Pharmacology: Drug Distribution Overview

Drug Distribution

• Drug distribution is the key factor in the onset of drug action. It involves the movement of a drug from the bloodstream to tissues.

• Drugs are distributed to organs and tissues via the bloodstream, diffusing into interstitial fluid and cells.

• Most drugs are not evenly distributed throughout the body's water content. Some drugs are limited to the extracellular fluid or plasma.

• Drugs with high lipid solubility easily diffuse through cell membranes.

• Other drugs concentrate within cells due to ion trapping.

• Active transport mechanisms also move drugs into cells.

Drug Distribution and Body Water

• Water in the body is divided into compartments: intravascular, interstitial, and intracellular.

• The total body water is approximately 70% of total body weight in healthy subjects.

• Extracellular fluid makes up about 25% of the total body water, while intracellular fluid constitutes about 45%.

Factors Affecting Drug Distribution

• Lipid solubility: Highly lipophilic drugs readily cross the blood-brain barrier (BBB).

• Polar and ionized drugs often cannot cross the BBB as easily.

• Ionization (pKa): Molecular size influences distribution, with extremely large molecules like heparin often confined to the plasma.

• Organ blood flow: High blood flow to organs like the brain, heart, liver, and kidneys leads to rapid distribution and faster onset of action. Distribution is slower in tissues with lower blood flow.

• Binding to plasma and tissue proteins: Drugs can bind reversibly to proteins in plasma or tissues, altering the effective concentration in target areas. Active transport and drug metabolism are also relevant.

Drugs in Vascular Space

• Drugs exist in two forms in the blood: free and bound.

• Free drugs are active, diffusible, and available for metabolism and excretion.

• Bound drugs are mainly bound to albumin, acting as a reservoir.

• Bound drugs are non-diffusible and thus not usable for metabolism or excretion.

Plasma Protein Binding

• Drug binding to plasma proteins is reversible (D + P ⇌ DP).

• The unbound/free drug is the pharmaceutically active form.

• Binding sites on plasma proteins become saturated with higher drug concentrations.

• Highly bound drugs stay in the blood for longer which results in a lower therapeutic activity.

• Acidic drugs often bind to albumin.

• Basic drugs frequently bind to α1-glycoprotein.

Significance of Plasma Protein Binding

• Highly bound drugs persist longer in the body, lowering therapeutic activity and making them less accessible to dialysis.

• Hypoalbuminemia (low albumin) leads to a higher concentration of free drug, potentially increasing the risk of side effects.

Clinically Important Drug Interactions Due to Displacement

• Drugs can displace each other from plasma protein binding sites.

• Acidic drugs do not usually displace basic drugs, and vice versa.

• Drug interactions can affect the efficacy or toxicity of other drugs.

Volume of Distribution (Vd)

• Vd is a measure of the apparent volume in the body that would be needed to contain the total amount of drug at a plasma concentration equal to the concentration in the body.

• Vd is a critical pharmacokinetic parameter.

• High Vd indicates extensive distribution throughout the body.

• Lower Vd indicates more drug is retained in the blood, affecting the efficacy and potential toxicity of the drug.

Clinical Significance of Vd

• A large volume of distribution suggests that the drug is distributed extensively throughout the body, reducing the efficacy of dialysis in cases of drug poisoning.

• The volume of distribution correlates to the drug's binding capacity and other properties.

Drugs Accumulated in Tissues

• Certain drugs (e.g., digoxin, chloroquine, iodine, chloroquine, tetracycline) accumulate in specific tissues, and these tissues' accumulation can increase the volume of distribution.

Barriers to Drug Distribution

• The blood-brain barrier (BBB) and placental barrier limit drug distribution.

• Tight junctions of endothelial cells limit permeability.

• Inflammation can decrease this barrier function.

• Lipid-soluble drugs cross the barriers more easily than water-soluble or protein-bound drugs.

Placental Barrier

• The placental barrier allows free passage for lipid-soluble drugs.

• The barrier for water-soluble or protein-bound drugs is not easily crossed.