Pharmacokinetics Pharmacology PDF

PHARMACOKINETIC S Part 1 Dr. Fatimah Almahasneh Department of Basic Medical Sciences Yarmouk University 1  Learning objectives 1. Define pharmacokinetics. 2. List the routes of drug administration and their properties. 3. D...

PHARMACOKINETIC S Part 1 Dr. Fatimah Almahasneh Department of Basic Medical Sciences Yarmouk University 1  Learning objectives 1. Define pharmacokinetics. 2. List the routes of drug administration and their properties. 3. Define absorption. 4. List the mechanisms of drug absorption. 5. Indicate the factors affecting drug absorption. 6. Explain the factors affecting drug distribution. 7. Calculate the apparent volume of distribution of a drug. 2  Pharmacokinetics Pharmacokinetics is the study of how an organism affects the drug. It refers to what the body does to a drug. 3  Pharmacokinetics Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including: the route of administration dose frequency duration of treatment Enjoy the video! 4 Routes of drug administration The route of administration is determined by: - properties of the drug (for example, water or lipid solubility, ionization) - therapeutic objectives (for example, the need for a rapid onset, the need for long-term treatment, or restriction of delivery to a local site). 5  Routes of drug administration Enteral Parenteral Administering a drug by Introduces drugs directly into the systemic mouth. circulation. It is the most common, For drugs that are poorly absorbed from the GI convenient, and tract or unstable in the GI tract. economical method of For patients unable to take oral medications drug administration. If a rapid onset of action is required. Provides the most control over the dose of drug delivered to the body. It is irreversible and may cause pain, fear, local 6 tissue damage, and infections.  Dosage forms A dosage form is the physical form in which a drug is manufactured or administered. Examples of dosage forms include: tablets, capsules, powders, oral and injectable solutions, suppositories, ointments, inhalers, spray… etc. A drug may be available in multiple dosage forms. 7  Enteral route of drug administration 1. Oral Oral drugs are easily self-administered, and toxicities and/or overdose may be overcome with antidotes, such as activated charcoal. Pathways involved in oral drug absorption are the most complicated, and the low gastric pH inactivates some drugs. 8  Two “special” oral preparations A. Enteric-coated preparations An enteric coating is a chemical envelope that protects the drug from stomach acid, delivering it to the intestine, where the coating dissolves and releases the drug. Enteric coating is useful for drugs that are acid labile or irritating to the stomach. 9  Two “special” oral preparations B. Extended-release preparations Have special coatings or ingredients that control drug release → slower absorption and prolonged duration of action. Doses less frequently → improve patient compliance. Advantageous for drugs with short half-lives. Maintain concentrations within the therapeutic range over a longer duration. 10  Two “special” oral preparations B. Extended-release preparations Are abbreviated ER, XR, XL, SR, etc.. 11  Enteral route of drug administration 2. Sublingual/buccal The sublingual route involves placement of drug under the tongue. The buccal route involves placement of drug between the cheek and gum. Ease of administration, rapid absorption, bypass of the harsh gastrointestinal (GI) environment, and avoidance of first-pass metabolism. 12  First pass metabolism Hepatic portal circulation 13 First-pass metabolism  Parenteral route of drug administration 14  Parenteral route of drug administration 1. Intravenous (IV) It is useful for drugs that are not absorbed orally. It permits a rapid effect and a maximum degree of control over the amount of drug delivered. As an IV bolus → the full amount of drug is delivered to the systemic circulation almost immediately. As an IV infusion → the drug is infused over a longer period → lower peak plasma concentrations and an increased duration of circulating drug. 15  Parenteral route of drug administration 2. Intramuscular (IM) Drugs administered IM can be in aqueous solutions, which are absorbed rapidly, or in specialized depot preparations, which are absorbed slowly. Depot preparations often consist of a suspension of drug in a nonaqueous vehicle. 16  Parenteral route of drug administration 3. Subcutaneous (SC) SC injection provides absorption via simple diffusion and is slower than the IV route. It minimizes the risks of hemolysis or thrombosis associated with IV injection and may provide constant, slow, and sustained effects. This route should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur. 17  Parenteral route of drug administration 4. Intradermal (ID) It involves injection into the dermis, the more vascular layer of skin under the epidermis. Agents for allergy testing are usually administered by this route. 18  Other routes of drug delivery 1. Inhalation and nasal preparations Provide rapid delivery of drug across a large surface area of mucous membranes of the respiratory tract. Drug effects are almost as rapid as are those with IV bolus. 19  Other routes of drug delivery 1. Inhalation and nasal preparations Drugs that are gases and those that can be dispersed in an aerosol are administered via inhalation. Drug is delivered directly to the site of action → minimize systemic side effects. The nasal route involves topical administration of drugs directly into the nose. 20  Other routes of drug delivery 2. Intrathecal/intraventricular The blood–brain barrier (BB) delays or prevents the absorption of some drugs into the central nervous system (CNS). When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid (CSF). 21  Other routes of drug delivery 3. Topical Topical application is used when a local effect of the drug is desired. 22  Other routes of drug delivery 4. Transdermal This route achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application, as well as the lipid solubility of the drug. 23  Other routes of drug delivery 5. Rectal First-pass metabolism is minimized with rectal administration. It prevents destruction of the drug in the GI environment. This route is useful if the patient is vomiting or unconscious. Rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa. 24 ABSORPTION 25  Absorption 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. 26  Mechanisms of absorption of drugs from the GI tract 1. Passive diffusion 2. Facilitated diffusion 3. Active transport 4. Endocytosis and exocytosis 27  Passive diffusion The driving force for passive diffusion is the concentration gradient across a membrane → does not require energy. It does not involve a carrier, is not saturable, and shows low structural specificity. The vast majority of drugs are absorbed by this mechanism. Water-soluble drugs → aqueous channels or pores Lipid-soluble drugs → solubility in the membrane lipid bilayers. 28  Facilitated diffusion It utilizes specialized transmembrane carrier proteins that facilitate the passage of large molecules. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier. 29  Active transport It involves specific carrier proteins that span the membrane. It is energy dependent, driven by the hydrolysis of adenosine triphosphate (ATP). It can move drugs against a concentration gradient. The process is saturable. Active transport systems are selective and may be competitively inhibited by other cotransported substances. 30  Endocytosis and exocytosis This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. Exocytosis is the reverse of endocytosis. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. 31  Mechanisms of absorption of drugs from the GI tract 32  Factors influencing absorption 1) Effect of pH on drug absorption Most drugs are either weak acids or weak bases. A drug passes through membranes more readily if it is uncharged. 33  Factors influencing absorption 34  Factors influencing absorption The distribution of a drug between its ionized and nonionized forms depends on the ambient pH and pKa of the drug. For illustrative purposes, the drug has been assigned a pKa of 6.5. 35  Factors influencing absorption 2) Blood flow to the absorption site The intestines receive much more blood flow than does the stomach, so absorption from the intestine is favored over the stomach. 36  Factors influencing absorption 3) Total surface area available for absorption With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. 37  Factors influencing absorption 4) Contact time at the absorption surface If a drug moves through the GI tract very quickly (as can happen with severe diarrhea) → it is not well absorbed. Anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption. The presence of food in the stomach both dilutes the drug and slows gastric emptying → drug taken with a meal is generally absorbed more slowly. 38  Factors influencing absorption 5) Expression of P-glycoprotein P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. 39  Factors influencing absorption 5) Expression of P-glycoprotein It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved in transportation of drugs from tissues to blood → P-glycoprotein reduces drug absorption. 40  Bioavailability Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 or 70%. Determining bioavailability is important for calculating drug dosages for non-IV routes of administration. 41  Determination of bioavailability Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral) with levels achieved by IV administration. 42  Factors that influence bioavailability 1) First-pass hepatic metabolism When a drug is absorbed from the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased. 43  Factors that influence bioavailability First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action. 44  Factors that influence bioavailability 2) Solubility of the drug Very hydrophilic drugs are poorly absorbed because of the inability to cross lipid-rich cell membranes. Drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. 45  Factors that influence bioavailability 3) Chemical instability Some drugs are unstable in the pH of gastric contents, and some are destroyed in the GI tract by degradative enzymes. 46  Factors that influence bioavailability 4) Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug. particle size, salt form, enteric coatings, and the presence of excipients → can influence the ease of dissolution → alter the rate of absorption. 47  Bioequivalence Bioequivalent drug formulations have comparable bioavailability and similar times to achieve peak blood concentrations. Pharmaceutically equivalent formulations have the same dosage form, contain the same active ingredient at the same strength, and use the same route of administration. Therapeutic equivalent drug products are bioequivalent and pharmaceutically equivalent. 48 DISTRIBUTION 49  Drug distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and tissues. 50  Drug distribution For drugs administered IV, absorption is not a factor, and the initial phase immediately following administration represents the distribution phase, during which the drug rapidly leaves the circulation and enters the tissues. 51  Factors affecting drug distribution 1) Blood flow Blood flow to “vessel-rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. 52  Factors affecting drug distribution 2) Capillary permeability Capillary permeability is determined by capillary structure and by the chemical nature of the drug. 53  Factors affecting drug distribution To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or undergo active transport. A significant portion of the basement membrane is exposed due to large, The capillary structure is These closely juxtaposed cells form discontinuous capillaries. continuous, and there are tight junctions that constitute the no slit junctions. blood–brain barrier (BBB). 54  Factors affecting drug distribution 2) Binding to plasma proteins Reversible binding to plasma proteins sequesters drugs in a nondiffusible form and slows transfer out of the vascular compartment. Albumin is the major drug-binding protein, and it may act as a drug reservoir. As the concentration of free drug decreases due to elimination, the bound drug dissociates from albumin. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma. 55  Plasma protein binding and drug availability (a) drug exists in a free state or bound to plasma protein (b) drug–protein complexes are too large to cross membranes 56 Copyright © 2017, 2014, 2011 Pearson Education, Inc. All Rights Reserved  Factors affecting drug distribution 3) Binding to tissue proteins Many drugs accumulate in tissues, leading to higher concentrations in tissues than in interstitial fluid and blood. Drugs may accumulate because of binding to lipids, proteins, or nucleic acids. Drugs may also undergo active transport into tissues. Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity. 57  Factors affecting drug distribution 4) Lipophilicity Lipophilic drugs readily move across most biologic membranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. By contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions. 58  Factors affecting drug distribution 5) Volume of distribution The apparent volume of distribution (Vd), is the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. 59  Factors affecting drug distribution Vd is a pharmacokinetic parameter representing an individual drug’s propensity to either remain in the plasma or redistribute to other tissue compartments. (C0 = drug plasma concentration at time zero) Note: Sometimes Vd is calculated per body weight (L/kg). 60  Distribution into the water compartments in the body Plasma compartment Extracellular fluid Total body water If a drug has a high molecular If a drug has a low molecular weight but If a drug has a low molecular weight or is extensively is hydrophilic, it can cross capillaries into weight and has enough protein bound, it is effectively the interstitial fluid, but cannot move lipophilicity, it can move into the “trapped” within the plasma across the plasma membranes to enter interstitium and pass through (vascular) compartment. the intracellular fluid. the cell membranes into the → it has a low Vd that → It distributes into a volume that is the intracellular fluid. approximates the plasma sum of the plasma volume and the → It distributes into a volume of volume (about 4 L in a 70-kg interstitial fluid (=the extracellular fluid). about 60% of body weight or individual). This is about 20% of body weight or 14 L about 42 L in a 70-kg individual. in a 70-kg individual. In general, a larger Vd indicates greater distribution into tissues; 61 a smaller Vd suggests confinement to plasma or extracellular fluid.  Determination of Vd – Example 1 Ten milligram of a drug is injected into a patient. The plasma concentration is extrapolated back to time zero and was found to be 1 mg/L. What is the volume of distribution of this drug? Vd = dose/C0 = 10 mg/1 mg/L = 10 L 62  Determination of Vd – Example 2 A patient weighing 60 kg is given a 1000 μg dose of Drug A. On measuring the plasma concentration, we get a value of 2 μg/L. What is the volume of distribution of drug A per kg patient body weight? Vd = (dose/C0)/body weight = (1000 μg/2 μg/L)/60 kg = 500 L / 60 kg = 8.33 L/kg 63  Effect of Vd on drug half-life (T1/2) Drug half-life (T1/2) is the time it takes to reduce the plasma drug concentration by half. If a drug has a large Vd, most of the drug is in the extraplasmic space and is unavailable to the excretory organs → elimination is delayed → T1/2 increases. Any factor that increases Vd can increase the half-life and extend the duration of action of the drug. 64  Thank you for listening!