Introduction to Pharmacokinetics

The Goal of Drug Therapy

• The goal of drug therapy is to achieve a desired beneficial effect, such as curing a disease, with minimal adverse effects.
• This requires a rational approach that combines pharmacodynamics and pharmacokinetics to understand the dose-effect relationship.
• This includes selecting the appropriate drug and the right dose/dosing interval.

Individual Variations

• Drug concentrations vary greatly among individuals, requiring personalized dosing.
• This is due to factors such as genetics, physiology, and lifestyle.

Dose-Response Relationship

• Describes the relationship between drug concentration and effect in the body.
• Can be studied through pharmacokinetics and pharmacodynamics.
• Pharmacokinetics studies how the body affects the drug, while pharmacodynamics studies how the drug affects the body.

Pharmacokinetics

• Focuses on the time course of drug absorption, distribution, metabolism, and excretion (ADME).
• All of these processes involve drug passage across cell membranes.
• Drug disposition refers to the fate of a drug after absorption, including distribution, metabolism, and excretion.
• Drug metabolism and excretion together are also called drug elimination.

Absorption

• Defined as the movement of a drug from its site of administration to the systemic circulation.
• Absorption depends on the physicochemical nature of the drug, drug formulation, route of administration, and patient's state.

The Henderson-Hasselbalch Equation

• Useful for calculating the ionized and unionized forms of a drug at a given pH.
• Helps understand drug absorption and distribution.

Gastric vs. Intestinal Absorption

• Gastric absorption is generally slower due to lower pH and lower surface area compared to the intestines.
• Intestinal absorption is more efficient due to higher pH and larger surface area.

Oral Administration

• Involves several steps: disintegration of the tablet/capsule, dissolution of small particles, absorption in the GI tract, first-pass metabolism by the liver, drug distribution, urinary excretion, and hepatic metabolism.
• Absorption primarily occurs in the small intestine.

Bioavailability (F)

• The fraction of unchanged drug reaching the systemic circulation following administration by any route.
• Measured by the area under the concentration-time curve (AUC).
• The AUC following IV administration is used as the reference value.
• For IV route, F = 1, as there is no absorption process involved.

Factors Affecting Oral Bioavailability

• Physicochemical properties of the drug:
  • A balance of hydrophilicity (water-loving) and lipophilicity (fat-loving) is needed for optimal absorption.
  • Too high hydrophilicity prevents passage through the lipid cell membrane.
  • Too high lipophilicity hinders dissolution in water.
• Formulation:
  • Has a major impact on bioavailability.
  • Different formulations can lead to different absorption rates and extents.
• First-pass elimination:
  • Metabolism of the drug in the liver before it reaches systemic circulation.
  • Reduces bioavailability.
• P-glycoprotein efflux pump:
  • Can actively transport drugs out of cells, limiting absorption.

Rate of Absorption

• Determined by physicochemical properties of the drug, drug formulation, and route of administration.
• Different from extent of absorption (bioavailability), measured by AUC.
• Determines the onset of action of the drug.
• Faster absorption leads to faster drug action.

Time Course of Drug Effect

• The temporal characteristics of drug effect and its relationship to the therapeutic window.
• The therapeutic window is the concentration range between minimal toxic concentration and minimal therapeutic concentration.
• Key factors include:
  • Lag time: Time delay from administration to onset of action.
  • tmax: Time to reach peak concentration (Cmax).