Pharmacokinetics “The study of drug movement throughout the body”

Application of Pharmacokinetics to Clinical Practice  Pharmacokinetics: the study of drug movement throughout the body  Know how the body handles medication  Understand actions and side effects of drugs  Understand obstacles drug faces to reach target cells

Drugs in the Body  Greatest barrier for many drugs is crossing many membranes  Enteral route drugs broken down by stomach acids and enzymes  Organs attempt to excrete medicines  Phagocytes may attempt to remove medicines seen as foreign

Four Categories of Pharmacokinetics 1. Absorption 2. Distribution 3. Metabolism 4. Excretion

Figure 4.1 The four processes of pharmacokinetics: absorption, distribution, metabolism, excretion.

Drugs Cross Plasma Membranes to Produce Effects  Diffusion or passive transport  Active transport

Diffusion or Passive Transport  Molecules move from higher to lower concentration  Usually small, nonionized, or lipid-soluble molecules

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

Absorption  Movement from site of administration, across body membranes, to circulating fluids  Primary factor determining length of time for effect of drug to occur

Factors Affecting Drug Absorption  Route of administration  Drug formulation  Drug dosage  Digestive motility  Digestive tract enzymes  Blood flow at administration site

Factors Affecting Drug Absorption (cont'd)  Degree of ionization of drug  In acid of stomach, aspirin is nonionized and easily absorbed by bloodstream  In alkaline of small intestine, aspirin is ionized and less likely to be absorbed  pH of surrounding environment  Drug-drug/drug-Food interactions  Dietary supplement/herbal product–drug interactions

Figure 4.2 Effect of pH on drug absorption: (a) a weak acid such as aspirin (ASA) is in a nonionized form in the acidic environment and absorption occurs; (b) in a basic environment, aspirin is mostly in an ionized form and the absorption is prevented.

Metabolism (Also Known as Biotransformation)  Changes drug so it can be excreted  Involves biochemical reactions  Liver—primary site  Addition of side chains, known as conjugates, makes drugs more water soluble and more easily excreted by the kidneys

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

Enzyme Induction  A drug increases metabolic activity in the liver  Changes in the function of the hepatic microsomal enzymes can significantly affect drug metabolism

Oral Drugs Enter Hepatic-Portal Circulation (First-Pass Effect)  Drug 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 rendered inactive by first-pass effect

Figure 4.4 First-pass effect: (a) drugs are absorbed; (b) drugs enter hepatic portal circulation and go directly to liver; (c) hepatic microsomal enzymes metabolize drugs to inactive forms; (d) drug conjugates, leaving liver; (e) drug is distributed to general circulation.

First Pass Effect

Distribution of Medications  Distribution involves the transport of pharmacologic agents throughout the body  Simplest factor determining distribution is the amount of blood flow to body tissues  Physical properties of drug have big influence  Certain tissues, such as bone marrow, have a high affinity, or attraction, for certain medications

Drugs Bind with Plasma Proteins  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

Figure 4.3 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.

Distribution of Medications  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

Blood brain barrier

Distribution of Medications (cont'd)  Blood-brain barrier and fetal-placenta barrier: special anatomic barriers that prevent many chemicals and medications from entering  Makes brain tumors difficult to treat  Fetal-placenta barrier protects fetus; no pregnant woman should be given medication without strong consideration of condition

Primary Site of Excretion of Drugs Is Kidneys  Free drugs, water-soluble agents, electrolytes, and small molecules are filtered  Drug-protein complexes are secreted into distal tubule  Secretion mechanism is less active in infants and older adults  pH of filtrate can increase excretion

Renal Failure Diminishes Excretion of Medications  Drugs retained for extended times  Dosages must be reduced

Other Organs Can Be Sites of Excretion  Respiratory system  Glands  Biliary system

Enterohepatic Recirculation of Drugs  Drugs excreted in bile  Bile recirculates to liver  Percentage of drug recirculated numerous times  Prolongs activity of drug  Activity of drug may last after discontinuation

Figure 4.5 Enterohepatic recirculation.

Drug Plasma Concentration and Therapeutic Response  Concentration of medication in target tissue often impossible to measure, so 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

Plasma Half-Life (t 1/2 ) 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 dosages

How Drug Reaches and Maintains Therapeutic Range  Repeated doses of drug given  Drug accumulates in bloodstream  Plateau reached  Amount administered equals amount eliminated

Figure 4.6 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; t1⁄2 = 4 hours

Figure 4.7 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

Loading Dose  Higher amount of drug given  Plateau reached faster  Quickly produces therapeutic response

Maintenance Dose  Keeps plasma-drug concentration in therapeutic range

Chapter 5 Pharmacodynamics

Frequency-Distribution Curve  Graphical representation of number of clients responding to drugs at different doses  Peak of curve indicates largest number of clients responding to drug  Does not show magnitude of response

Know Principles of Pharmacodynamics and Clinical Practice  Pharmacodynamics – how a medicine changes the body  Helps to predict if drug will produce change  Will ensure that drug will provide safe, effective treatment  Combination of drug guides and intuitive knowledge will guide safe treatment

Figure 5.1 Frequency distribution curve: Interpatient variability in drug response.

Median Effective Dose (ED 50 )  Middle of frequency-distribution curve  Dose that produces therapeutic response in 50% of a group  Sometimes called “average” or “standard” dose  Many clients require more or less

Skill of Nurse Critical in Determining if Average Dose Is Effective  Client observation  Taking of vital signs  Monitoring lab data

Median Lethal Dose (LD 50 )  Used to assess safety of a drug  Shown on frequency-distribution curves  Determined in preclinical trials  Is lethal dose in 50% of group of animals  Cannot be experimentally determined in humans

Median Toxicity Dose (TD 50 )  Dose that will produce given toxicity in 50% of group of clients  Value may be extrapolated from  Animal data or  Adverse effects in client clinical trials  Needed because Median Lethal Dose cannot be tested in humans

Therapeutic Index  Measure of a drug’s safety margin  The higher the value, the safer the drug

Calculating Therapeutic Index

Figure 5.2 Therapeutic index: (a) drug X has a therapeutic index of 4: drug Z has a therapeutic index of 2.

Graded Dose-Response  Graphically visualizes differences in responses to medications in a single patient  Obtained by observing and measuring patient’s response at different doses of the drug

Figure 5.3 Dose – response relationship.

Two Ways to Compare Medications  Potency  Efficacy

Figure 5.4 Potency and efficacy: (a) drug A has a higher potency than drug B (b) drug A has a higher efficacy that drug B

Drugs That Act as Agonists  Bind to receptor  Produce same response as endogenous substance  Sometimes produce greater maximal response

Drugs That Act as Partial Antagonists  Bind to receptor  Produce weaker response than agonist

Drugs That Act as antagonists  Occupy receptor  Prevent endogenous chemical from acting  Often compete with agonist for receptor  Functional antagonists inhibit the effects of an agonist not by competing for a receptor, but by changing pharmacokinetic factors

Receptor Is Macromolecule  Molecule to which medication binds in order to initiate its effects  Binds endogenous molecules  Hormones, neurotransmitters, growth factors  Most drug receptors are proteins  Associated with plasma membrane or intracellular molecules

In the Future: Customized Drug Therapy  End of single-drug, one-size-fits-all policy  DNA test before receiving drug  Prevention of idiosyncratic responses – unpredictable and unexplained drug reactions  Pharmacogenetics - area of pharmacology that examines role of heredity in drug response

Receptor Subtypes Still Being Discovered  Permit “fine-tuning” of pharmacology  Two basic receptor types  Alpha  Beta  Drugs affect each subtype differently

Nonspecific Cellular Responses  Caused by drugs that act independently of receptors  Example: changing the permeability of cellular membranes