Drug distribution Drug distribution is the process by which a

drug reversibly leaves the blood stream and enters into the interstitial and intracellular fluids.

The delivery of a drug from the plasma primarily depends on-

1. Blood flow2. Capillary permeability3. The degree of binding of the drug to

plasma & tissue proteins4. The relative hydrophobicity of the drug

1. Blood flowThe rate of blood flow to the tissue

capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs.

Organ % of cardiac outputBone 5 Brain 14 Fat 4Heart 4Kidney 22Liver 27Muscle 15Skin 6

Heart, liver, kidney, brain and other well-perfused organs receive most of the drug during the first few minutes after absorption.

Delivery of drug to muscle, peripheral organs, skin and fat is slower, and these tissues may require several minutes to several hours before steady state is attained.

Another phase of distribution is also possible for some drugs where the drug slowly accumulates in some tissues like fat tissue and other tissues.The drug can be moved from the plasma to the tissue until the equilibrium is established (for unbound drug present in plasma).

The differential blood flow partly explains the short duration of hypnosis produced by a bolus intravenous injection of thiopental.

The high blood flow together with the superior lipid solubility of thiopental permit it to rapidly move into and out of the CNS and produce anesthesia.

Slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration sufficiently so that the higher concentrations within the CNS decrease and consciousness regained.Penicillin is quite polar and is thus slowly permeable. Permeability limited transfer is faster in muscle, as muscle capillaries are less restrictive. Thus transfer of penicillin is faster in muscle than brain.

Thiopental is an ultra-short-acting anesthesia.

Following intravenous injection the drug rapidly reaches the brain and causes unconsciousness within 30–45 seconds.

At one minute, the drug attains a peak concentration of about 60% of the total dose in the brain.

Thereafter, the drug distributes to the rest of the body and in about 5–10 minutes the concentration is low enough in the brain such that consciousness returns.

2. Capillary permeability Drug permeation occurs largely in the

capillary bed, where both surface area and time available for exchange are maximal (extensive vascular branching, low velocity of flow).

Drugs rapidly cross capillary membranes into tissues because of passive diffusion and hydrostatic pressure.

Capillary permeability is determined by-

2a. Capillary structure2b. Chemical nature of the drug

Fig: Capillary

2a. Capillary structure:

The capillary wall consists of an endothelial cell layer and a basement membrane enveloping the endothelial cell layer.

Capillary structure varies widely in terms of the basement membrane that is exposed by slit (tight) junctions between endothelial cells.

In the brain, the capillary structure is continuous, and there are no slit junctions.

Endothelial cell layer

Basement membrane

Tight junction

Capillary structure: CNS

The capillaries of the brain are surrounded by glial cells that create the blood brain barrier that acts as a thick lipid membrane. Polar and ionic hydrophilic drugs cross this barrier slowly.

In order to enter the brain, drugs must be actively transported through the endothelial cells or pass through the endothelial cells of the capillaries of the central nervous system (brain and spinal cord).

For example, the large neutral amino acid carrier transports levodopa into the brain.

Lipid-soluble drugs readily penetrate into the CNS, since they can dissolve in the membrane of the endothelial cells.

Ionized or polar drugs generally fail to enter the CNS, since they are unable to pass through the endothelial cells of the CNS.This selectivity of transport is known as blood- brain barrier.

Both the diaphragm and basement membrane can be readily penetrated by substances of low molecular weight— the majority of drugs— but less so by macromolecules, e.g., proteins such as insulin.

Fenestrated endothelia are found in the capillaries of the gut and endocrine glands.

In some capillary beds (e.g., in the pancreas), endothelial cells exhibit fenestrations (an opening). Although the cells are tightly connected by continuous junctions by diaphragms.

Capillary structure: Pancreas

Drugs exchange freely between blood and interstitium in the liver, where endothelial cells exhibit large fenestrations and where neither diaphragms nor basement membranes impede drug movement.

Capillary structure: Liver

2b. Chemical nature of the drug:

The chemical nature of the drug strongly influences its ability to cross cell membranes.

Hydrophobic drugs (lipophilic drugs), readily move across most biological membranes. The major factor influencing the hydrophobic drug's distribution is the blood flow to the area.By contrast, hydrophilic drugs, do not readily penetrate cell membranes and must go through the junctions of endothelial cells in capillary beds.

Small drug molecules can freely diffuse out of the blood vessel while large drug molecules are confined to the plasma. Heparin is a good example of a drug like this.

3. Binding of drugs to proteins Having entered the blood, drugs may bind

to the protein molecules that are present in abundance, resulting in the formation of drug-protein complexes.

Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment.

After absorption more than 90% phenytoin (antiepileptic) bound to plasma protein.

Protein binding involves albumin for acidic drug and acidic glycoproteins for basic drug. Nonspecific binding to other plasma proteins generally occurs to a much smaller extent.

The degree of binding is governed by the concentration of the drugs and the affinity of a drug for a given protein.

As a rule, drugs exhibit much lower affinity for plasma proteins than for their specific binding sites (receptors).

Binding is relatively non-selective as to chemical structure and takes place at sites on the protein to which endogenous compounds such as bilirubin, normally attach.

Drug-binding protein may act as a drug reservoir, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein.

This maintains the free drug concentration as a constant fraction of the total drug in the plasma.

Drug reservoirsThe body compartments in which a drug

accumulates are potential reservoirs for the drug.

If stored drug is in equilibrium with that in plasma and is released as the plasma concentration declines, a concentration of the drug in plasma and at its locus of action is sustained, and pharmacological effects of the drug are prolonged.

Fat as a reservoir:Many lipid-soluble drugs are stored in fat. In obese persons, the fat content of the

body may be as high as 50% and fat can serve as an important reservoir for lipid-soluble drugs.

Bones:

Tetracycline antibiotics (by forming complex with calcium) and heavy metals may accumulate in bone and bone can become a reservoir for the slow release of toxic agents such as lead or radium into the blood; their effects can thus persist long after exposure has ceased.

Fat is a rather stable reservoir because it has a relatively low blood flow.

Placental transfer of drugsThe transfer of drugs across the placenta is of

critical importance because drugs may cause anomalies in the developing fetus.

Lipid solubility, extent of plasma binding, and degree of ionization of weak acids and bases are important general determinants in drug transfer across the placenta.

The fetal plasma is slightly more acidic than that of the mother (pH 7.0 to 7.2 versus 7.4), so that ion trapping of basic drugs occurs.

The placenta is a barrier to drugs, however, a number of influx transporters are also present.

The fetus is to some extent exposed to all drugs taken by the mother.

Volume of distribution

The actual volume in which drug molecules are distributed within a patient’s body cannot be measured.

However, volume of distribution (Vd) of drug

can be obtained and may be of some clinical usefulness.

The volume of distribution (Vd) also known as

apparent volume of distribution. It is not a real volume.

Volume of distribution is the ratio of the amount of a drug in the body to its concentration in the plasma or blood.

The volume of distribution relates the amount of drug in the body to the plasma concentration according to the following equation:

Volume of distribution (Vd)=Plasma drug concentration

Amount of drug in the body

(Units = volume)

- This volume does not necessarily refer to an identifiable physiological volume but rather to the fluid volume that would be required to contain all the drug in the body at the same concentration measured in the blood or plasma.

- The plasma volume of a typical 70-kg man is 3 L, blood volume is about 5.5 L, extracellular fluid volume outside the plasma is 12 L, and the volume of total-body water is approximately 42 L. Many drugs exhibit volumes of distribution far in excess of these values.

The volume of distribution (Vd) may be defined

as the volume of fluid in which the drug appears to distribute with a concentration equal to that in plasma.

If a drug is highly tissue bound the plasma

concentration will be low and the Vd become

very large.

- Drug with large volume of distribution: Digoxin (Approximately 420L).

- Drug with small volume of distribution: Heparin (Approximately 5L).

For drugs that accumulate outside the plasma compartment (e.g. in fat or by being bound to

tissues), Vd may exceed total body volume.

Relationship between the extent of distribution and Vd in a 70 kg normal person (The numbers are only rough approximation)

Vd, L % Body Weight

Extent of Distribution

5 7 Only in plasma

5-20 7-28 In extracellular fluids

20-40

28-6 In total body fluids.

>40 >56 In deep tissues; bound to peripheral tissues

In some clinical situations it is important to achieve the target concentration instantaneously.

A loading dose is often used and Vd is the

determinant of the size of the loading dose:

(Desired plasma concentration, mg/L)

(Vd, L) X

Loading dose (mg) =

Clinical importance of volume of distribution

Many acids including salicylates, sulfonamides and penicillins are either too highly bound to plasma proteins or too water soluble to enter cells and adipose tissue in large amounts.

Therefore, their Vd is low (approximately 8-20

L).

In contrast, lipid soluble bases are taken up by many tissues. Concentrations in plasma are

low, and Vd exceeds the volume of total body

fluids. For example, Vd for antihypertensive

drug propranolol is about 200L.