Pharmacokinetics Overview

Study Notes

Pharmacokinetics (PK) describes the movement of drugs within the body and involves four key processes: absorption, distribution, metabolism, and elimination (ADME).
Understanding PK is crucial for determining the appropriate dosage and route of administration of drugs.

Absorption is the process of a drug entering the bloodstream from its administration site.
Factors affecting absorption include drug formulation, route of administration, and drug properties (solubility, ionization, molecular size).
Passive Diffusion: Most common mechanism; drugs move from high concentration to low concentration without energy. Lipid-soluble and non-ionized drugs favor passive diffusion.
Facilitated Diffusion: Uses carrier proteins to move drugs along a concentration gradient (e.g., glucose transport via GLUT transporters).
Active Transport: Requires energy to move drugs against their concentration gradient using carriers like P-glycoprotein (important in the gut and brain).
Endocytosis: Larger molecules (e.g., proteins or antibodies) are engulfed by cell membranes in vesicles for cellular uptake (e.g., vitamin B12 absorption).
Example: Aspirin (weak acid) is mainly absorbed in the stomach due to the acidic environment favoring its non-ionized form for passive diffusion.

Distribution describes how drugs move from the bloodstream into tissues and organs.
Influenced by blood flow, tissue permeability, drug binding to plasma proteins (like albumin), and drug's lipid solubility.
Volume of Distribution (Vd): A theoretical volume representing how widely a drug distributes into body tissues relative to blood.
Low Vd: Drugs that stay in the bloodstream (e.g., heparin).
High Vd: Drugs that distribute widely into tissues (e.g., lipophilic drugs like chloroquine).
Example: Warfarin (anticoagulant) binds extensively to albumin, meaning only the free (unbound) portion exerts its effect, resulting in a low Vd.

Primarily occurs in the liver, converting lipophilic drugs into more water-soluble metabolites for excretion.
Divided into two phases:
- Phase I (Functionalization Reactions): Introduces or exposes functional groups on the drug molecule via oxidation (often via cytochrome P450 enzymes), reduction, or hydrolysis. These reactions usually increase the drug's polarity.
- Example: Diazepam (Valium) metabolism through oxidation by CYP3A4.
- Phase II (Conjugation Reactions): The drug or its Phase I metabolite is conjugated with a larger polar molecule (e.g., glucuronide, sulfate) to increase solubility and facilitate renal excretion.
- Example: Glucuronidation of morphine increases its solubility for excretion.
- Cytochrome P450 (CYP) Enzymes: CYP enzymes are responsible for many Phase I reactions. Inducers (e.g., rifampin) increase enzyme activity, leading to faster drug clearance. Inhibitors (e.g., ketoconazole) slow down metabolism, increasing drug levels.

Removal of drugs from the body through metabolism and excretion (primarily renal and biliary routes).
Elimination kinetics determine how drug levels decline over time.
First-Order Kinetics: Most drugs follow first-order kinetics, where a constant fraction of the drug is eliminated per unit time. The rate of elimination is proportional to the drug concentration.
Example: Most antibiotics follow first-order elimination where higher concentrations lead to faster clearance.
Zero-Order Kinetics: A constant amount of the drug is eliminated per unit time, regardless of concentration. This occurs when elimination pathways are saturated.
Example: Ethanol exhibits zero-order kinetics; a constant amount is cleared per hour, regardless of the total amount in the system.
Half-life (t½): Time required for the drug concentration to decrease by half in the body. Important for determining dosing intervals.