives to be completely eliminated from the body E.g. Paracetamol (ACET) 500 mg half-life 4 hrs after 1st 4 hrs = 250 mg after 2nd 4 hrs = 125 mg after 3rd 4 hrs = 62.5 mg after 4th 4 hrs = 31.25 after 5th 4 hrs = 15. 635

CLEARANCE Defined as the volume of blood cleared of the drug in unit time. It represents the relationship between the rate of drug elimination and its plasma level. the measure of the ability of the body to eliminate the drug the sum of hepatic metabolism and renal excretion

**Higher Vd , lower half life = faster clearance **Lower Vd, higher half life = slower clearance that can lead to toxicity KINETIC ORDER 1. Zero Order Kinetics - constant rate - rate is independent of the amount of drug - linear - active transport - A constant amount of drug is eliminated per unit time; For example, if 80mg is administered and 10mg is eliminated every 4hours, the time course of the drug elimination is 80mg (4hrs) 70mg (4hrs) 60mg (4hrs)50m g (4hrs) 40mg - Drugs with zero elimination include ethanol (except low blood levels), phenytoin (high therapeutic doses), and salicylates (Toxic doses) 2. First Order Kinetics  not uniform  proportional to the amount of drug  Curvilinear  passive diffusion  fraction of drug eliminated is constant  rate is dependent on the amount of drug undergoing the process  For example, if 80mg of a drug is administered and its elimination half life = 4hrs, the time course of its elimination is

Vd = volume of distribution Cl = Clearance **0.7 or 0.693 can be use** The longer the t , the longer the plasma concentration to stay in the therapeutic range. STEADY STATE the point where rate of drug availability equals rate of elimination constant drug concentration point where expect maximum drug effect usually attained after 4-5 half lives

80mg (4h) 40mg (4h) 20mg (4h) 10mg (4 h) 5mg  Most drugs follow 1st order elimination rates.

____________End of Transcription ____________ Come to me all who labor and are heavy laden, and I will give you rest. Matthew 11:28