Therapeutic States

Understanding the interplay between drug pharmacokinetics and therapeutic states is essential for effective therapeutic drug monitoring (TDM)

Pharmacokinetics: The Body’s Effect on Drugs

• Definition: The study of how the body affects a drug after administration, including the processes of absorption, distribution, metabolism, and excretion (ADME)

Absorption

• Definition: The process by which a drug enters the bloodstream from its site of administration
• Factors Affecting Absorption
  • Route of Administration: Oral, intravenous, intramuscular, subcutaneous, transdermal, etc
  • Drug Formulation: Tablet, capsule, solution, etc
  • Physicochemical Properties of the Drug: Solubility, ionization, molecular size
  • Physiological Factors: Gastric emptying time, intestinal motility, blood flow, pH
  • First-Pass Metabolism: Metabolism of a drug in the liver before it reaches systemic circulation (for orally administered drugs)
• Bioavailability: The fraction of an administered dose of a drug that reaches the systemic circulation unchanged
  • Intravenous administration: Bioavailability is 100%
  • Oral administration: Bioavailability is often less than 100% due to incomplete absorption and first-pass metabolism

Distribution

• Definition: The process by which a drug is transported from the bloodstream to various tissues and organs in the body
• Factors Affecting Distribution
  • Blood Flow: Highly perfused organs (brain, heart, liver, kidneys) receive the drug more rapidly
  • Tissue Permeability: Ability of the drug to cross cell membranes and enter tissues
    • Lipid-soluble drugs can easily cross cell membranes
    • Water-soluble drugs may require transport proteins
  • Protein Binding: Binding of drugs to plasma proteins (albumin, alpha-1-acid glycoprotein)
    • Only unbound (free) drug can exert pharmacological effects
    • Drugs with high protein binding have limited distribution
  • Volume of Distribution (Vd): A measure of the apparent space in the body available to contain the drug
    • Vd = Dose / Plasma Concentration
    • High Vd: Indicates extensive tissue distribution
    • Low Vd: Indicates limited tissue distribution

Metabolism

• Definition: The process by which the body chemically alters a drug, usually to make it more water-soluble and easier to excrete
• Primary Site: Liver
• Phases of Metabolism
  • Phase I Reactions: Introduce or expose a functional group on the drug molecule
    • Oxidation, reduction, hydrolysis
    • Enzymes: Cytochrome P450 (CYP) enzymes, flavin-containing monooxygenases (FMOs)
  • Phase II Reactions: Conjugate a polar molecule to the drug molecule
    • Glucuronidation, sulfation, acetylation, glutathione conjugation
    • Enzymes: UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs)
• Enzyme Induction and Inhibition
  • Enzyme Inducers: Increase the activity of metabolizing enzymes, leading to decreased drug levels
    • Examples: Rifampin, carbamazepine
  • Enzyme Inhibitors: Decrease the activity of metabolizing enzymes, leading to increased drug levels
    • Examples: Ketoconazole, erythromycin
• Prodrugs: Drugs that are inactive in their administered form and must be metabolized to active metabolites to exert their effects * Examples: Codeine, prednisone

Excretion

• Definition: The process by which the body eliminates a drug
• Primary Routes
  • Kidneys: Most drugs are excreted in the urine
    • Glomerular filtration, tubular secretion, tubular reabsorption
  • Liver: Some drugs are excreted in the bile and eliminated in the feces
  • Other Routes: Lungs, sweat, saliva, breast milk
• Factors Affecting Excretion
  • Renal Function: Glomerular filtration rate (GFR), tubular secretion, and tubular reabsorption affect renal drug excretion
  • Liver Function: Bile flow and hepatic metabolism affect biliary drug excretion
  • Drug Properties: Molecular size, ionization, and protein binding affect excretion
• Clearance (CL): A measure of the body’s ability to eliminate a drug
  • CL = Rate of Elimination / Plasma Concentration
  • High CL: Indicates rapid drug elimination
  • Low CL: Indicates slow drug elimination

Therapeutic States in TDM

• Objective of TDM: To optimize drug therapy by maintaining drug concentrations within a specific therapeutic range
• Therapeutic Range: The range of drug concentrations associated with a high probability of desired therapeutic effect and a low probability of adverse effects
• Factors Influencing the Therapeutic Range
  • Drug Properties: Potency, selectivity, and therapeutic index
  • Patient Factors: Age, sex, weight, genetics, disease state, and concurrent medications
• Therapeutic States
  • Subtherapeutic: Drug concentration is below the therapeutic range, resulting in inadequate therapeutic effect
  • Therapeutic: Drug concentration is within the therapeutic range, achieving the desired therapeutic effect with minimal adverse effects
  • Toxic: Drug concentration is above the therapeutic range, increasing the risk of adverse effects
  • Supratherapeutic: Drug concentration is above the therapeutic range, but not necessarily associated with toxicity
    • Supratherapeutic levels may be intentional in certain situations (e.g., antibiotic dosing for severe infections)

Subtherapeutic State

• Definition: Drug concentration is below the therapeutic range, resulting in inadequate therapeutic effect
• Causes
  • Inadequate Dose: The prescribed dose is too low
  • Poor Adherence: The patient is not taking the medication as prescribed
  • Drug Interactions: Other medications or substances are decreasing drug levels
  • Rapid Metabolism: The patient is metabolizing the drug too quickly
  • Increased Clearance: The patient’s kidneys are eliminating the drug too quickly
  • Malabsorption: Drug is not adequately absorbed in the GI tract
• Consequences
  • Lack of therapeutic effect: The drug is not effectively treating the condition
  • Disease progression: The condition may worsen due to lack of treatment
  • Development of resistance: In the case of antibiotics, subtherapeutic levels can promote the development of drug-resistant bacteria
• Management
  • Increase the dose
  • Improve adherence through patient education and support
  • Adjust the dosing interval
  • Avoid or manage drug interactions
  • Use an alternative drug

Therapeutic State

• Definition: Drug concentration is within the therapeutic range, achieving the desired therapeutic effect with minimal adverse effects
• Goal of TDM: To maintain drug concentrations within the therapeutic range
• Factors Influencing the Therapeutic Range
  • Individual variability in drug metabolism and response
  • Patient-specific factors (age, weight, genetics, disease state)
  • Drug interactions
• Management
  • Monitor drug concentrations regularly
  • Adjust the dose or dosing interval as needed
  • Monitor for adverse effects
  • Educate the patient about the importance of adherence and potential drug interactions

Toxic State

• Definition: Drug concentration is above the therapeutic range, increasing the risk of adverse effects
• Causes
  • Excessive Dose: The prescribed dose is too high
  • Decreased Clearance: The patient’s kidneys or liver are not eliminating the drug efficiently
  • Drug Interactions: Other medications or substances are increasing drug levels
  • Overdose: Intentional or accidental ingestion of too much drug
• Consequences
  • Adverse effects: The drug causes unwanted side effects
  • Organ damage: The drug damages organs, such as the liver or kidneys
  • Life-threatening conditions: The drug causes serious complications, such as arrhythmias or seizures
• Management
  • Reduce the dose
  • Increase the dosing interval
  • Discontinue the drug
  • Administer an antidote, if available
  • Provide supportive care

Supratherapeutic State

• Definition: Drug concentration is above the therapeutic range, but not necessarily associated with toxicity
• Intentional Supratherapeutic Levels
  • Certain situations may require supratherapeutic levels to achieve the desired effect (e.g., antibiotic dosing for severe infections, chemotherapy)
  • Monitor patients closely for adverse effects
• Unintentional Supratherapeutic Levels
  • May occur due to errors in dosing, drug interactions, or impaired drug elimination
  • Monitor patients for adverse effects and adjust the dose accordingly

Summary Table of Therapeutic States

Therapeutic State	Drug Concentration	Therapeutic Effect	Adverse Effects	Management
Subtherapeutic	Below therapeutic range	Inadequate	Low	Increase the dose, improve adherence, avoid drug interactions, use alternative drug
Therapeutic	Within therapeutic range	Desired	Minimal	Monitor drug concentrations, adjust dose as needed
Toxic	Above therapeutic range	May or may not increase; monitor for adverse effects	High	Reduce the dose, discontinue drug, administer antidote, provide supportive care
Supratherapeutic	Above therapeutic range	May be intentional or unintentional	May be present	Monitor for adverse effects, adjust dose as needed

Key Terms

• Pharmacokinetics: The study of how the body affects a drug (ADME)
• Absorption: The process by which a drug enters the bloodstream
• Distribution: The process by which a drug is transported to tissues
• Metabolism: The process by which the body chemically alters a drug
• Excretion: The process by which the body eliminates a drug
• Therapeutic Range: The range of drug concentrations associated with optimal therapeutic effect and minimal toxicity
• Subtherapeutic: Drug concentration is below the therapeutic range
• Therapeutic: Drug concentration is within the therapeutic range
• Toxic: Drug concentration is above the therapeutic range
• Supratherapeutic: Drug concentration is above the therapeutic range, but not necessarily toxic
• Clearance: The measure of the body’s ability to eliminate a drug
• Bioavailability: The fraction of a drug reaching systemic circulation
• Volume of Distribution: Apparent space in the body available to contain the drug
• Protein Binding: Binding of drugs to plasma proteins reducing distribution