Study Notes for BS2013: Physiology and Pharmacology

BS2013: Physiology and Pharmacology

Topic Overview

Topic 3: Applied Pharmacology
- Part 1: General Principles
- Part 2: Kinetic Models

Recommended Resources

TEXTBOOK:
- Chapters: 9-11 of Rang and Dale’s Pharmacology (9th Edition)
- Access: Available on the University Catalogue through the Blackboard site: Readings & Sources > Module Reading List > Reading for Pharmacokinetics Lectures

Introduction to Pharmacokinetics

Effectiveness of Drugs:
  - Pharmacokinetics refers to how drugs are processed in the body, covering the following key stages:
    - Absorption
    - Distribution
    - Metabolism
    - Excretion
  - These factors determine the concentration and time-course of drug distribution in the body, influencing optimal dosage and dosing regimens.
  - Drug-Receptor Interactions:
    - At the molecular level, these interactions relate to concepts such as potency and efficacy.

Drug Absorption

General Mechanism:
- Drugs, in most cases, travel to tissues via the plasma.
Routes of Administration:
  1. Oral & Swallowed:
     - Common for small molecule drugs; may be subject to degradation in the GI tract.
  2. Sublingual:
     - Rapid absorption from the oral cavity (e.g., Glyceryl Trinitrate for vasodilation).
  3. Rectal:
     - Provides local or systemic effects when oral intake is not possible (e.g., nausea/vomiting).
  4. Epithelial Surfaces:
     - Includes skin, cornea, and nasal mucosa.
  5. Inhalation:
     - Utilized for gaseous anaesthetics and bronchodilators.
  6. Injection:
     - Most direct route, with forms including intravenous (fastest), subcutaneous, intramuscular, and intrathecal (lumbar puncture).
Factors Affecting Absorption:
  1. Site/Method of Administration
  2. Molecular Weight:
     - Major determinant of the rate of diffusion.
  3. Lipid Solubility:
     - Critical for crossing lipid membranes by diffusion.
  4. pH and Ionization:
     - Many drugs are weak acids or bases.
     - Example: Weak acid HA ⇌ H⁺ + A⁻ with the equation
$ext{pKa} = ext{pH} + ext{log}_{10}\frac{[ ext{AH}]}{[ ext{A}^-]}$
     - Note that at low pH, weak acids remain mostly un-ionized, allowing diffusion across lipid bilayers (e.g., stomach pH 1.5-2).
  5. Carrier Mediated Transport:
     - Active or facilitated transport for polar molecules such as amino acids and metal ions.
     - Example: Gases, with diffusivity (D \propto \frac{1}{\sqrt{\text{MWt}}}).

Drug Distribution

Major Body Compartments:
  1. Extracellular Fluids:
     - Plasma: 4.5% body weight
     - Interstitial Fluid: 16%
     - Lymph: 1-2%
  2. Intracellular Fluids:
     - 30-40%
  3. Transcellular Fluids:
     - Examples include cerebrospinal fluid (CSF) and intraocular fluid, constituting 2.5%.
  4. Fat:
     - Accounts for 20%, influencing drug distribution based on lipid solubility and permeability.
Blood-Brain Barrier:
  - Comprised of endothelial cells forming tight junctions, which create a barrier to systemically acting drugs (typically those >400-500 daltons).
  - Drugs must cross cell membranes and tight junctions may become leaky during inflammation.
  - Example Experiment: Paul Ehrlich's Injection of water-soluble dye (trypan blue), which stained all organs except the brain; conversely, injecting it into the brain stained it but not the rest of the body.

Drug Metabolism

Definition:
- Refers to the enzymatic modification of drugs prior to excretion, usually rendering the drugs pharmacologically inactive, though exceptions exist (e.g., thienopyridines serve as prodrugs for P2Y12 inhibition).
Phases of Metabolism:
  1. Phase 1
     - Involves oxidation, reduction, or hydrolysis via the Cytochrome P450 (CYP) monooxygenase system, primarily located in the smooth endoplasmic reticulum of the liver.
     - Notable CYP enzymes (e.g., CYP1A2 metabolizes caffeine and paracetamol).
     - Other systems include alcohol dehydrogenase (cytoplasmic).
  2. Phase 2
     - Involves conjugation, the addition of substituent groups (e.g., methyl, sulfate, acetyl) that generally inactivate substances.
     - Both phases decrease lipid solubility, therefore enhancing kidney clearance.

Drug Excretion

General Mechanism:
- Drugs are eliminated from the body primarily through renal mechanisms but also via gastrointestinal and pulmonary pathways.
Renal Excretion:
  - Four basic processes:
    1. Glomerular Filtration (GF):
       - Non-discriminant filtration of protein-free plasma into Bowman’s capsule, approximately 20% of glomerular blood flow with a cut-off near 20 kDa, with 99% of water reabsorbed.
    2. Tubular Reabsorption (TR):
       - Selective movement from the tubular lumen into peritubular capillaries.
    3. Tubular Secretion (TS):
       - Selective movement of non-filtered substances from peritubular capillaries into tubular lumen.
    4. Urine Excretion (UE):
       - Creation of the medullary vertical osmotic gradient.
    - Characteristics of Renal Excretion:
       - Active tubular secretion is crucial for weak acids and plasma protein-bound drugs, with poor reabsorption for poorly lipid-soluble compounds.
       - Renal disease may impair drug clearance and result in toxicity.
Gastrointestinal (GI) Excretion:
- Biliary excretion from the liver; relevant for certain drugs.
Lung Excretion:
- Expulsion of volatile or gaseous agents; example includes rapid clearance of penicillin versus the slower clearance of diazepam, which is contingent on urine pH affecting weak acid/base excretion.

Kinetic Models in Pharmacokinetics

Purpose of Kinetic Models:
- To predict the time-course of drug action, integrating absorption, distribution, metabolism, and elimination.

One-Compartment Model

Concept:
- Represents the body as a single well-stirred compartment where drug elimination is proportional to plasma drug concentration.
Key Variables:
  - (K_A): Rate of drug absorption
  - (V_d): Volume of drug distribution
  - (C_P): Concentration of drug in the compartment
  - (K_{El}): Rate of elimination (excretion + metabolism), also referred to as clearance.
Single Drug Infusion:
- The decay of the drug concentration follows an exponential time-course characterized by the half-life (T½), which indicates the time taken for the concentration to reduce by 50%.
- For an intravenous bolus, drug concentration spiking occurs instantly, later declining exponentially.

Two-Compartment Model

Concept:
- More complex, applicable to many drugs where drug disappearance does not follow a single exponential decay.
- Characterized by a central compartment (plasma) and a peripheral compartment (tissues).
Key Rate Constants in Two-Compartment Model:
- (K_{Pl:Tiss}): Rate of transfer from plasma to tissues, typically greater than (K_{El}).
Decay Phases:
- Slow decay estimates the elimination rate constant.

Summary Points on Pharmacokinetics

Drug Administration Routes:
- Approximately six routes exist, including inhalation and injection.
Chemical Properties:
- Properties such as lipid solubility govern drug distribution across body compartments due to their effects on absorption, distribution, metabolism, and excretion.
Blood-Brain Barrier:
- Access to the brain compartment is tightly regulated due to the properties of the blood-brain barrier.
One-Compartment Model:
- Models the kinetics of drug concentration with single exponential decay, while more complex models are often required to accurately depict multi-compartmental behavior.

Sample Single Best Answer Questions (SBAQ)

SBAQ 1:
   - Question: A patient is taking drug K once a day to achieve the optimal average plasma concentration required to treat their medical condition. After starting an additional drug F that promotes kidney excretion of drug K, what could result from taking both drugs compared to just drug K?
   - Options:
     - A. No change in the average concentration of drug K in the plasma
     - B. Need to increase frequency of administration of drug K to achieve same average effective concentration in plasma
     - C. Increase in average concentration of drug K in the plasma
     - D. Increase in the half-life of drug K in the plasma
SBAQ 2:
   - Question: If the half-life of a drug in the body is 2 hours, how long would it take for the concentration of the drug to drop from 4 µg/ml to 125 ng/ml?
   - Options:
     - A. 5 hours
     - B. 8 hours
     - C. 10 hours
     - D. 16 hours
   - Calculation Path:
     - Initial concentration: 4 µg/ml = 4000 ng/ml.
     - Steps: 4000 → 2000 → 1000 → 500 → 250 → 125 = 5 half-lives = 10 hours.