Drug Distribution in the Body

## From Blood to Tissues

After reaching the systemic circulation, a drug distributes throughout the body. Distribution is not uniform — drugs concentrate in certain tissues based on blood flow, membrane permeability, protein binding, and tissue affinity.

## Protein Binding

In plasma, drugs bind reversibly to proteins — primarily albumin (acidic drugs) and alpha-1-acid glycoprotein (basic drugs). Only the **free (unbound) fraction** is pharmacologically active because bound drug cannot cross membranes or interact with receptors.

Clinically significant protein binding:

- **Warfarin**: 99% bound; a small displacement (99% to 98%) doubles the free fraction
- **Phenytoin**: ~90% bound; hypoalbuminemia in cirrhosis or nephrotic syndrome increases free drug and toxicity risk
- **Diazepam**: ~98% bound to albumin

Protein binding displacement rarely causes sustained clinical effects because increased free drug is quickly redistributed and eliminated, reaching a new equilibrium.

## Tissue Barriers

Several specialized barriers restrict drug access:

- **Blood-brain barrier (BBB)**: Tight junctions between endothelial cells exclude most polar and large molecules. Only lipophilic, un-ionized drugs (e.g., diazepam, fentanyl) cross readily. Inflammation can transiently increase BBB permeability.
- **Placental barrier**: Not a true barrier — most drugs cross by passive diffusion. Molecular weight, lipophilicity, and protein binding influence transfer rate.
- **Blood-testis barrier**: Sertoli cell tight junctions limit drug penetration, complicating treatment of testicular infections.

## Factors Governing Distribution

| Factor | Effect |
|--------|--------|
| Cardiac output | Higher output delivers drug to tissues faster |
| Regional blood flow | Highly perfused organs (brain, liver, kidney) receive drug first |
| Capillary permeability | Fenestrated capillaries (liver) allow large molecules; tight capillaries (brain) restrict them |
| Tissue binding | Lipophilic drugs accumulate in adipose tissue (thiopental) |
| Lipophilicity | Determines membrane crossing and tissue uptake |

## Redistribution

Highly lipophilic drugs like thiopental initially concentrate in the well-perfused brain, causing rapid anesthesia. Within minutes, the drug redistributes into less-perfused muscle and fat, and consciousness returns — even before significant elimination occurs.

## Key Takeaways

- Only free (unbound) drug is pharmacologically active
- The BBB, placenta, and blood-testis barrier selectively restrict drug access
- Cardiac output and regional blood flow determine initial distribution
- Redistribution from well-perfused to poorly-perfused tissues can terminate drug effect before elimination