class two: chapter two

Chapter 2: Drugs and the Body

Pharmacodynamics vs. Pharmacokinetics

  • Pharmacokinetics

    • Definition: The study of absorption, distribution, metabolism (biotransformation), and excretion of drugs.

    • Phrase: "What the body does to the drug."

  • Pharmacodynamics

    • Definition: The study of interactions between the chemical components of living systems and foreign chemicals, including drugs, that enter those systems.

    • Explanation: When a new chemical enters the system, multiple changes or interferences with cell functioning may occur.

    • Phrase: "What the drug does to the body."

Pharmacokinetics

  • Kinetics refers to movement.

  • ADME: Acronym for the key pharmacokinetic processes.

    • Absorption: The process through which a drug moves into the bloodstream.

    • Distribution: The dispersion of the drug throughout the fluids and tissues of the body.

    • Metabolism/Biotransformation: The chemical alteration of the drug by the body.

    • Excretion: The removal of the drug from the body.

  • Route of administration impacts absorption significantly.

Absorption

  • Definition: What happens to a drug from the time it is introduced to the body until it reaches the circulating fluids and tissues.

  • Key Concepts:

    • Bioavailability:

    • Definition: The extent and rate at which the active ingredient or active moiety is absorbed and becomes available at the site of action.

    • Factors that Impact Bioavailability:

      • Dose/amount of drug.

      • Formulation of the drug.

      • Physical and chemical properties of the drug.

    • Significance: Provides an estimation of the extent of absorption.

    • Variability: Changes depending on the drug's method of administration:

      • Intravenous (IV) administration: 100% bioavailability, as the drug is administered directly into circulation.

      • Oral (PO) administration: Most frequently used; however, it is subject to various barriers aimed at destroying ingested foreign chemicals.

  • Note: A bioavailable drug can reach its pharmacologic target and produce a therapeutic response.

Additional Factors Affecting Absorption

  • Routes of Administration and Their Influence on Drug Absorption:

    • Intravenous (IV) Administration:

    • Bypasses absorption processes as it delivers drugs directly into the circulation, ensuring maximum bioavailability (100%).

    • Oral Administration (PO):

    • Most common route for drug administration.

    • Influenced by the first-pass effect, which reduces bioavailability due to metabolism in the liver before reaching systemic circulation.

Plasma Level Time Curve and Absorption

  • Bioavailability: The absorption of drugs varies significantly depending on the route of administration, affecting how drugs enter systemic circulation.

Absorption: Factors Affecting Absorption

  • Table 2.1 Factors That Affect Absorption of Drugs

    • Routes of Administration:

    • Intravenous (IV)

      • Absorption is immediate due to direct entry into the venous system.

    • Intramuscular (IM)

      • Factors affecting absorption:

      • Perfusion or blood flow to the muscle: Influences drug uptake.

      • Solubility of medication in water: Higher solubility results in faster absorption.

      • Temperature of the muscle:

        • Cold temperatures cause vasoconstriction, decreasing absorption.

        • Heat causes vasodilation, increasing absorption.

    • Subcutaneous

      • Factors affecting absorption:

      • Perfusion or blood flow to the tissue: Critical for drug absorption.

      • Fat content of the tissue: Can affect drug distribution.

      • Temperature of the tissue: Similar effects as described for the muscle.

    • Oral (PO)

      • Factors affecting absorption:

      • Acidity of the stomach: Can affect dissolution and absorption.

      • Length of time in stomach: Prolonged retention can enhance absorption.

      • Health of the gastrointestinal tract: Affects absorption efficiency.

      • Blood flow to gastrointestinal tract: Increased flow enhances absorption.

      • Presence of interacting foods or drugs: Can delay or enhance absorption.

      • Presence of mucus: May influence absorption through the gastrointestinal tract.

    • Inhalation

      • Factors affecting absorption:

      • Perfusion or blood flow to the area: Essential for effective uptake.

      • Integrity of the lung lining: Impacts absorption rate.

      • Length of time retained for absorption: Affected by inhalation technique (inspiratory effort).

    • Topical or intradermal (skin)

      • Factors affecting absorption:

      • Integrity of skin: Must allow drug to penetrate.

      • Adequacy of subcutaneous tissue: Fat thickness and perfusion impact absorption.

      • Presence of drugs: Some drugs can alter the skin barrier.

Absorption: First Pass Effect

  • The Liver: Acts as the anatomical "First Stop" for all orally administered drugs:

    • Drugs taken orally are directed to the liver before entering systemic circulation.

    • Impact of First Pass Effect:

    • Each pass through the liver reduces the quantity of drug that reaches systemic circulation due to metabolism/biotransformation.

    • The greater the degree of metabolism, the lower the bioavailability—leading to variations in drug effectiveness between oral and IV dosing.

    • Exogenous Chemicals: The liver processes all ingested substances, regardless of their nature—therapeutic or toxic.

    • Variations in Metabolism:

    • Medications may either pass through the liver unchanged into circulation or undergo metabolism, leading to different outcomes:

      • Active metabolite: A form that has therapeutic effects.

      • Inactive metabolite: A form that does not provide therapeutic effects.

      • Parent compound (prodrug): A medication that becomes active after metabolism.

Distribution

  • Definition: Distribution refers to the transport of drugs from the bloodstream to various tissues throughout the body.

  • Factors Affecting Distribution:

    • Blood flow/perfusion to tissues:

    • Cardiac output to organs is vital; decreased cardiac output results in reduced blood flow to organs, leading to decreased drug delivery.

    • Plasma protein binding:

    • Distinction between Free drug (active form) vs. Bound drug (inactive form).

    • Capillary membrane permeability:

    • Barriers such as the blood-brain barrier and the blood-placenta barrier restrict or facilitate drug passage.

Drug Distribution

Plasma Protein Binding

  • Drugs in the bloodstream are transported to their sites of action.

  • Drugs can be categorized as:

    • Free-drug: Unbound to plasma proteins.

    • Only unbound drugs can act on target sites in tissues to produce pharmacologically relevant effects.

    • Must leave circulation to reach receptors in tissues.

    • Only unbound drugs are subject to metabolism or excretion.

    • Bound drug: Bound to circulating plasma proteins.

    • When drugs bind to plasma proteins, they create a drug–protein complex, which is reversible.

    • This bound form of the drug is inactive or unavailable for pharmacological effect and serves as a storage depot in circulation.

  • The typical ratio of bound drug to free drug remains stable; however, exceptions exist:

    1. Competition for binding sites: Occurs during drug-drug interactions.

    2. Insufficient binding sites available: Particularly relevant during low albumin levels in the blood.

  • Both situations result in increased amounts of free drug available, which raises the risk of potential toxicity.

Capillary Membrane Permeability

  • Unbound drugs are critical for pharmacological effects as they can leave circulation and target sites in tissues.

  • The ability of a drug to cross a cell membrane (and access pharmacological targets) is influenced by:

    • Plasma protein binding.

    • Physiochemical properties of the drug (e.g., lipophilicity, molecular size).

    • Characteristics of the cell membrane, particularly capillary membrane permeability.

Specific Barriers in Distribution

  • Blood-Brain Barrier:

    • A specialized capillary barrier in the brain that restricts the entry of various substances, thus imparting a selective permeability that affects drug distribution.

Placental Barrier

  • Drug distribution can be affected by the placental barrier which determines the passage of substances between maternal and fetal blood.

  • Types of Drugs:

    • Lipid-soluble drugs: Easily pass through cell membranes due to their lipophilic nature.

    • Ionic and polar drugs: Typically have reduced permeability due to their hydrophilic characteristics.

Metabolism/Biotransformation

  • The liver functions as the primary site for drug biotransformation (metabolism).

Key Mechanisms of Biotransformation

  • Biotransformation involves a chemical change in the structure of a drug molecule via enzymatic reactions, specifically via:

    • CYP-450 enzymes (Cytochrome P-450 system):

    • Responsible for the metabolism of the majority of medications.

    • Converts drugs into more water-soluble forms, which are more easily excreted by the kidneys.

    • Results in the formation of new, less active chemicals that are excretion-friendly.

    • Not all drugs undergo biotransformation; some are excreted unchanged.

Types of Metabolites

  • Inactive Metabolites: Do not have pharmacological activity post-metabolism.

  • Active Metabolites: Retain pharmacological activity even after biotransformation.

  • Prodrugs: Pharmacologically inactive compounds that become active upon metabolic conversion.

Important Concepts related to Drug Metabolism

  • First-Pass Effect: A phenomenon where the concentration of a drug is significantly reduced before it reaches systemic circulation. It typically occurs after oral administration, subjecting the drug to hepatic metabolism before reaching the systemic circulation.

  • Hepatic enzyme system: The system in the liver includes the CYP-450 enzymes, which play a crucial role in drug metabolism.

Metabolism / Biotransformation

  • Overview of Metabolism/Biotransformation

    • Many drug-drug interactions involve the hepatic enzyme system, specifically CYP-450 enzymes.

  • Key Drug Interactions Involving Drug Metabolism

    • Enzyme Induction

    • Description:

      • Patient is on a specific drug (referred to as Drug-A) and a second drug or chemical (referred to as Drug-B) is introduced that increases the activity of hepatic enzymes.

      • Result:

      • This process leads to an increased metabolism of Drug-A, potentially lowering its effectiveness and resulting in subtherapeutic levels of Drug-A.

    • Enzyme Inhibition

    • Description:

      • Patient is on Drug-A and a second drug or chemical (Drug-B) is introduced that decreases or inhibits the activity of hepatic enzymes.

      • Result:

      • This process results in decreased metabolism of Drug-A, which can lead to toxic levels of Drug-A.

Excretion

  • Overview of Excretion

    • Refers to the removal of drugs from the body.

    • The kidneys play the most significant role in the excretion of medications.

  • Other Routes of Excretion

    • Skin

    • Saliva

    • Lungs

    • Bile/Feces

  • Three Processes for Drug Excretion (Kidney/Renal)

    • Glomerular Filtration

    • Involves the filtration of free-drug molecules and small molecules (Molecular Weight < 500 Daltons).

    • Active Renal Secretion

    • Occurs in the proximal tubules of the kidney.

    • Unwanted molecules are “carried” out of the plasma using various transporter molecules.

    • Tubular Reabsorption

    • Takes place in the distal tubules.

    • Here, drug molecules may be reabsorbed back into the plasma rather than being excreted into the urine.

Half-Life

  • Key Concept of Half-Life

    • Definition:

    • The half-life of a drug is the time it takes for 50% of the drug in the body to decrease to one half of its peak level.

    • Importance:

    • Critical for determining appropriate dosing schedules and the duration of drug effects.

  • Factors Affecting Half-Life

    • Absorption Rate

    • Distribution to Tissues

    • Speed of Biotransformation

    • Refers to liver function and its impact on the metabolism of drugs.

    • Speed of Excretion

    • Related to kidney function and how quickly drugs are eliminated from the body.

Factors Influencing the Body’s Response to a Drug

  • Weight

  • Age

  • Sex

  • Physiological Factors

  • Pathological Factors

  • Genetic Factors

  • Immunological Factors

  • Psychological Factors

  • Environmental Factors

  • Tolerance

  • Accumulation

  • Interactions

    • All of these factors play a role in how the body responds to medications, affecting their efficacy and potential side effects.

Pharmacogenetic Differences

  • Overview

    • Pharmacogenetic differences refer to how different patients metabolize drugs based on genetic variations within the same patient group.

  • Patient Group Considerations

    • Different patient groups may process drugs differently, affecting toxicity and benefit.

    • Categorization of Metabolism:

      • Fast Metabolizers

      • Normal Metabolizers

      • Slow Metabolizers

  • Drug Outcomes Based on Metabolism

    • The same drug can have varying outcomes based on metabolic rate even if the diagnosis and prescription are the same.

    • Scenarios:

      • Drug Not Toxic and Not Beneficial

      • Drug Not Toxic but Beneficial

      • Drug Toxic but Beneficial

      • Drug Toxic and Not Beneficial

Drug Interactions

  • Types of Drug Interactions

    • Drug interactions can occur when two or more drugs are taken together, affecting their efficacy and safety.

Drug-Drug Interactions

  • Situations Where Drug-Drug Interactions Occur

    • At the Site of Absorption

      • Absorption can be affected by environmental changes or by drugs forming insoluble complexes.

    • During Distribution

      • Competition for protein binding sites may alter drug distribution in the body.

    • During Biotransformation/Metabolism

      • Involves induction and inhibition of CYP enzymes, which are critical in drug metabolism.

    • During Excretion

      • Interactions may occur during the competition for reabsorption or secretion processes in the renal tubule.

    • At the Site of Action

      • Receptor site competition can lead to altered therapeutic effects.

Drug-Food Interactions

  • Mechanism of Interaction

    • Generally, drug-food interactions occur when a drug and food are in direct contact in the stomach.

  • Absorption Considerations

    • Oral drugs typically absorb fastest when taken on an empty stomach.

    • In many cases, absorption speed may not be clinically significant, allowing normal eating and drinking.

    • Taking medication with small meals can potentially decrease nausea associated with drug intake.

  • Labeling and Information

    • Drug labels usually provide information on important drug-food interactions.

Drug-Lab Interactions

  • Effects on Laboratory Testing

    • Some drugs can alter the accuracy of laboratory test results.

    • Lab tests are often utilized to monitor the impacts of other medications.