Factors Affecting Drug Distribution

Overview

Drug distribution refers to the transport of a drug from the bloodstream to tissues and organs. It affects the drug's efficacy, duration, and concentration across the body and is influenced by several key factors.

Factors Influencing Drug Distribution

1. Blood Flow to Tissues

- High Blood Flow: Tissues with high blood flow, like the liver, kidneys, and brain, experience quicker and higher drug concentrations.

- Low Blood Flow: Slower distribution occurs in areas with lower blood flow, such as adipose tissue, skin, and bones.

2. Capillary Permeability

- Type of Capillaries: Varies by organ. For example, liver capillaries are highly permeable, while the blood-brain barrier has tight junctions limiting drug entry.

- Lipophilicity: Lipid-soluble drugs cross capillary membranes more easily, especially across selective barriers like the blood-brain barrier.

3. Plasma Protein Binding

- Protein Binding: Drugs bind to plasma proteins (e.g., albumin for acidic drugs, alpha-1 acid glycoprotein for basic drugs).

- Bound vs. Free Drug: Only free (unbound) drugs can cross membranes and exert effects. Highly protein-bound drugs have reduced distribution and prolonged action.

4. Lipid Solubility of the Drug

- Lipophilic Drugs: These readily cross cell membranes and distribute widely, especially in fatty tissues.

- Hydrophilic Drugs: Limited to the extracellular fluid, generally leading to a restricted distribution.

5. Volume of Distribution (Vd)

- High Vd: Drugs with high Vd accumulate in tissues.

- Low Vd: Drugs with low Vd remain in the bloodstream.

6. pH and Ionization

Drug distribution is influenced by pH and pKa. Drugs are more likely to cross membranes when in their non-ionized form. Acidic drugs concentrate in basic compartments, and basic drugs in acidic compartments.

7. Physiological Barriers

- Blood-Brain Barrier (BBB): Highly selective, only lipophilic drugs or those with specific transport mechanisms can enter the CNS.

- Placental Barrier: Less restrictive than the BBB, but limits certain drugs from reaching the fetus. Lipophilic drugs cross more easily.

8. Tissue Binding

Some drugs have high affinity for specific tissues, accumulating there (e.g., tetracyclines in bones). Tissue binding can extend drug action but may increase toxicity risk.

9. Disease States

- Liver or Kidney Disease: May alter plasma protein levels, affecting the free fraction of protein-bound drugs.

- Cardiovascular Disorders: Can impair blood flow, reducing drug delivery to tissues.

10. Drug-Drug Interactions

Co-administered drugs may compete for plasma protein binding sites, increasing free drug concentration and possibly enhancing or reducing effects.