Pharmacokinetics and Pharmacodynamics

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 cellsesch ta

• Greatest barrier for many drugs is crossing many membranes

• Enteral route drugs are broken down by stomach acids and digestive enzymes

• Organs attempt to excrete medicines

• Phagocytes may attempt to remove medicines seen as foreignrget\

Four Categories of Pharmacokinetic Processes

• Absorption • Distribution • Metabolism • Excretion

The Passage of Drugs through Plasma Membranes

• Active transport

• Diffusion or passive transport

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

Diffusion or Passive Transport

• Molecules move from higher to lower concentration

• Usually small, nonionized, or lipid-soluble molecules

Absorption of Medications

• Movement from site of administration, across body membranes, to circulating fluids

• Primary pharmacokinetic factor determining length of time for drug to produce effectcells

Factors Affecting Drug Absorption

• 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

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

Distribution of medications

• Distribution: transport of drugs throughout the body

– Simplest factor determining distribution is the amount of blood flow to body tissues

• Physical properties of drug have great influence

• Lipid solubility is an important characteristic

• Certain tissues (bone marrow, teeth, eyes, adipose tissue) have a high affinity, or attraction, for certain medications

•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

• 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

• Drug – drug interactions – Addition – Synergism – Antagonism – Displacement

• 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

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

Metabolism in the Liver

• Hepatic microsomal enzyme system (P450 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

• Drugs having the ability to reduce metabolism in the liver are known as enzyme inhibitors

• Hepatic metabolic activity

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

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

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

Renal Failure Diminishes Excretion of Medications

• Drugs are 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 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

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

Plasma Half-Life ( ) t½ (t Subscript One Half) 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

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

Loading Dose

• Higher amount of drug given

• Plateau reached faster

• Quickly produces therapeutic response

Maintenance Dose

• Keeps plasma-drug concentration in therapeutic range

Pharmacodynamics andInterpatientt Variability

• 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 experience will guide safe treatment

Frequency Distribution Curve

• Graphical representation of number of patients responding to a drug action at different doses

• Peak of curve indicates largest number of patients responding to drug

• Does not show magnitude of response

Median Effective Dose (ED Subscript 50)

• Middle of frequency distribution curve

Dose that produces therapeutic response in 50% of a group

• Sometimes called “average” or “standard” dose • Many patients require more or less

Nurses Skill Critical in Determining if Average Dose Is Effective

• Patient observation

• Taking vital signs

• Monitoring lab data

Median Lethal Dose (L D Subscript 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 (T D Subscript 50)

• Dose that will produce given toxicity in 50% of group of patients

• Value may be extrapolated from – Animal data – Adverse effects in patient clinical trials

• Needed because median lethal dose cannot be tested in humans

Therapeutic Index and Drug Safety

• Measure of a drug’s safety margin
• The higher the value, the safer the drug

The Graded Dose—Response Relationship and Therapeutic 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

Three Phases of Graded Dose— Response Curve

• Phase 1: occurs at lowest dose – Few target cells affected by drug

• Phase 2: straight-line portion of curve – Most desirable range – Linear relationship between amount of drug administered and degree of patient response

• Phase 3: plateau reached – Increasing dose has no therapeutic effect – Increased dose may produce adverse effects

Two Ways to Compare Medications

• Potency

• Efficacy

Potency

• Drug with higher potency produces a therapeutic effect at a lower dose, compared with another drug in the same class

Efficacy

• Magnitude of maximal response that can be produced from a particular drug

• From a pharmacotherapeutic perspective, efficacy almost always more important than potency

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 protein agonists

• Associated with plasma membrane or intracellular molecules

Drug Attaches to Receptor

• Comparable to how thumb drive docks to USB port on a computer

• May trigger second messenger events – e.g., activation of specific G proteins and associated enzymes

• Initiates drug action

Receptor Subtypes Still Being Discovered

• Permit “fine-tuning” of pharmacology

• Two basic receptor types – Alpha – Beta

• Drugs affect each subtype differently

• Intercellular molecules (DNA or enzymes in the cytoplasm) – Interact with receptors by inhibiting protein synthesis or regulate cell events

Nonspecific Cellular Responses

• Caused by drugs that act independently of receptors

• Example: changing the permeability of cellular membranes

Drugs That Act as Agonists

• Bind to receptor

• Produce same response as endogenous chemical

• Sometimes produce greater maximal response

Drugs That Act as Partial Agonists

• Bind to receptor

• Produce weaker, less effective response than agonists

Drugs That Act as Antagonists

• Occupy receptor

• Prevent endogenous chemical from acting

• Often compete with agonists for receptor

• Functional antagonists inhibit the effects of an agonist not by competing for a receptor but by changing pharmacokinetic factors

Pharmacology of the Future: Customized Drug Therapy

• End of single-drug, one-size-fits-all policy

• DNA test before receiving drug

• Prevention of idiosyncratic (unpredictable and unexplained) drug reactions

• Pharmacogenetics—area of pharmacology that examines role of heredity in drug response