Volume of Distribution

Drugs are distributed around the body via the blood or lymphatic tissue. Perfusion of tissues dictates blood flow. Blood supply to fatty tissues is poor so different drug concentrations are often given to obese patients. The membrane of the target cells must be permeable to the drug.

Biological barriers that a drug must be able to cross to reach its target include the gastrointestinal mucosa (orally administered drugs only), the blood brain barrier and the placenta. Volume of distribution is affected by the number and type of biological barriers present.

Volume of distribution is a theoretical measure and varies for each drug. If the body is observed as a single compartment where the plasma concentration represents the size of that compartment, we measure the volume of distribution as concentration = dose/volume.

Large molecules mainly stay in the plasma and they have a very small Vd.

Hydrophilic/highly polar small molecule drugs eg penicillin distribute into the extracellular fluid and have a relatively small Vd.

Highly lipid soluble drugs eg tricyclic antidepressants distribute far more widely into tissues and have a large Vd.

Drugs with Vd of 0.4 L/kg or less are thought of as confined to the plasma.

Drugs with Vd larger than 0.6 L/kg are thought of as distributed to all tissues in the body, especially the fatty tissue.

Some drugs have extremely large (>10,000L) Vd values meaning most of the drug is in the tissue with very little circulating the plasma so they may not be excreted from the body for a long time.

Factors affecting distribution include molecular size, lipid solubility, ionisation, binding to plasma proteins, rate of blood flow, and drug chemistry.

Highly protein bound drugs distort the volume of distribution value as only the free drug concentration is considered.

Tissue distribution of drug is controlled by blood flow rate, membrane permeability, tissue partitioning, tissue binding and plasma protein binding, and is mediated by transporter proteins.

membrane permeability is affected by tight junctions in the capillary walls. Whether the membrane is permeable to the drug depends on the drug size, lipophilicity and pKa value.

If tissue drug distribution is transporter mediated, the drug functional group must be considered as well as the distribution of transporters and whether they’re present at the target tissue.

Tissue partitioning is affected by tissue composition and drug ionisation and lipophilicity is important.

Tissue binding is affected by albumin, lipoprotein, acidic phospholipid lysosomal binding, lipophilicity and drug pKA,

The one compartment model for Vd is where the drug is taken and it’s assumed the drug is immediately where it’s meant to be as the body is homogenous. The two compartment model of Vd considers other tissues of the body and how distribution is different.

Some drugs accumulate in specific compartments.

Ex asthma drug tetracycline accumulates in bones and teeth as they have high calcium affinity and this may lead to tooth discolouration.

Amiodarone may accumulate in the liver and lungs → hepatitis and interstitial pulmonary fibrosis.

Chloroquine has high melanin affinity and can accumulate in the retina leading to ocular toxicity.

Blood circulation to fat is low (poor perfusion, <2% of cardiac output) so partition into fat can be a minor clinical issue. However some drugs eg benzodiazepines and some insecticides accumulate in fat.

Drugs which commonly need dose adjustment for obese patients inc low molecular weight heparins, aminoglycoside antibiotics, some anaesthetics, monoclonal antibodies and chemotherapeutics.

In the bloodstream, drugs are partly transported as free drug and partly reversibly bound to blood components eg plasma proteins and blood cells.

Acidic drugs are usually more extensively bound to albumin whereas basic drugs are usually bound more to alpha-1 acid glycoprotein, lipoproteins or both.

Only free unbound drug is available for passive diffusion to extravascular or tissue sites where the pharmacologic effects of the drug occur. Therefore unbound drug concentration in systemic circulation typically determines drug concentration at the active site and therefore determines efficacy.

The body acts as a reservoir for the drug, slowly delivering it to the organs of elimination (liver and kidney) via the blood.