Pharmacology-1 Lecture 3: Pharmacokinetics (Part 1)

Pharmacology-1 Lecture 3: Pharmacokinetics (Part 1)

• Pharmacology: The study of drugs and their interaction with living systems through chemical processes.
• Pharmacokinetics: The study of how the body affects a drug. It describes the changes in drug plasma concentration.
• ADME: Absorption, Distribution, Metabolism, Excretion. These are the key processes in pharmacokinetics.
• Objectives of the lecture:
  • Understand the definition of pharmacology
  • Recognize pharmacokinetics
  • Define ADME
  • Describe drug absorption
  • Understand factors that affect absorption
  • Understand bioavailability and factors affecting it.
  • Learn about routes of administration

Introduction to Pharmacology

• Drug: Substance that interacts with a living system.
• Ology: Study or knowledge (in the context of science).
• Pharmacology is the study of drugs and their interaction with living systems via chemical processes.

Pharmacology and Subdivisions

• Pharmacokinetics: How the body processes the drug.
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
• Pharmacodynamics: How the drug affects the body.
  • Mechanism of action
  • Pharmacological action
  • Side effects

1- Pharmacokinetics

• Pharmacokinetics: Is the study of drug disposition in the body, specifically what the body does to the drug.
• Determining appropriate drug regimes requires an understanding of pharmacokinetic parameters.
• Parameters:
  • Route of administration
  • Amount and frequency of each dose
  • Duration of treatment

1.1 Absorption

• Absorption: Movement of a drug from the site of administration to the bloodstream.
• Requires drugs crossing cell and cell membrane layers.
• Exceptions to general drug absorption include topical and intravenous administrations.
• Factors impacting absorption:
  • pH
  • Blood flow to absorption site
  • Total surface area available for absorption
  • Contact time at the absorption surface
  • Expression of P-glycoprotein

1.2 Transport across Membranes

• All human cells bounded by lipid bilayer membrane.
• Membrane lipids mainly consist of phospholipids, sterols (like cholesterol), and glycolipids.
• Amphiphilic nature of membrane lipids leads to a hydrophobic core with two hydrophilic surfaces.
• Drugs need to be at least somewhat lipid-soluble for absorption.

1.3 Mechanisms of Drug Absorption

• Passive diffusion: Movement of drug from higher to lower concentration based on concentration gradient.
  • Not carrier mediated
  • Not saturable
  • Often depends on drug size and partition coefficient (lipid solubility)
• Carrier-mediated transport: Transmembrane proteins transfer drugs
  • Facilitated diffusion: Does not necessitate energy, follows the concentration gradient.
  • Active transport: Uses energy to move drug against the concentration gradient.
• Endocytosis and exocytosis: Absorption mechanisms for larger molecules which are not lipid soluble and are too large to simply diffuse.

1.4 Factors Influencing Absorption

• pH: Acidity or alkalinity influences drug ionization (charged or uncharged) and therefore, its ability to cross cell membranes..
• Ionized drugs are generally less lipid-soluble.
• Blood flow: Higher blood flow increases absorption rate.
• Surface area: Large surface area enhances absorption.
• Contact time: Longer contact time generally increases absorption.
• P-glycoprotein: A transporter protein that can limit absorption of drugs from the intestines and other tissues

1.5 Bioavailability

• Bioavailability (BAV): Fraction (F) of a drug that reaches systemic circulation in active form after administration.
• Calculating bioavailability from the AUC (area under the curve) of plasma concentration vs time for an oral administration vs an intravenous (IV) administration.
• Bioavailability is important in determining non-IV dosing.

1.6 Factors Affecting Bioavailability

• First-pass hepatic metabolism: Drugs absorbed from the GI tract go to the liver, via the hepatic portal vein, and are sometimes deactivated by the liver before reaching systemic circulation.
• The quantity of a drug that makes it through the first pass metabolism is a factor influencing bioavailability.

1.7 Drug Distribution

• Distribution: Transport of drug from bloodstream to other compartments (extracellular fluid, interstitial fluid, transcellular fluid, and tissues).
• Depends on:
  • Capillary permeability (e.g, size and lipophilicity): Drugs that are small and lipid soluble can pass through narrow pores of tissues more easily
  • Binding to plasma proteins and tissues: Bound drugs are often inactive, non-diffusible, and not cleared as readily.
  • Volume of distribution (Vd): A proportionality constant representing the relationship between the amount of drug in the body and the plasma concentration at a given time.
    • Large Vd → most of the drug is outside plasma, requiring higher doses to achieve the same concentration
    • Small Vd → drug remains primarily in plasma, requiring lower doses to achieve the same concentration.
    • Vd is not an actual physical volume–it's a concept describing drug distribution, though it affects clearance and half-life.

1.8 Factors Related to Drug Distribution affecting Vd:

• Drug Size: Larger drugs tend to be confined to plasma as they can't readily pass through capillary junctions.
• Lipid Solubility: Lipid soluble drugs tend to be more easily distributed into other tissues compared to water-soluble drugs
• Plasma protein binding: Binding to plasma proteins limits distribution.

1.9 Factors Related to Body affecting Vd:

• Total Body Fluid Volume: Larger volume leads to more distribution.
• Plasma Protein Availability: Impacts rate of drug distribution.

1.10 Clinical Significance of Vd

• Drug Half-Life: Vd affects how quickly the drug is eliminated.
• Drug Loading Dose: Vd impacts how much of a drug needs to be administered to reach the desired plasma concentration.

1.11 Clearance (CL) and Half-Life (t½)

• Clearance (CL): The volume of blood from which a drug is eliminated per unit time (e.g., ml/min or L/hr).
• Half-life (t½): The time for plasma concentration of a drug to decrease by 50%. Vd is a key factor in half-life.

1.12 Factors affecting Half-Life

• Age: Aging can affect body fluid and tissue composition leading to a reduced Vd, thereby affecting half-life.
• Obesity: Obesity can lead to an increased Vd and therefore an increased half-life.
• Pathologic Conditions: Pathologic conditions involving increased fluid accumulation leading to an increased volume of distribution and potentially affecting half-life.

1.13 Determination of Drug Loading Dose

• Loading Dose (Priming Dose): Initial higher dose to achieve desired plasma concentration quickly. Vd is a component in the equation.
• Maintenance Dose: Lower dose to maintain the desired plasma concentration. Clearance is a component in the equation.

This quiz focuses on Pharmacology, specifically the pharmacokinetics of drugs. It covers key concepts such as ADME (Absorption, Distribution, Metabolism, Excretion) and factors affecting drug absorption and bioavailability. Test your knowledge on the fundamental principles of how the body interacts with medications.