PC1320_W5_Lecture_5a_Pharmacokinetics_Absorption

• Absorption: The process by which a drug enters the bloodstream from its site of administration. Factors affecting absorption include:

  • Route of administration (oral, intravenous, intramuscular, etc.)

  • Drug formulation (tablet, liquid, etc.)

  • Presence of food in the stomach

  • pH of the environment

  • Blood flow to the absorption site.

Page 3: Learning Outcomes

• Define basic concepts and medical terminology in pharmacokinetics.

• Understand pharmacokinetic parameters related to drug safety and efficacy.

• Use pharmacokinetics to guide administration of IV and orally administered drugs.

• Identify main routes of drug administration and their absorption mechanisms.

• Explain factors that affect pharmacokinetics (ADME).

• Recognize the influence of patient and disease state on pharmacokinetic parameters.

Page 4: Learning Objectives

• Understand principles of absorption.

• Describe mechanisms of drug absorption.

• Identify physicochemical properties affecting absorption rates:

  • Drug molecule ionization

  • Partitioning

• Explain roles of drug administration routes in absorption.

• Recognize the small intestine as a key site for drug absorption.

Page 5: Pharmacokinetics Overview

• PK involves Absorption, Distribution, Metabolism, Excretion (ADME).

• PK data represent simplified physiological processes.

Page 6: Pharmacokinetic Terminologies

• Biopharmaceutics, Clinical Pharmacokinetics, Population Pharmacokinetics, Toxicokinetics.

• Understand pharmacodynamics – mechanisms and dose-response relationships.

Page 7: Clinical Applications of Pharmacokinetics

• Drug development for pharmacology and toxicology investigations.

• Design and evaluation of dosage forms (formulation).

• Evaluation of organ function/failure.

• Therapeutic drug monitoring and dosing regimen design.

Page 8: Absorption Principles

• Rate of drug entry into circulation from administration site.

• Drug molecules diffuse down concentration gradients for absorption.

• Cell membranes act as barriers to diffusion, particularly for lipophilic agents.

Page 9: Drug Absorption Pathways

• Absorption routes include:

  • Bile

  • Portal system (Liver)

  • Kidney (urine)

  • Oral/rectal (gut)

  • Percutaneous (skin)

  • Intravenous (plasma)

  • Intramuscular (muscle)

  • Inhalation (lung)

  • CSF (Intrathecal)

  • Effects through systemic circulation to target sites including milk (lactation) and skin (sweat).

Page 10: Absorption Methods

• Most common method: transcellular passive diffusion influenced by blood flow.

• Key equations:

  • Rate of diffusion = dA/dt = (DKS/h)(Cabs - Cp)

  • Where D = diffusion coefficient, K = partition coefficient, S = membrane surface area, h = membrane thickness.

Page 11: Rate of Drug Diffusion

• Variables in drug diffusion:

  • dA/dt = rate of diffusion.

  • D = diffusion coefficient for specific drugs in environments.

  • K = partition coefficient.

  • S = surface area.

  • h = membrane thickness.

  • (Cabs - Cp) = concentration difference across membrane.

Page 12: Carrier-Mediated Transport

• Specific transport mechanisms for different drugs:

  • Jmax = maximum transport rate.

  • Cabs = drug concentration at absorption site.

  • Km = affinity constant for transporters.

Page 13: Paracellular Transport

• Transport defined by endothelial and epithelial limits.

• Differences exist between barriers at peripheral and blood-brain barriers (BBB).

Page 14: Absorption Mechanisms

• Modes of transport:

  • Aqueous channels for low molecular weight molecules.

  • Carrier-mediated transport (facilitated or active requiring ATP).

  • Pinocytosis for larger substances.

Page 15: Permeability Properties

• Influenced by size, lipophilicity, and charge of molecules.

Page 16: Size and Shape Influence

• Determinants of permeability include shape more often than size or molecular weight.

• Rate of diffusion correlates inversely with molecular radius.

Page 17: Partition Coefficient

• Log P = log ([oil]/[water]) indicates lipid versus aqueous solubility.

• Drug concentration in oil relative to water affects solubility properties.

Page 18: Lipophilic Drug Diffusion

• Lipophilic drugs can diffuse passively through membranes (important for CNS drugs).

• Based on Log P and Rule of 5 for drug absorption.

Page 19: Ionization Effects on Absorption

• Unionized state = high lipid solubility.

• Ionized state = low lipid solubility.

• Impact of pH on ionization illustrated with examples.

Page 20: Henderson-Hasselbalch Equation

• pKa calculations for weak acids/bases provide insight into absorption mechanisms.

• pKa correlates with the proportion of ionized to unionized molecules.

Page 21: Aspirin Ionization Example

• Example of Aspirin as a weak acid and how pH affects drug ionization.

• Low pH environments favor the unionized form, enhancing absorption.

Page 22: Ionization Calculation Exercise

• Calculation exercise for determining pH at which 90% of Warfarin is ionized.

Page 23: Impact of Urine pH on Excretion

• Alkalinization decreases excretion of weak bases, increases weak acids.

• Acidification has opposite effects on weak bases and acids.

Page 24: Routes of Drug Administration

• Examples of administration routes:

  • Oral (p.o.), sublingual, rectal, topical, inhalation, parenteral (various injections).

Page 25: Absorption in Gastrointestinal Tract

• Factors affecting absorption:

  • Stomach mucous barriers slow absorption.

  • Acidic pH enhances absorption of weak acids; enteric-coated drugs avoid stomach.

Page 26: Small Intestine Absorption

• Key site for absorption due to large surface area and vascularity.

• Optimal pH and permeability conditions extend absorption efficiency.

Page 27: Other Factors Affecting GI Absorption

• Portal circulation facilitates drug metabolism leading to reduced bioavailability.

• GI motility, particle size, blood flow, and food intake all affect absorption.

Page 28: Rectal Administration Absorption

• Unique absorption profile through the rectum with certain advantages.

• Facilitates localized treatment and bypasses digestive metabolism in critical situations.

Page 29: Sublingual Administration Benefits

• Rapid absorption aided by thin mucosa and vascular supply, avoiding first-pass metabolism.

Page 30: Topical/Transdermal Absorption

• Drug permeability affected by skin properties.

• Factors like hydration and inflammation can enhance absorption.

Page 31: Topical/Transdermal Absorption Factors

• Influences include surface area, thickness, hydration, and blood flow.

• Applications for local versus systemic effects.

Page 32: Intranasal Administration Benefits

• Rapid absorption directly into circulation, allowing avoidance of adverse first-pass effects.

Page 33: Inhalation Techniques

• Effective due to large surface area in lungs, facilitating rapid absorption.

Page 34: Subcutaneous Injection Dynamics

• Absorption influenced by tissue characteristics and blood flow.

Page 35: Intramuscular Injection Characteristics

• Rate of absorption dependent on drug formulation and tissue characteristics.

Page 36: Intramuscular Injection Considerations

• Depot formulations allow for slower release and reduced need for frequent dosing.

Page 37: Advantages of Intravenous Administration

• Immediate bioavailability but risks of high plasma concentrations demand careful administration.

Page 38: Advanced Injection Techniques

• Various specialized injections (i.p., intrathecal, i.c.v., intra-articular) for targeting specific areas in the body.

Page 39: References

• Rang & Dale’s Pharmacology 9th Ed.

• Hedaya MA (ed). Basic Pharmacokinetics, 2nd edition.