💊Intro to Pharmacology Unit 3 – Pharmacokinetics: Drug ADME Processes

What's Pharmacokinetics Anyway?

• Pharmacokinetics (PK) describes how the body processes a drug
• Involves the journey of a drug from administration to elimination
• Includes four main processes: absorption, distribution, metabolism, and excretion (ADME)
• Helps determine the appropriate dose, route, and frequency of drug administration
• Plays a crucial role in understanding drug efficacy, safety, and potential interactions
• Pharmacokinetic principles apply to various drug formulations (oral, intravenous, topical)
• Considers factors such as age, weight, gender, and disease states that influence drug processing

The ADME Lowdown

• ADME stands for Absorption, Distribution, Metabolism, and Excretion
• Represents the four key processes that a drug undergoes in the body
• Absorption involves the drug entering the bloodstream from the site of administration
• Distribution describes the drug's journey to various tissues and organs
• Metabolism refers to the chemical modification of the drug by enzymes, primarily in the liver
• Excretion is the removal of the drug and its metabolites from the body
• Understanding ADME helps predict drug behavior and optimize therapeutic outcomes

Absorption: Getting Drugs into Your System

• Absorption is the process by which a drug enters the bloodstream
• Occurs at various sites depending on the route of administration (oral, intravenous, intramuscular)
• Factors influencing absorption include drug formulation, pH, and gastrointestinal motility
• Bioavailability refers to the fraction of the administered dose that reaches the systemic circulation
  • Oral drugs often have lower bioavailability due to first-pass metabolism in the liver
  • Intravenous administration results in 100% bioavailability
• Absorption rate and extent can be modified by drug formulation techniques (extended-release, enteric coating)
• Food and other medications can affect absorption by altering gastrointestinal pH or motility
• Diseases affecting gastrointestinal function (Crohn's disease, celiac disease) can impact drug absorption

Distribution: Drugs on Tour in Your Body

• Distribution refers to the movement of a drug from the bloodstream to various tissues and organs
• Depends on factors such as blood flow, tissue permeability, and protein binding
• Drugs bind to plasma proteins (albumin, alpha-1-acid glycoprotein), affecting their distribution
  • Highly protein-bound drugs (warfarin) have limited distribution to tissues
  • Drugs with low protein binding (acetaminophen) distribute more readily
• Some drugs accumulate in specific tissues (fat-soluble drugs in adipose tissue, bone-seeking agents)
• Distribution can be influenced by disease states that alter protein levels or tissue permeability
• The volume of distribution (Vd) is a measure of the extent of drug distribution in the body
  • Calculated as: $Vd = Amount of drug in the body / Plasma drug concentration$
  • Drugs with high Vd (digoxin) distribute widely, while those with low Vd (gentamicin) remain primarily in the bloodstream

Metabolism: Breaking Down the Party

• Metabolism is the chemical modification of a drug by enzymes, primarily in the liver
• Converts drugs into more water-soluble compounds (metabolites) for easier excretion
• Cytochrome P450 (CYP) enzymes play a significant role in drug metabolism
  • Genetic variations in CYP enzymes can lead to interindividual differences in drug response
  • Some drugs (rifampin) induce CYP enzymes, while others (grapefruit juice) inhibit them
• Phase I metabolism involves oxidation, reduction, or hydrolysis reactions
• Phase II metabolism involves conjugation reactions (glucuronidation, sulfation)
• Metabolism can result in the formation of active, inactive, or toxic metabolites
• Factors affecting metabolism include age, liver function, and concomitant medications
• Understanding metabolism helps predict drug interactions and adjust dosages in liver impairment

Excretion: The Final Exit

• Excretion is the removal of a drug and its metabolites from the body
• Primary routes of excretion include renal (kidneys), biliary (liver), and pulmonary (lungs)
• Renal excretion involves glomerular filtration, tubular secretion, and tubular reabsorption
  • Drugs that are highly protein-bound (aspirin) undergo less glomerular filtration
  • Some drugs (penicillins) are actively secreted into the tubular lumen
• Biliary excretion involves the transport of drugs from the liver into the bile
  • Drugs excreted in the bile (rifampin) may undergo enterohepatic recirculation
• Pulmonary excretion is significant for volatile anesthetics and alcohol
• The elimination half-life (t1/2) is the time required for the plasma concentration to decrease by 50%
  • Calculated as: $t1/2 = 0.693 × Vd / Clearance$
• Clearance is the volume of plasma cleared of a drug per unit time
• Factors affecting excretion include renal and hepatic function, urine pH, and drug-drug interactions

Factors That Mess with ADME

• Age: Infants and the elderly may have altered ADME due to differences in organ function and body composition
• Genetics: Polymorphisms in drug-metabolizing enzymes (CYP2D6) can lead to poor or ultra-rapid metabolism
• Disease states: Renal impairment, liver dysfunction, and cardiovascular disease can affect ADME processes
• Drug-drug interactions: Concomitant medications can induce or inhibit drug-metabolizing enzymes or transporters
  • Inducers (rifampin) increase enzyme activity, leading to reduced drug exposure
  • Inhibitors (ketoconazole) decrease enzyme activity, leading to increased drug exposure
• Food and herb-drug interactions: Certain foods (grapefruit juice) and herbal products (St. John's Wort) can alter drug ADME
• Pregnancy: Physiological changes during pregnancy can impact drug ADME and necessitate dose adjustments
• Obesity: Altered body composition and organ function in obesity can affect drug distribution and clearance

Why This Stuff Matters in Real Life

• Understanding ADME helps optimize drug therapy by selecting appropriate doses and routes of administration
• Pharmacokinetic principles guide dose adjustments in special populations (pediatrics, geriatrics, renal impairment)
• Knowledge of ADME is crucial for managing drug interactions and avoiding adverse effects
• Pharmacokinetic studies are essential in drug development to determine dosing regimens and formulation strategies
• Therapeutic drug monitoring (TDM) relies on pharmacokinetic principles to ensure drug concentrations are within the therapeutic range
  • TDM is particularly important for drugs with narrow therapeutic indices (aminoglycosides, antiepileptics)
• Personalized medicine utilizes pharmacokinetic data to tailor drug therapy based on individual patient characteristics
• Understanding ADME helps healthcare professionals educate patients on proper drug use and adherence