Lecture 2 Pharmacokinatics PDF

Lecture: 2 Pharmacokinetics [email protected] Date: / Pharmacokinetics: How the Body Handles Medications Pharmacokinetics: the study of drug movement throughout the body Know how the body deals with medication Understand and predict actions and side effects...

Lecture: 2 Pharmacokinetics [email protected] Date: / Pharmacokinetics: How the Body Handles Medications Pharmacokinetics: the study of drug movement throughout the body Know how the body deals with medication Understand and predict actions and side effects of medications Understand obstacles that a drug faces to reach target cells Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Pharmacokinetics: How the Body Handles Medications Greatest barrier for many drugs is crossing many membranes Enteral route drugs are broken down by stomach acids and digestive enzymes Phagocytes may attempt to remove medicines seen as foreign Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Four Categories of Pharmacokinetic Processes Absorption Distribution Metabolism Excretion Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved The Passage of Drugs through Plasma Membranes Active transport Diffusion or passive transport Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Active Transport Chemicals move against concentration or electrochemical gradient Usually large, ionized, or water-soluble molecules Cotransport involves the movement of two or more chemicals across the membrane Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Diffusion or Passive Transport Molecules move from higher to lower concentration Usually small, nonionized, or lipid-soluble molecules Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Date: / Absorption Movement from site of administration, across body membranes, to circulating fluids Primary pharmacokinetic factor determining length of time for drug to produce effect Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Factors Affecting Drug Absorption (1 of 2) Drug formulation Dose Route of administration Size of the drug molecule Surface area of the absorptive site Digestive motility Blood flow Lipid solubility of the drug Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Date: / Factors Affecting Drug Absorption (2 of 2) Degree of ionization of drug – In stomach acid, aspirin nonionized and easily absorbed by bloodstream – In small intestine alkaline, aspirin ionized and less likely to be absorbed pH of local environment Drug-drug/food-drug interactions Dietary supplement/herbal product–drug interactions Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Effect of pH on Drug Absorption (1 of 3) A weak acid, such as aspirin (ASA), is in a nonionized form in an acidic environment and absorption occurs Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Effect of pH on Drug Absorption (2 of 3) In a basic environment, aspirin is mostly in an ionized form and absorption is prevented Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Effect of pH on Drug Absorption (3 of 3) Acidic drugs are best absorbed from acidic environments Basic drugs are best absorbed from basic environment Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Bioavailability The fraction of the administered dose reaching the systemic circulation unchanged for i.v.: 100% for non i.v.: ranges from 0 to 100% e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism Affected by: – First-pass hepatic metabolism – Solubility of the drug – Chemical instability Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Distribution of Medications (1 of 5) Distribution: transport of drugs throughout the body – Simplest factor determining distribution is the amount of blood flow to body tissues Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Distribution of Medications (2 of 5) Physical properties of drug have great influence Certain tissues (bone marrow, teeth, eyes, adipose tissue) have a high affinity, or attraction, for certain medications Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Distribution of Medications (3 of 5) Many drug molecules form drug–protein complexes— binding reversibly to plasma proteins—and thus never reach target cells Cannot cross capillary membranes Drug not distributed to body tissues Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved 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 Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Distribution of Medications (4 of 5) Drugs and other chemicals compete for plasma protein– binding sites – Drug–drug and drug–food interactions may occur when one drug displaces another from plasma proteins Some have greater affinity Displaced drug can reach high levels – Can produce adverse effects Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Distribution of Medications (5 of 5) Blood-brain barrier and fetal-placenta barrier: special anatomic barriers that prevent many chemicals and medications from entering – Make brain tumors difficult to treat – Fetal-placenta barrier protects fetus; no pregnant woman should be given medication without strong consideration of condition Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Metabolism of Medications Also known as biotransformation Chemically converts drug so it can be easily removed from body Involves complex biochemical reactions Liver—primary site Addition of side chains, known as conjugates, makes drugs more water soluble and more easily excreted by the kidneys Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Metabolism in the Liver Hepatic microsomal enzyme system (P-450 system) – Inactivates drug – Accelerates drug excretion – Some agents, known as prodrugs, have no pharmacologic activity unless first metabolized to active form by body Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Enzyme Induction A drug increases metabolic activity in the liver Changes in the function of the hepatic microsomal enzymes can significantly affect drug metabolism Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Oral Drugs Enter Hepatic Portal Circulation (First-Pass Effect) Drug is absorbed Drug enters hepatic circulation, goes to liver Drug is metabolized to inactive form Drug conjugates and leaves liver Drug is distributed to general circulation Many drugs are rendered inactive by first-pass effect Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Date: / First-Pass Effect: Oral Drug Is Metabolized to an Inactive Form Before It Has an Opportunity to Reach Target Cells Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Metabolism and Pharmacotherapy Metabolic activity may be decreased in some patients: – Infants and older adults – Patients with severe liver disease – Patients with certain genetic disorders Dosages in patients with decreased metabolic activity must be reduced to prevent toxicity Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Excretion of Medications Primary site of excretion of drugs is kidneys Free drugs, water-soluble agents, electrolytes, and small molecules are easily filtered Drug–protein complexes and large substances are secreted into distal tubule of nephron Secretion mechanism is less active in infants and older adults pH of filtrate can increase excretion Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Other Organs Can Be Sites of Excretion Respiratory system Glands Biliary system Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Enterohepatic Recirculation of Drugs Drugs are excreted in bile Bile recirculates to liver Percentage of drug may be recirculated numerous times Prolongs activity of drug – Activity of drug may last after discontinuation Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Date: / Enterohepatic recirculation Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Drug Plasma Concentration and Therapeutic Response Concentration of medication at target tissue is often impossible to measure, so it must be measured in plasma – Minimum effective concentration—amount of drug required to produce a therapeutic effect – Toxic concentration—level of drug that will result in serious adverse effects – Therapeutic range—plasma drug concentration between the minimum effective concentration and the toxic concentration Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Plasma Half-Life (t½) of Drugs Length of time needed to decrease drug plasma concentration by one half The greater the half-life, the longer it takes to excrete Determines frequency and dosage Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved How Drug Reaches and Maintains Therapeutic Range Repeated doses of drug are given Drug accumulates in bloodstream Plateau is reached Amount administered equals amount eliminated Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Figure 4.5 Single dose drug administration: pharmacokinetic values for this drug are as follows: onset of action = 2 hours; duration of action = 6 hours; termination of action = 8 hours after administration; peak plasma concentration = 10 mcg/mL; time to peak drug effect = 5 hours; t½ = 4 hours Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Figure 4.6 Multiple-dose drug administration: Drug A and drug B are administered every 12 hours; drug B reaches the therapeutic range faster because the first dose is a loading dose Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Loading Dose Higher amount of drug given Plateau reached faster Quickly produces therapeutic response Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Maintenance Dose Keeps plasma-drug concentration in therapeutic range Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Maintenance Dose Keeps plasma-drug concentration in therapeutic range Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved Maintenance Dose Keeps plasma-drug concentration in therapeutic range Copyright © 2020, 2017, 2014 Pearson Education, Inc. All Rights Reserved