distribution of drugs

Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and then the cells of the tissues. For a drug administered IV, when absorption is not a factor, the initial phase (that is, from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which a drug rapidly disappears from the circulation and enters the tissues. This is followed by the elimination phase, when drug in the plasma is in equilibrium with drug in the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on cardiac output and regional blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity of the drug.  

The extent and pattern of distribution of a drug depends on its: 

• lipid solubility 

• ionization at physiological pH (a function of its pKa) 

• extent of binding to plasma and tissue proteins 

• presence of tissue-specific transporters 

• differences in regional blood flow.

Plasma protein binding

 Most drugs possess physicochemical affinity for plasma proteins and get reversibly bound to these. Acidic drugs generally bind to plasma albumin and basic drugs to α1 acid glycoprotein. Binding to albumin is quantitatively more important. Extent of binding depends on the individual compound; no generalization for a pharmacological or chemical class can be made.

Increasing concentrations of the drug can progressively saturate the binding sites: fractional binding may be lower when large amounts of the drug are given. The generally expressed percentage binding refers to the usual therapeutic plasma concentrations of a drug. The clinically significant implications of plasma protein binding are: 

(i) Highly plasma protein bound drugs are largely restricted to the vascular compartment because protein bound drug does not cross membranes (except through large paracellular spaces, such as in capillaries). They tend to have smaller volumes of distribution.

(ii) The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma and dissociates when the concentration of the latter is reduced due to elimination. Plasma protein binding thus tantamounts to temporary storage of the drug.

(iii) High degree of protein binding generally makes the drug long acting, because bound fraction is not available for metabolism or excretion, unless it is actively extracted by liver or by kidney tubules. Glomerular filtration does not reduce the concentration of the free form in the efferent vessels, because water is also filtered. Active tubular secretion, however, removes the drug without the attendant solvent → concentration of free drug falls → bound drug dissociates and is eliminated resulting in a higher renal clearance value of the drug than the total renal blood flow. Highly protein bound drugs are not removed by haemodialysis and need special techniques for treatment of poisoning. 

(iv) The generally expressed plasma concentrations of the drug refer to bound as well as free drug. Degree of protein binding should be taken into account while relating these to concentrations of the drug that are active in vitro, e.g. MIC of an antimicrobial. 

(v) One drug can bind to many sites on the albumin molecule. Conversely, more than one drug can bind to the same site. This can give rise to displacement interactions among drugs bound to the same site(s). The drug bound with higher affinity will displace that bound with lower affinity. If just 1% of a drug that is 99% bound is displaced, the concentration of free form will be doubled. This, however, is often transient because the displaced drug will diffuse into the tissues as well as get metabolized or excreted.

(vi) In hypoalbuminemia, binding may be reduced and high concentrations of free drug may be attained, e.g. phenytoin and furosemide. 

Barriers

Penetration into brain

Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells. In the liver and spleen, a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. This is in contrast to the brain, where the capillary structure is continuous, and there are no slit junctions. To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported. For example, a specific transporter for the large neutral amino acid transporter carries levo dopa into the brain. By contrast, lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized, or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS, which have no slit junctions. These tightly juxtaposed cells form tight junctions that constitute the so-called blood-brain barrier.

   

Passage across placenta   

Placental membranes are lipoidal and allow free passage of lipophilic drugs, while restricting hydrophilic drugs. The placental efflux P-gp and other transporters like BCRP, MRP3 also serve to limit foetal exposure to maternally administered drugs. Placenta is a site for drug metabolism as well, which may lower/modify exposure of the foetus to the administered drug. However, restricted amounts of nonlipid-soluble drugs, when present in high concentration or for long periods in maternal circulation, gain access to the foetus. Some influx transporters also operate at the placenta. Thus, it is an incomplete barrier and almost any drug taken by the mother can affect the foetus or the newborn (drug taken just before delivery, e.g. morphine).

Redistribution 

Highly lipid-soluble drugs get initially distributed to organs with high blood flow, i.e. brain, heart, kidney, etc. Later, less vascular but more bulky tissues (muscle, fat) take up the drug—plasma concentration falls and the drug is withdrawn from the highly perfused sites.  If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of drug action. Greater the lipid solubility of the drug, faster is its redistribution. Anaesthetic action of thiopentone sod. injected i.v. is terminated in few minutes due to redistribution. A relatively short hypnotic action lasting 6–8 hours is exerted by oral diazepam or nitrazepam due to redistribution despite their elimination t ½ of > 30 hr. However, when the same drug is given repeatedly or continuously over long periods, the low perfusion high capacity sites get progressively filled up and the drug becomes longer acting.

Volume of distribution 

Usually drugs donot get remain in only one water compartment of the body. It gets distributed in several compartments where binding cellular components are more. For example, Components like lipids that are abundantly present in adipose tissue and cell membranes, proteins abundant in plasma and within the cells or components like nucleic acids present in nuclei of cells are the storage sites of drugs getting distributed. Therefore to what extend drug is getting distributed to different compartment according to the component of body ‘Apparent volume of distribution (Vd)” will give idea of distribution of drugs. Therefore Vd is the volume into which the drugs get distributed and calculated as 

  Vd = Amount of drug in the body        

Concentration of drug in plasma

The apparent volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0). 

Significance:

(i) High Vd indicated high lipophilicity or many receptors are present for the drug.

(ii) In overdose the drug has low Vd, are easily removed by hemodialysis, but drugs having high Vd are less available for dialysis because they get distributed in total body fluid.

(iii) It helps to calculate the loading dose.