4. Drug Distribution

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 on1. Blood flow 2. Capillary permeability 3. The degree of binding of the drug to plasma & tissue proteins 4. The relative hydrophobicity of the drug

1. Blood flow The 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 Bone Brain Fat Heart Kidney Liver Muscle Skin

% of cardiac output 5 14 4 4 22 27 15 6

Heart, liver, kidney, brain and other wellperfused 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 otherThe tissues. 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 Penicillin is quite polar and is thus slowly regained. permeable. Permeability limited transfer is faster in muscle, as muscle capillaries are less restrictive. Thus transfer of penicillin is faster in

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 by2a. Capillary structure 2b. 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. Capillary structure: CNS

Endothelial cell layer Tight junction

Basement membrane

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 endothelial of the is CNS. Thisthe selectivity of cells transport known as blood- brain barrier.

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

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

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 theBy area. 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

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 drugprotein 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 reservoirs The 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

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

Placental transfer of drugs The 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:

Amount of drug in the body Volume of distribution (Vd)= Plasma drug concentration (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

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 5 5-20 2040 >40

% Body Weight 7 7-28 28-6 >56

Extent of Distribution Only in plasma In extracellular fluids In total body fluids. In deep tissues; bound to peripheral tissues

Clinical importance of volume of distribution 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: Loading dose (mg) = (Vd, L) X (Desired plasma concentration, mg/L)

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.