Lecture on Pharmacokinetics

Introduction

• Today's Topic: Pharmacokinetics
• Previous Topic: Pharmacodynamics (covered in videos)
• Key Components: Absorption, Distribution, Metabolism, Elimination
• Objective: Understanding how the body affects the drug

Overview of Pharmacokinetics

• How the body affects drugs: 4 components
  • Absorption
  • Distribution
  • Metabolism
  • Elimination
• Study Movement: How drugs move throughout the body and are ultimately eliminated.
• Other Concepts: Loading doses, steady states, etc.

Absorption

Permeation

• Movement of drugs through barriers
  • Types of barriers: Intestinal wall, capillary wall, blood-brain barrier
• Aquous and Lipid Diffusion:
  • Aquous Diffusion: Passive process, concentration gradient (high to low), no energy required
  • Lipid Diffusion: Movement across lipid bilayers, dependent on molecule size, lipophilicity, pH
• Carrier-mediated Diffusions:
  • Uses energy (ATP), can go against concentration gradient
  • Example: Sodium-potassium ATPase pump
• Fick's Law: Describes flux of drug across a membrane
  • Factors: Concentration gradient, surface area, permeability coefficient, membrane thickness

Practical Examples

• Surface Area & Thickness:
  • Stomach vs. Small Intestine (small intestine has larger surface area)
• Membrane Thickness Example:
  • Thin skin areas (axilla, groin, face) absorb more compared to thick skin
• Clinical Relevance:
  • Example of a steroid causing systemic effects like blood sugar changes if applied to thin skin areas.

Polar and Non-Polar Drugs

• More Polar = More Water-Soluble (Less Lipophilic)
• Charged Drugs: More lipid insoluble
• pH & pKa: Determines amount in charged vs uncharged state

Henderson-Hasselbalch Equation

• Describes protonated vs unprotonated ratio of weak acids and bases
• Unprotonated Acid (A-) is charged; Protonated Acid (HA) is uncharged
• Weak Base (B) is uncharged; Protonated Base (BH+) is charged
• 50/50 Split: pH = pKa

Clinical Examples

• Aspirin (acidic) & Morphine (basic) in different states
• Advising Lactating Patients: Handling ion trapping in breast milk

Permeation Continued

• Special Carriers: Weak acid carriers, amino acid carriers (blood-brain barrier)
  • Capacity Limited: Transporters can be saturated
• Endocytosis/Exocytosis: Mechanisms for large or lipid-insoluble substances

Distribution

Volume of Distribution (VD)

• Theoretical Number: Describes how far drug distributes
• Low VD: Drug stays in bloodstream
• High VD: Drug distributes extensively (e.g., lipophilic drugs)
• Calculation: VD = Dose/Concentration
• Impact of Patient Factors: Age, weight, etc.

Examples & Case Studies

• Comparison of Hydrophilic vs. Lipophilic Drugs: Differences in distribution
• Factors Affecting VD: Plasma protein binding, dehydration, etc.

Metabolism

Role and Phases

• Terminates or Alters drug activity, making it more water soluble for elimination
• Phases: Phase I (introduce/uncover polar groups), Phase II (adds polar groups)
• Key System: Cytochrome P450
  • Phase I Reactions: Oxidation (most important), reduction, hydrolysis
  • Phase II Reactions: Conjugation (e.g. glucuronidation)
• First-Pass Effect: Drugs pass through liver first from the GI tract

Examples

• Prodrugs: Activate after metabolism (e.g., Codeine to Morphine)
• Acetaminophen Overdose: Pathways of metabolism and toxicity
• Drug Interaction Example: Grapefruit juice affects cytochrome P450 enzymes

Elimination and Clearance

Renal Elimination

• Filtration and Reabsorption in kidneys
• pH Impacts: Affects drug reabsorption (ion trapping)
• Clearance: How much blood is cleared of drug per unit time

Measuring Kidney Function

• Serum Creatinine as a surrogate for GFR
  • Equations: Cockcroft-Gault, MDRD, etc.
  • Factors: Age, weight, serum creatinine levels

Half-Life and Steady State

Calculations and Concepts

• Half-Life (t1/2): Time to reduce drug concentration by 50%
• Steady State: Equilibrium between drug intake and elimination
• First Order vs Zero Order Kinetics:
  • First Order: Constant percentage eliminated
  • Zero Order: Constant amount eliminated
• Time to Steady State: 4-5 Half-lives
• Loading Dose: Achieves steady state quickly, followed by maintenance dose

Clinical Implications

• Dosing Strategies: Tailoring doses to patient needs (frequency vs concentration)
• Monitoring and Adjustments: Checking levels, patient compliance, handling changes in clearance
• Side Effects: Considering receptor locations and drug interactions

Conclusion

• Pharmacokinetics Important for Understanding Drug Effects
• Topics Covered: Absorption, Distribution, Metabolism, Elimination, Half-Life
• Importance of Patient-Specific Factors: In dosing and drug management
• Encourage Questions and Further Discussion