💊Medicinal Chemistry Unit 2 – Pharmacokinetics

What's Pharmacokinetics?

• Pharmacokinetics studies how the body processes drugs and other substances over time
• Encompasses absorption, distribution, metabolism, and excretion (ADME) of drugs
• Quantifies drug concentration changes in different body compartments
• Helps determine optimal dosing regimens for therapeutic efficacy and safety
• Considers factors like route of administration, drug formulation, and patient characteristics
  • Examples include oral, intravenous, or topical administration
  • Formulations can be immediate-release or extended-release
• Pharmacodynamics, in contrast, studies the biochemical and physiological effects of drugs on the body
• Mathematical models describe pharmacokinetic processes and predict drug behavior
• Clinical applications include drug development, personalized medicine, and drug interaction studies

Key Concepts and Terminology

• Bioavailability: fraction of administered drug that reaches systemic circulation unchanged
  • Influenced by factors like first-pass metabolism and drug solubility
• Volume of distribution (Vd): theoretical volume needed to contain the total amount of drug at the same concentration found in plasma
• Clearance: volume of plasma cleared of drug per unit time
  • Represents the efficiency of drug elimination processes
• Half-life (t1/2): time required for drug concentration to decrease by half
• Steady-state: equilibrium reached when drug administration and elimination rates are equal
• Area under the curve (AUC): total drug exposure over time, calculated from a concentration-time graph
• Maximum concentration (Cmax): highest drug concentration achieved after administration
• Time to maximum concentration (Tmax): time to reach Cmax after drug administration

The ADME Process

• Absorption: process by which a drug moves from the site of administration into the bloodstream
  • Influenced by factors like pH, surface area, and blood flow at the absorption site
• Distribution: movement of drug from the bloodstream into various tissues and organs
  • Depends on drug properties (lipophilicity, protein binding) and tissue characteristics (perfusion, permeability)
• Metabolism: chemical modification of the drug by enzymes, primarily in the liver
  • Biotransformation reactions (Phase I and Phase II) can activate or inactivate drugs
  • Cytochrome P450 (CYP) enzymes play a crucial role in drug metabolism
• Excretion: removal of the drug and its metabolites from the body
  • Major routes include renal excretion (via urine) and biliary excretion (via feces)
• The ADME process determines the onset, duration, and intensity of drug action
• Understanding ADME helps optimize drug delivery and minimize adverse effects

Factors Affecting Drug Absorption

• Physicochemical properties of the drug (solubility, lipophilicity, ionization)
  • Lipophilic drugs tend to have higher absorption rates
  • Ionization state depends on the pH of the environment and the drug's pKa
• Route of administration (oral, parenteral, topical, inhalation)
  • Oral route is most convenient but subject to first-pass metabolism
  • Parenteral routes (intravenous, intramuscular) bypass absorption barriers
• Formulation and dosage form (tablets, capsules, solutions, suspensions)
  • Disintegration and dissolution rates affect drug release and absorption
• Physiological factors (gastrointestinal motility, pH, food intake)
  • Food can delay gastric emptying and alter drug absorption
  • Gastrointestinal diseases (Crohn's, celiac) can impair absorption
• Drug interactions (chelation, adsorption, enzyme induction/inhibition)
  • Antacids can chelate drugs and reduce their absorption
  • Grapefruit juice inhibits CYP3A4, increasing bioavailability of some drugs

Drug Distribution in the Body

• Plasma protein binding affects drug distribution and activity
  • Albumin and α1-acid glycoprotein are major drug-binding proteins
  • Only unbound (free) drug can exert pharmacological effects
• Tissue perfusion and permeability determine drug access to target sites
  • Highly perfused organs (liver, kidneys) receive drug more rapidly
  • Blood-brain barrier restricts entry of many drugs into the central nervous system
• Drug reservoirs can accumulate in certain tissues (fat, bone)
  • Lipophilic drugs tend to have larger volumes of distribution
  • Redistribution from reservoirs can prolong drug effects
• Special populations may have altered distribution patterns
  • Elderly patients often have reduced muscle mass and increased body fat
  • Pregnancy can change drug distribution due to physiological adaptations
• Drug transporters (P-glycoprotein, organic anion transporters) influence distribution
  • Efflux transporters can limit drug access to certain tissues
  • Influx transporters can facilitate drug uptake into cells

Metabolism and Biotransformation

• Liver is the primary site of drug metabolism, but other organs also contribute
• Phase I reactions (oxidation, reduction, hydrolysis) modify drug structure
  • Cytochrome P450 (CYP) enzymes catalyze many Phase I reactions
  • Examples include CYP3A4, CYP2D6, and CYP2C9
• Phase II reactions (conjugation) attach polar groups to drugs or their metabolites
  • Common conjugation reactions include glucuronidation, sulfation, and acetylation
  • Conjugation generally increases drug water solubility and facilitates excretion
• Genetic polymorphisms can affect enzyme activity and drug metabolism rates
  • Poor metabolizers may have higher risk of adverse effects or therapeutic failure
  • Ultrarapid metabolizers may require higher doses for therapeutic effect
• Drug-drug interactions can occur through enzyme induction or inhibition
  • Inducers (rifampin, carbamazepine) increase enzyme activity and drug metabolism
  • Inhibitors (ketoconazole, erythromycin) decrease enzyme activity and drug metabolism
• Prodrugs are inactive compounds that undergo biotransformation to active drugs
  • Examples include codeine (metabolized to morphine) and enalapril (metabolized to enalaprilat)

Elimination and Excretion

• Renal excretion is the primary route of drug elimination
  • Glomerular filtration, tubular secretion, and tubular reabsorption determine drug clearance
  • Renal impairment can lead to drug accumulation and toxicity
• Biliary excretion and fecal elimination are important for some drugs
  • Drugs and their metabolites can be secreted into bile and eliminated in feces
  • Enterohepatic recirculation can prolong drug presence in the body
• Other minor elimination routes include sweat, saliva, and breast milk
• Elimination rate constant (ke) and half-life (t1/2) characterize drug elimination
  • Ke represents the fraction of drug eliminated per unit time
  • t1/2 is the time required for drug concentration to decrease by half
• Clearance (CL) is the volume of plasma cleared of drug per unit time
  • Total clearance is the sum of renal clearance, hepatic clearance, and other routes
  • Clearance determines the maintenance dose rate required to achieve steady-state concentrations
• Dosage adjustments may be necessary for patients with organ dysfunction
  • Renal dosing adjustments based on creatinine clearance or estimated glomerular filtration rate (eGFR)
  • Hepatic dosing adjustments based on Child-Pugh classification or liver function tests

Pharmacokinetic Models and Equations

• Compartmental models describe drug distribution and elimination
  • One-compartment model assumes rapid distribution and a single elimination phase
  • Two-compartment model includes a central compartment and a peripheral compartment
  • Multi-compartment models can be used for more complex drug behavior
• Non-compartmental analysis uses statistical moments to estimate pharmacokinetic parameters
• Absorption rate constant (ka) describes the rate of drug absorption into the systemic circulation
• Elimination rate constant (ke) describes the rate of drug elimination from the body
• Volume of distribution (Vd) relates the amount of drug in the body to the plasma concentration
  • Calculated as: $Vd = Dose / (AUC × ke)$
• Clearance (CL) is the volume of plasma cleared of drug per unit time
  • Calculated as: $CL = ke × Vd$
• Bioavailability (F) is the fraction of administered drug that reaches systemic circulation unchanged
  • Calculated as: $F = (AUC_{oral} / AUC_{IV}) × (Dose_{IV} / Dose_{oral})$
• Half-life (t1/2) is the time required for drug concentration to decrease by half
  • Calculated as: $t_{1/2} = 0.693 / ke$

Clinical Applications and Case Studies

• Therapeutic drug monitoring (TDM) uses pharmacokinetic principles to optimize dosing
  • Drugs with narrow therapeutic indices (digoxin, lithium) require careful monitoring
  • TDM helps maintain drug concentrations within the therapeutic range
• Pharmacogenomics considers genetic variations in drug metabolism and response
  • Genetic testing can guide drug selection and dosing for certain medications (warfarin, clopidogrel)
  • Personalized medicine aims to tailor drug therapy based on individual genetic profiles
• Drug interactions can be predicted and managed using pharmacokinetic knowledge
  • Dose adjustments or alternative medications may be necessary to avoid adverse interactions
  • Examples include the interaction between digoxin and clarithromycin (increased digoxin levels)
• Special populations require pharmacokinetic considerations
  • Pediatric and geriatric patients may have altered drug absorption, distribution, and elimination
  • Obesity can affect drug distribution and dosing requirements
  • Pregnancy and lactation involve unique physiological changes and safety concerns
• Case studies illustrate the application of pharmacokinetic principles in clinical practice
  • Example: Adjusting vancomycin dosing based on renal function and serum concentrations
  • Example: Managing drug therapy in a patient with liver cirrhosis and hepatic encephalopathy