DISTRIBUTION / WHAT IS THE DISTRIBUTION / NOTES OF DISTRIBUTION / KDT NOTES OF PHARMACOLOGY

 DISTRIBUTION 

Once a drug has gained access to the blood stream, it gets distributed to other tissues that initially had no drug, concentration gradient being in the direction of plasma to tissues. The extent of distribution of a drug and its pattern of tissue distribution 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. 

 Movement of drug proceeds until an equilibrium is established between unbound drug in the plasma and the tissue fluids. Subsequently, there is a parallel decline in both due to elimination. Apparent volume of distribution (V) Presuming that the body behaves as a single homogeneous compartment with volume V into which the drug gets immediately and uniformly distributed

Since in the example shown in Fig. 2.8, the drug does not actually distribute into 20 L of body water, with the exclusion of the rest of it, this is only an apparent volume of distribution which can be defined as “the volume that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma”. Thus, it describes amount of the drug present in the body as a multiple of that contained in a unit volume of plasma. Considered together with drug clearance, this is a very useful pharmacokinetic concept. Lipid-insoluble drugs do not enter cells— V approximates extracellular fluid volume, e.g. streptomycin, gentamicin 0.25 L/kg. Distribution is not only a matter of dilution, but also binding and sequestration. Drugs extensively bound to plasma proteins are largely

  restricted to the vascular compartment and have low values of V, e.g. diclofenac and warfarin (99% bound) V = 0.15 L/kg. A large value of V indicates that larger quantity of drug is present in extravascular tissue. Drugs sequestrated in other tissues may have, V much more than total body water or even body mass, e.g. digoxin 6 L/kg, propranolol 4 L/kg, morphine 3.5 L/kg, because most of the drug is present in other tissues, and plasma concentration is low. Therefore, in case of poisoning, drugs with large volumes of distribution are not easily removed by haemodialysis. Pathological states, e.g. congestive heart failure, uraemia, cirrhosis of liver, etc. can alter the V of many drugs by altering distribution of body water, permeability of membranes, binding proteins or by accumulation of metabolites that displace the drug from binding sites. More precise multiple compartment models for drug distribution have been worked out, but the single compartment model, described above, is simple and fairly accurate for many drugs

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 t½ 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. 

Penetration into brain and CSF

 The capillary endothelial cells in brain have tight junctions and lack large paracellular spaces. Further, an investment of neural tissue (Fig. 2.9B) covers the capillaries. Together they constitute the so called blood-brain barrier (BBB). A similar blood CSF barrier is located in the choroid plexus: capillaries are lined by choroidal epithelium having tight junctions. Both these barriers are lipoidal and limit the entry of nonlipid-soluble drugs, e.g. streptomycin, neostigmine, etc. Only lipid-soluble drugs, therefore, are able to penetrate and have action on the central nervous system. In addition, efflux transporters like P-gp and anion transporter (OATP) present in brain and choroidal vessels extrude many drugs that enter brain by other processes and serve to augment the protective barrier against potentially harmful xenobiotics. Dopamine does not enter brain but its precursor levodopa does; as such,

the latter is used in parkinsonism. Inflammation of meninges or brain increases permeability of these barriers. It has been proposed that some drugs accumulate in the brain by utilizing the transporters for endogenous substances. There is also an enzymatic BBB: Monoamine oxidase (MAO), cholinesterase and some other enzymes are present in the capillary walls or in the cells lining them. They do not allow catecholamines, 5-HT, acetylcholine, etc. to enter brain in the active form. The BBB is deficient at the CTZ in the medulla oblongata (even lipid-insoluble drugs are emetic) and at certain periventricular sites— (anterior hypothalamus). Exit of drugs from the CSF and brain, however, is not dependent on lipid-solubility and is rather unrestricted. This is due to bulk flow of CSF (alongwith the drug dissolved in it) back into blood through the arachnoid villi. Further, nonspecific organic anion and cation transport processes (similar to those in renal tubule) operate at the choroid plexus.

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). 

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 (which is more abundant) is quantitatively more important. Extent of binding depends on the individual compound; no generalization for a pharmacological or chemical class can be made (even small chemical change can markedly alter protein binding), for example the binding percentage of some benzodiazepines is 

Flurazepam 10%

 Alprazolam 70% 

Lorazepam 90% 

Diazepam 99%

 Movement of drug proceeds until an equilibrium is established between unbound drug in the plasma and the tissue fluids. Subsequently, there is a parallel decline in both due to elimination. Apparent volume of distribution (V) Presuming that the body behaves as a single homogeneous compartment with volume V into which the drug gets immediately and uniformly distributed

Since in the example shown in Fig. 2.8, the drug does not actually distribute into 20 L of body water, with the exclusion of the rest of it, this is only an apparent volume of distribution which can be defined as “the volume that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma”. Thus, it describes amount of the drug present in the body as a multiple of that contained in a unit volume of plasma. Considered together with drug clearance, this is a very useful pharmacokinetic concept. Lipid-insoluble drugs do not enter cells— V approximates extracellular fluid volume, e.g. streptomycin, gentamicin 0.25 L/kg. Distribution is not only a matter of dilution, but also binding and sequestration. Drugs extensively bound to plasma proteins are largely

  restricted to the vascular compartment and have low values of V, e.g. diclofenac and warfarin (99% bound) V = 0.15 L/kg. A large value of V indicates that larger quantity of drug is present in extravascular tissue. Drugs sequestrated in other tissues may have, V much more than total body water or even body mass, e.g. digoxin 6 L/kg, propranolol 4 L/kg, morphine 3.5 L/kg, because most of the drug is present in other tissues, and plasma concentration is low. Therefore, in case of poisoning, drugs with large volumes of distribution are not easily removed by haemodialysis. Pathological states, e.g. congestive heart failure, uraemia, cirrhosis of liver, etc. can alter the V of many drugs by altering distribution of body water, permeability of membranes, binding proteins or by accumulation of metabolites that displace the drug from binding sites. More precise multiple compartment models for drug distribution have been worked out, but the single compartment model, described above, is simple and fairly accurate for many drugs

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 t½ 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. 

Penetration into brain and CSF

 The capillary endothelial cells in brain have tight junctions and lack large paracellular spaces. Further, an investment of neural tissue (Fig. 2.9B) covers the capillaries. Together they constitute the so called blood-brain barrier (BBB). A similar blood CSF barrier is located in the choroid plexus: capillaries are lined by choroidal epithelium having tight junctions. Both these barriers are lipoidal and limit the entry of nonlipid-soluble drugs, e.g. streptomycin, neostigmine, etc. Only lipid-soluble drugs, therefore, are able to penetrate and have action on the central nervous system. In addition, efflux transporters like P-gp and anion transporter (OATP) present in brain and choroidal vessels extrude many drugs that enter brain by other processes and serve to augment the protective barrier against potentially harmful xenobiotics. Dopamine does not enter brain but its precursor levodopa does; as such,

the latter is used in parkinsonism. Inflammation of meninges or brain increases permeability of these barriers. It has been proposed that some drugs accumulate in the brain by utilizing the transporters for endogenous substances. There is also an enzymatic BBB: Monoamine oxidase (MAO), cholinesterase and some other enzymes are present in the capillary walls or in the cells lining them. They do not allow catecholamines, 5-HT, acetylcholine, etc. to enter brain in the active form. The BBB is deficient at the CTZ in the medulla oblongata (even lipid-insoluble drugs are emetic) and at certain periventricular sites— (anterior hypothalamus). Exit of drugs from the CSF and brain, however, is not dependent on lipid-solubility and is rather unrestricted. This is due to bulk flow of CSF (alongwith the drug dissolved in it) back into blood through the arachnoid villi. Further, nonspecific organic anion and cation transport processes (similar to those in renal tubule) operate at the choroid plexus.

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). 

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 (which is more abundant) is quantitatively more important. Extent of binding depends on the individual compound; no generalization for a pharmacological or chemical class can be made (even small chemical change can markedly alter protein binding), for example the binding percentage of some benzodiazepines is 

Flurazepam 10%

 Alprazolam 70% 

Lorazepam 90% 

Diazepam 99%