Lec 4. Kinetics and Elimination I, Dr. Hoang Nguyen- Full Slides.pdf

Fundamentals of Pharmacology-COM5082 Lecture 4: Pharmacokinetics-Drug Absorption, Distribution, and Excretion Hoang Nguyen, M.D., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for que...

Fundamentals of Pharmacology-COM5082 Lecture 4: Pharmacokinetics-Drug Absorption, Distribution, and Excretion Hoang Nguyen, M.D., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for questions or appointment: [email protected] Learning Objectives After Completion of this section of Pharmacokinetic Overview, first year M1 students will be able to: 1. Describe the different mechanisms by which drugs are absorbed 2. Define the properties of drugs that govern absorption, distribution and excretion. 3. Pregnancy Category Pharmacokinetics  The magnitude of a drug response depends upon the concentration of the drug at the site of action. Absorption  Drug absorption is the movement of the drug into the bloodstream after administration.  Drug absorption is controlled by:  Cell membrane  Capillary walls  Barriers (blood brain barriers, placenta) Drug Absorption: Capillaries Wall    Capillaries is the site of exchange of materials between blood and cells Capillary walls one cell thick  Pores allow materials (ions, water, nutrients, unbound drugs) to move in/out The capillaries of liver and kidney are more porous, where a large part of the basement membrane is exposed due to large and discontinuous capillaries through which large plasma proteins are able to pass. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Drug Absorption: Blood-Brain-Barrier (BBB) Barrier between circulating blood & CNS • Network of Capillaries – Consists of tight junctions around capillaries – "barrier" results from the selectivity of the tight junctions between endothelial cells that restricts the passage of large hydrophilic molecules • Becomes porous with – Inflammation – Hypertonic solutions (mannitol) Example: Levodopa To enter the brain, drugs must pass through the endothelia cells of the CNS capillaries or undergo active transport. A specific transporter carries levodopa into the brain. Lipid-soluble drugs readily penetrate the CNS because they dissolve in the endothelia cell membrane. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Determinants of Absorption rate 1. 2. 3. 4. Surface Area of absorption site. Blood flow at absorption site. Concentration gradient Drug formations (different sizes, such as crystals, micronized particles, or ultra-micronized particles) 5. Lipid solubility: more lipophilic will increase absorption 6. Un-Ionized: will increase absorption Neonates vs. Aging on Drug Absorption The main effect of neonates/infants on drug absorption  Small skeletal muscle mass, result in lower blood flow to muscle. Absorption after IM injections is slower.  Skin is thinner and topically applied drugs are more rapidly and completely absorbed into the systemic circulation.  Less acidic in gastro of premature babe The main effect of aging on drug absorption  Decreased intestinal surface area  Decreased blood flow to intestine  Decreased GI motility  Decreased onset of action  Decreased drug absorption of medication Drug Absorption: Cell Membrane Membrane is permeable to many drug molecules but depends on their lipid solubility. Contains small pores permitting entry of small molecules such as alcohol and water. • • Passive diffusion- Passage through lipid cell membrane by dissolution in membrane; rate markedly higher for lipophilic molecules; rate of transport is proportional to concentration gradient at transport site (Fick’s law) – Requires no energy – Cannot be inhibited • Carrier-mediated transport- Passage facilitated by a carrier mechanism such that transport (active) can occur against a concentration gradient ; transporters include the family of ATP-dependent proteins (ex: the multidrug resistance p-glycoprotein) • Endocytosis- selective process – large molecules (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Drug Distribution  After a drug gains access to the blood, it is distributed to the various tissues and organs of the body, and it is called “distribution” Factors affecting Distribution  Blood Flow: Organ such as liver, kidneys and brain have the largest blood supply, thus exposed to the largest amount of drug.  Blood-Brain Barrier: Brain is composed of a large amount of lipid (nerve membranes and myelin), lipid-soluble drugs pass readily into the brain.  Plasma Protein Binding: drug=%bound to protein and %unbound to protein (more pharmacological action). (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Factors affect Distribution – Rate of blood flow, distribution occurs most rapidly into tissues with high blood flow ”richvessel organ” (lungs, kidneys, liver, brain) and least rapidly in tissues with less flow (fat) Example: IV bolus of Propofol. Mechanism: high blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia. A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration so that the drug diffuses out of the CNS, down the concentration gradient, and consciousness is regained. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Factors affecting Distribution  Why does a patient wake up after 5 minutes after an injection of thiopental when it is known that it takes several hours to eliminate this drug from the body?  Initially the drug is all in the blood and this blood goes to "vessel rich" organs; principally the brain. After a few minutes the drug starts to venture off and redistributes into adipose tissue, the concentration in the brain decreases and the patient wakes up. The drug thus redistributes into adipose tissue, which can act as a storage site, or drug reservoir. Distribution Water Soluble Drug Distribution Water Soluble Drug Distribution Water Soluble Drug Distribution Water Soluble Drug Distribution Water Soluble Drug Fat Soluble Drug Distribution Water Soluble Drug Fat Soluble Drug Distribution Water Soluble Drug Fat Soluble Drug Distribution Water Soluble Drug Fat Soluble Drug Distribution Water Soluble Drug Fat Soluble Drug Factors Affecting Drug Binding %Drugs bound to plasma protein – Generally not pharmacologically active (No Effect) – Have longer duration of action and low volumes of distribution – Not filtered by the glomerulus _ High binding % reduces free drug available for distribution into tissue because of restricted diffusion out of the vascular compartment. – Decreased metabolism –Displaced by other drugs – Ex: warfarin, diazepam, propranolol, phenytoin 1. Aging: No nutrition, thus decreased plasma protein, will lead to increased unbounding (free drug), decreased drug metabolism, finally will increase duration of action, and increase intensity of drug effect. Lean body mass, total body water, concentration of plasma protein; All decrease in elderly. 2. Neonate/Infants: lower percentage of body fat, thus decreased distribution to body tissues and organs. Drug stays in body longer, thus cause higher drug levels in blood. Pediatrics have higher percentages of water, more easily dehydrated by vomiting and diarrhea, since reduction of body fluid will increase drug concentration. Also, lower plasma protein, will increase unbound drug, there will be greater intensity of drug effect. Volume Distribution Formula Vd= Amount of drug in the body Plasma drug concentration (C) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Drug Excretion  The common pathways of drug excretion are:  Renal (urine),  GI (feces) (e.g. Doxazosin)  Respiratory (exhaled gases). The kidneys are the most  important organs for drug excretion. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Drug Excretion   Renal excretion: After the blood is filtered through the glomerulus of the kidney, most of the filtered substances are eventually reabsorbed into the blood. In order for drug excretion to occur, drug must be water soluble and preferably in an ionized form. Acid drugs are mostly ionized in alkaline urine and basic drugs are mostly ionized in an acid urine. GI excretion: After oral administration, a certain portion of drug (unabsorbed) passes through the GI tract and is excreted in the feces. The duration of action of few drugs is greatly prolonged because of enterohepatic cycling of the drug (liver to bile to intestine to blood to liver).   Respiratory excretion: General anesthetic gases are not totally metabolized. These drugs are excreted primarily by the lungs. Excretion by other routes: Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. Drug Excretion  Neonate/Infants: There is a reduced capacity for drug excretion during the first year of life. Drug excretion more slowly and duration of drug action is prolonged. After the first year, drug excretion gradually become proportional to those of the adult.  Aging: Almost all measures of real function, such as GFR and creatinine clearance, are significantly reduced with age. Thus, the duration of drug action, plasma drug concentration, and pharmacological effects will all be increased for drugs that are eliminated primarily by renal excretion, thus, required dosage reduction. FDA Teratogenic Risk Categories • Category A- No risk demonstrated to the fetus in any trimester • Category B- No adverse effects in animals; no human studies available • Category C- Only given after risks to the fetus are considered; animal studies have shown adverse reactions; no human studies available • Category D- Definite fetal risks; may be given in spite of risks if needed in life-threatening situations • Category X- Absolute fetal abnormalities; not to be used at any time during pregnancy (Adapted, First Aid USMLE Review 2020) Resources  1. Basic and clinical pharmacology by Katzung, 15th edition.  2. Videos: https://sketchy.com/