Introduction to Pharmacology and Pharmacokinetics

The movement of drugs across biological membranes (cell membranes) occurs through several distinct transport mechanisms:

• Passive Diffusion: Molecules move along a concentration gradient from an area of high concentration to low concentration without requiring any cellular energy.
• Facilitated Diffusion: Molecules move along a concentration gradient but require the assistance of a carrier protein to cross the membrane.
• Active Transport: Molecules move against a concentration gradient (from low to high concentration). This process requires energy, which can be derived from ATP hydrolysis (primary active transport) or an electrochemical gradient (secondary active transport).
• Endocytosis: A form of active transport where the cell engulfs molecules using energy, such as through pinocytosis ("cell drinking") or phagocytosis ("cell eating").

Exam Tip: Remember that "Passive" means no energy and "Active" means energy is required. If a drug is moving from a low concentration to a high concentration, it must be active transport.

2. Distribution

Once absorbed, the drug enters the bloodstream and undergoes distribution. The drug reversibly leaves the bloodstream to enter interstitial and intracellular fluids. The extent of this movement is often measured by the Volume of Distribution ($V_d$), which depends on the drug's physicochemical properties and the body's composition.

Several factors influence how a drug distributes:

• pKa: This measures the relative strength or degree of ionization of a weak acid or base. A drug is 50% ionized at its $pKa$. At physiological pH, a lower $pKa$ generally indicates greater lipophilicity (fat-solubility).
• Plasma Protein Binding: Many drugs bind to proteins in the blood (e.g., acidic drugs bind to albumin, while basic drugs bind to glycoproteins). Bound drugs generally have a longer duration of action because they remain in the body longer.
• Barriers: Certain areas, like the brain, are protected by the Blood-Brain Barrier (BBB), which is highly selective and primarily allows lipophilic drugs to pass.

3. Metabolism (Biotransformation)

Metabolism is the enzymatic modification of compounds, often to convert a xenobiotic (a foreign chemical substance like a drug or pesticide) into a more water-soluble form for easier removal. The liver is the primary site of metabolism.

Metabolism typically occurs in two phases:

• Phase I: Introduces or uncovers functional groups (like $-OH$ or $-NH_2$) through reactions such as oxidation (the most important), reduction, or hydrolysis.
• Phase II: Involves conjugation, where an ionized group (like glucuronic acid, sulfate, or glutathione) is attached to the drug to make it highly water-soluble.

A notable phenomenon is First Pass Metabolism, where orally administered drugs are metabolized in the intestinal wall or liver before they ever reach the systemic circulation.

4. Excretion

Excretion is the final removal of the drug or its metabolites (substances produced during breakdown) from the body. Common routes include the kidneys, lungs, bile, intestines, skin, and even saliva or milk.

Two mathematical concepts are vital for understanding excretion:

1. Clearance (CL): The theoretical volume of plasma from which a drug is completely removed in a unit of time. $CL = \frac{\text{Rate of elimination}}{\text{Plasma concentration}}$
2. Plasma Half-life ($t_{1/2}$): The time required for the plasma concentration of a drug to reduce to half of its original value.