Distribution of Drugs

Introduction

Distribution: Process of a drug moving from the bloodstream to various tissues/organs to exert effects.
Influencing factors include blood flow, capillary permeability, and protein binding.

Different organs receive varying amounts of blood flow.
- High Blood Flow: Kidneys, liver, brain lead to higher potential distribution.
- Low Blood Flow: Skin, adipose tissues lead to lower potential distribution.
Clinical relevance in shock states (e.g., septic, cardiogenic, hypovolemic) where reduced blood flow may decrease drug distribution.

Capillaries vary in permeability: sinusoidal (leaky), fenestrated (moderately leaky), continuous (tight).
- Sinusoidal: Liver, spleen, bone marrow; high distribution due to large intracellular clefts and pores.
- Fenestrated: Kidneys, glands; moderate distribution.
- Continuous: Brain (BBB), muscles; low distribution unless drug is small, hydrophobic, or has transporters.
Septic shock increases permeability, causing capillary leak syndrome, reducing serum drug concentration, necessitating higher doses.

Plasma Protein (e.g., Albumin): Liver synthesizes, kidneys maintain albumin, which binds drugs in blood.
- High Protein Binding: Decreased free drug, lower distribution, acts as a reservoir for prolonged effect (e.g., phenytoin for seizures).
- Low Protein Binding: Increased free drug, higher distribution (e.g., in CKD or liver disease where albumin levels are low, leading to toxic side effects).

Hydrophobic, Small, Nonpolar Drugs: High distribution, easily pass through membranes.
Hydrophilic, Large, Polar Drugs: Low distribution, tend to stay in the blood.

Represents the theoretical volume in which a drug is distributed in the body.
Low Volume of Distribution: Drug concentrates in plasma (high protein binding, low capillary permeability, hydrophilic).
Medium Volume of Distribution: Drug present in plasma and interstitial fluid.
High Volume of Distribution: Drug extensively distributed in plasma, interstitial fluid, and intracellular fluid (nonpolar, hydrophobic, not protein-bound).

Warfarin: Low Vd (~8L), concentrates in plasma, important for its role as a blood thinner.
Chloroquine: Very high Vd (~150,000L), disperses widely, used for malaria.

Formula: Vd = (Bioavailability x Dose) / Plasma Concentration
Example Calculation: For a drug with a 2,000 mg dose, peak plasma concentration of 28.5, and IV administration (bioavailability = 1), Vd = 2000/28.5 ≈ 70L or 1L/kg if patient's weight is 70kg.

Distribution is influenced by multiple factors including blood flow, capillary permeability, protein binding, and solubility.
Volume of distribution (Vd) helps determine how widely a drug disperses in the body.