Lecture PK 2024 PDF

Branko Radojkovic [email protected] The pharmaceutical sciences are a group of interdisciplinary areas of study that deal with the design, action, delivery, disposition, and use of medicines. This field draws on many areas of the basic and applied science, such as chemistry, biology, mathema...

Branko Radojkovic [email protected] The pharmaceutical sciences are a group of interdisciplinary areas of study that deal with the design, action, delivery, disposition, and use of medicines. This field draws on many areas of the basic and applied science, such as chemistry, biology, mathematics, physics, and chemical engineering, and applies their principles to the study of medicines Pharmaceutical sciences Pharmacology Pharmacodynamics Pharmacokinetics Pharmaceutical toxicology Medicinal chemistry Pharmaceutics Pharmacogenomics Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Pharmaceutical drug is any substance used in the diagnosis, treatment, or prevention of a disease It may be a synthetic, semi-synthetic, or naturally occurring compound or mixture of compounds Most drugs interact with a part of the body (organ, tissue, or cell) to alter an existing physiological or biochemical process Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  The site of action of a drug is the location in the body where the drug performs its desired function Most drugs work by interacting with target molecules found at the site of action; Drug targets are usually biomolecules such as proteins, protein complexes, or nucleic acids that play a role in a particular disease process In most cases, the drug must temporarily attach (bind) to the target to exert its action A common type of drug target is a receptor, generally a protein on the cell membrane, that can bind with a specific molecule (such as an endogenous compound or a drug) to alter the cell's behavior Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  A simple analogy often used to describe drug-target interactions is that of a lock and key—the target is a lock on a door that only a certain drug (the key) can bind to and open Using this analogy, the target is a molecular lock that contains a ‘keyhole’ with a very specific and consistent size and shape. This molecular keyhole is termed the active site of the target and can interact with only molecular keys of a complementary size, shape, and charge Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Structure of the full NMDA receptor, obtained via cryo-electron microscopy. Adopted from: Regan, M. C., Grant, T., McDaniel, M. J., Karakas, E., Zhang, J., Traynelis, S. F., Grigorieff, N., & Furukawa, H. (2018). Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors. Neuron (Cambridge, Mass.), 98(3), 521–529.e3. https://doi.org/10.1016/j.neuron.2018.03.034  A drug can exert its intended action only after reaching its intended target at the site of action It is often inconvenient or impossible to apply a drug directly at its site of action; instead, drugs must be given at an administration site far removed from the site of action Localised vs. systemic administration For accuracy and convenience of dosing, the drug is almost always incorporated into a dosage form or drug delivery system (such as tablets, patches, inhalers) Delivery systems can also be designed to provide controlled or sustained release of the drug Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  The method and form of administration must consider the body's protective barriers, the drug's physical and chemical properties, clinical need, and patient acceptance Most systemic drugs are given orally because patients prefer this administration method After oral dosing, the drug must be released from the delivery system and enter the bloodstream (a process called absorption) so that it can reach the site of action Another common but less convenient administration route is by injection, which is usually reserved for drugs that cannot be absorbed orally, or in situations where a patient cannot take an oral medication Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  After absorption, circulating blood carries the drug throughout the body in a process called distribution How much drug reaches each tissue, and how long it remains in the tissue, depends on the properties of each drug and of the tissue After the drug has carried out its intended action, the body must be able to inactivate and eliminate the drug by normal physiological processes Enzymes in the body break down drugs (by a process called metabolism or biotransformation) and convert them into inactive products Drugs and their breakdown products are removed from the body in waste fluids such as urine (by a process termed excretion) The acronym ADME (using the first letters from the words absorption, distribution, metabolism, and excretion) describes the absorption and disposition behavior of a drug in the body Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Adopted from: del Amo Páez, E. M. Ocular and Systemic Pharmacokinetic Models for Drug Discovery and Development. http://urn.fi/URN:ISBN:978-951-51-1426-6  For most drugs, the targets are some distance away from the site of administration. The effectiveness of a drug depends on how much and how rapidly it reaches its site of action A drug may have to cross several types of epithelial tissues to reach its site of action, and eventually, its target; For example, when a drug is administered orally, it must cross the intestinal lining before it can enter the bloodstream, from the bloodstream, the drug must leave capillaries through the capillary wall and enter various organs and tissues The primary constituents of the cell membrane are lipids, proteins, and carbohydrates attached to these lipids and proteins The fluid mosaic model provides a good, simple description of cell membrane structure; It proposes that the basic structural unit of almost all cell membranes is the lipid bilayer in which a variety of proteins are embedded; It also depicts the cell membrane as a fluid structure in which many of the constituent molecules are free to diffuse in the plane of the membrane Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Cell membranes are semipermeable or selectively permeable in that they allow certain types of molecules to cross and restrict or limit the transport of others Primary mechanisms for transport of a substance across a cell membrane are: 1. Passive diffusion (small MW solutes) 2. Carrier-mediated transport (small and large molecules) 3. Endocytosis and exocytosis (macromolecules, small particles) These processes exist to transport substances necessary for the cell's survival; Drugs and other molecules that are similar in structure or properties to these substances can also use these transport mechanisms Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Talevi, A., & Quiroga, P. A. M. (2018). ADME Processes in Pharmaceutical Sciences : Dosage, Design, and Pharmacotherapy Success (1st ed. 2018.). Springer International Publishing : Imprint: Springer.  When a drug or other molecule encounters a layer of cells such as the epithelial tissue, it can hypothetically cross this functional membrane barrier by either diffusing through the aqueous space between the cells or by going through the cell Which of these two pathways are available to the drug depends on the characteristics of the molecule and the characteristics of the epithelial tissue in question Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  The internal cavities and external surfaces of the body are lined with a tissue called the epithelial tissue, epithelial membrane or simply, the epithelium. When a drug is administered by any route except by injection, it encounters an epithelium at the site of administration; In theory, the drug can cross this epithelial tissue either paracellularly or transcellularly Most drug molecules will not be able to cross an epithelial membrane paracellularly because they are too large to diffuse through epithelial tight junctions - the only pathway available to most drugs is to cross epithelia by a transcellular mechanism Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  A specialized type of epithelial tissue, called the endothelium or endothelial membrane, makes up the walls of blood vessels, lymph vessels, and the internal surfaces of body cavities Endothelial cells line the entire circulatory system, from the heart to the smallest capillary, with a single layer of endothelial cells forming the walls of most capillaries Gaps between cells contain a loose network of proteins that act as filters, retaining very large molecules and letting smaller ones through Because of the looser junctions between endothelial cells, the paracellular pathway is very important for transport of drug molecules across the endothelium Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Drugs are given to patients at a variety of locations in or on the body called administration sites; the drug must travel from the site of administration and reach its site of action where it can perform its function There are many ways to administer a drug, and drugs are available in a variety of dosage forms; the choice of administration method and dosage form depends on many factors (e.g. the physicochemical properties of the drug, physiological limitations of the administration or absorption site, clinical situation, personal preferences) In some situations, the site of action is localised and is readily accessible; in these cases the drug can be administered very close to, or right at, this site; Such an approach to drug administration is termed topical, non-systemic, or local administration (e.g. application of a cream to the skin to treat skin condition, or use of a local anesthetic during dental procedures) Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  In many conditions, the site of action is difficult to reach, or the drug may not penetrate deep enough into the tissue after topical administration to be completely effective - the drug has to be administered at some other convenient location, from where it is absorbed into the bloodstream which carries it to the site of action. Sometimes, the site of action is not a single location but involves many tissues - drug must reach all these sites to effectively treat the patient, so the best approach is to use the bloodstream to carry drug to all the target sites Such an approach to drug administration is called systemic administration The first step in the journey of a systemically administered drug is absorption into the bloodstream; only then can the drug reach the sites of action Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Systemically administered drugs may be absorbed directly from the site of administration into the bloodstream (e.g. sublingual, transdermal) – the site of administration = the site of absorption For other systemically administered drugs, the drug must travel from the site of administration to a different region from where it is absorbed (e.g. oral) – the site of administration ≠ the site of absorption Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Regardless of where the site of absorption is located, the dissolved drug molecules have to cross the epithelial tissue at the absorption site, and then the capillary endothelium of blood vessels at the absorption site, to enter the bloodstream Most drugs are small enough to cross the capillary endothelium readily by paracellular passive diffusion, regardless of their physicochemical properties; thus, the slowest, or rate-limiting, step in absorption is usually the drug's ability to cross epithelial membranes at the absorption site, and this is what determines the overall rate of absorption This Photo by Unknown Author is licensed under CC BY Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Oral administration, in which a drug product is administered by mouth, is the most common and patient-preferred route of systemic administration The dosage form moves down the gastrointestinal (GI) tract and can be absorbed in any of several regions Intestinal epithelium is designed for efficient absorption of nutrients and is also the most important region for absorption of orally administered drugs due to large surface area and long residence time The drug must be dissolved in the intestinal fluids for it to permeate through the intestinal epithelium Oral administration is an effective means of dosing if the drug is able to cross the epithelial membranes of the GI tract efficiently Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Most patients prefer to take drugs orally than by other routes however, this is not always possible Parenteral administration (meaning ‘other than enteral’) – the term is reserved for routes in which a drug is injected into the body Parenteral administration avoids the epithelial barriers that can be difficult for some drugs to cross. The drug may be injected directly into the bloodstream by intravenous (IV) or intraarterial (in an artery) administration. Alternatively, the drug may be injected into a tissue from which it can reach the bloodstream, such as in subcutaneous (SC), intramuscular (IM), or intraperitoneal (in the abdomen) administration. Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  The Rectal Route: administration through the anus into the rectum Buccal or Sublingual Route: These routes involve placing the medication in the mouth, without swallowing, enabling absorption through buccal (cheek) or sublingual (below the tongue) mucosal membranes Transdermal Route: the intention is to deliver drugs systemically through the skin into the bloodstream Pulmonary Route: drug is inhaled into the lungs where absorption takes place Nasal Route: Nasal delivery involves depositing drug in the nose, usually as drops or a liquid spray Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Talevi, A., & Quiroga, P. A. M. (2018). ADME Processes in Pharmaceutical Sciences : Dosage, Design, and Pharmacotherapy Success (1st ed. 2018.). Springer International Publishing : Imprint: Springer.  Drug can enter the vascular space by intravascular administration, or after absorption of drug administered by another route A drug administered systemically relies on the circulatory system to take it to the site of action and to other tissues in the body. After absorption into blood, most drugs must leave the bloodstream and enter the site of action to exert their effect. Distribution is the reversible transfer of drug between the vascular space and the extravascular space The dynamic nature of drug distribution also means that drug concentrations in blood and tissues are constantly changing as drug is absorbed, distributed, metabolised, and excreted Apparent volume of distribution (Vd) is a proportionality constant between the total amount of drug in the body and drug plasma concentration: VD (L) = Total amount of drug in the body (mg) / Drug blood plasma concentration (mg/L) Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  There is a constant exchange of fluid and dissolved materials between vascular and extravascular fluids. The overall distribution of a drug between blood and extravascular space can be viewed as a series of processes: Movement of drug out of the bloodstream into ISF Movement of drug from ISF into tissue cells Movement of drug from cells into ISF Movement of drug from ISF back into blood Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Body eliminates a drug from plasma by either putting it in a waste fluid such as urine or bile (excretion), or by chemically changing the drug into one or more different compounds called metabolites (metabolism) The physicochemical properties of a drug (lipophilicity, ionisation, protein binding, and molecular weight) determine the extent to which a drug is excreted or metabolized. In general, polar compounds are more likely to be eliminated by excretion, while lipophilic compounds must be metabolised Many drugs are eliminated by both these pathways Clearance (Cl) is a proportionality factor between the rate of elimination of a drug and its concentration in blood plasma: Cl (mL/min) = drug elimination rate (mg/min) / drug plasma concentration (mg/mL) Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Adopted from: https://www.osmosis.org/learn/Pharmacokinetics:_Drug_elimination_and_clearance Talevi, A., & Quiroga, P. A. M. (2018). ADME Processes in Pharmaceutical Sciences : Dosage, Design, and Pharmacotherapy Success (1st ed. 2018.). Springer International Publishing : Imprint: Springer.  Excretion is a process by which a drug is eliminated from the body without any chemical change; We say that drugs are excreted unchanged, intact, or as the parent drug. The body excretes drugs and other substances by taking them out of plasma and putting them in a waste fluid such as urine Excreted drugs can also appear in other fluids such as saliva, bile, sweat, breast milk, and exhaled air; Generally, the contribution of these alternative excretion fluids is small compared to urine Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Excretion of the body's waste products, and of drugs and drug metabolites, which are excreted in urine The kidney continuously regulates the composition of blood within narrow limits, through tight regulation of excretion, reabsorption, and secretion The kidneys are involved to some extent in the excretion of almost every drug or drug metabolite from the body Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Although the primary role of the liver in drug elimination is via metabolism, the liver also secretes a fluid called bile that may play a role in drug excretion The liver removes drugs from the blood for metabolism - while in the liver, these drugs can also be secreted unchanged into bile Drugs secreted into bile are emptied along with bile into the duodenum, from where they can be removed from the body in the feces; this elimination pathway is called biliary excretion Enterohepatic Recirculation Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Excretion in Saliva Drugs are secreted into saliva made by salivary glands in the mouth Not a significant route of drug excretion because saliva is usually swallowed and enters the GI tract; The drug, therefore, can be reabsorbed from the small intestines, resulting in a process of salivary recycling One application of salivary drug excretion is for routine and noninvasive monitoring of drug levels in patients by measuring concentrations in saliva Excretion in Breast Milk Many drugs pass into the milk of lactating mothers The appearance of high concentrations of drugs in breast milk can have serious consequences for the infant Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Excretion in Sweat The primary purpose of sweat production is heat regulation; consequently, the amount of sweat produced is highly dependent on environmental conditions Because the volume of sweat produced is small, excretion in sweat is a possible but not significant mode of drug excretion Sweat is being examined as a convenient fluid for detecting illegal drug use Excretion in Expired Air The lung is a major organ of excretion for gaseous and volatile substances (e.g. volatile drugs such as anesthetics) The breathalyser test is based on a measurement of pulmonary excretion of ethanol in expired air Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Adopted from: https://www.innovativemonitoringnetwork.com/scram-continuous-alcohol-monitoring-drug-alcohol-testing-shreveport-la/  Metabolism (also termed biotransformation) describes enzyme-catalysed biochemical reactions, in which molecules are either broken down, or used to synthesize new molecules. The physicochemical properties of a drug (lipophilicity, ionization, protein binding, and molecular weight) determine the extent to which a drug is excreted or metabolized; Many drugs are eliminated by both these pathways Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Drugs that are polar, and significantly ionized in the pH 5 - 7, can be readily eliminated in the urine unchanged (i.e. without being metabolised); On the other hand, if a compound is lipophilic, extensively bound to plasma proteins, and reabsorbed from the tubular filtrate, it must usually be converted to polar metabolites that are suitable for excretion in urine For extensive biliary excretion, a compound needs to have a MW > 500; Drugs with MW 300 - 500 can be excreted to some extent in bile; Many drugs have MW < 500, and only their higher molecular weight metabolites undergo significant biliary excretion Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Drug metabolites are usually more polar, and more likely to be ionized, than the parent drug; Consequently, they are distributed less effectively into intracellular fluid, are less plasma protein-bound, and are less likely to be reabsorbed and more likely to be secreted in the kidney These differences enable metabolites to be excreted in the urine much more readily than the parent drug Many metabolites have a higher molecular weight than the parent drug, facilitating their secretion into bile Most metabolites are less biologically active than the parent drug First pass metabolism (first pass effect, presystemic metabolism) In some cases, the compound administered to the patient (a prodrug) is inactive, and becomes pharmacologically active only after being metabolised; i.e., the metabolite is the actual ‘drug’ that binds to the receptor Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Enzymes capable of metabolizing drugs are present in cells of most tissues and organs; Some enzymes, such as digestive enzymes, are extracellular and carry out reactions outside cells. Significant drug metabolism occurs only in organs that contain high concentrations of enzymes, and receive a large fraction of administered drug The liver, because of its structure and location, is the most important organ for drug metabolism Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins  Cmax is the max concentration of the drug in blood/plasma (peak conc.) Tmax is the time it takes to reach the Cmax AUC represents the total exposure of the drug t1/2 (half-life) is the time it takes for concentration to drop from Cmax to ½ Cmax Cmin – minimum concentration (trough) Cl, Vd, etc. Pandit, N. K., & Soltis, R. P. (2012). Introduction to the pharmaceutical sciences : an integrated approach (2nd edition.). Wolters Kluwer Health/Lippincott Williams and Wilkins Talevi, A., & Quiroga, P. A. M. (2018). ADME Processes in Pharmaceutical Sciences : Dosage, Design, and Pharmacotherapy Success (1st ed. 2018.). Springer International Publishing : Imprint: Springer.