Distribution of Drugs and factors effecting

Distribution of drugs

1. Dr . Adeel Sattar DISTRIBUTION OF DRUGS

2.  Distribution may be defined as a process by which drugs reversibly leave the blood stream and enter the extravascular fluid and tissues.  Distribution is an important pharmacokinetic process as it determines the transport of drugs to their site of action and to the organs of metabolism and excretion.  Distribution of a drug is not uniform throughout the body because of difference i n perfusion rates.

3.  The tissue permeability of a drug is determined by a number of factors including the physico-chemical properties of the drug, binding to plasma and tissue proteins, blood flow, special compartments and barriers, disease states, etc.  Some important factors which govern distribution of drugs are considered briefly next. 3

4. 1. Physicochemical Properties of The Drug 4  Almost all drugs having molecular weight less than 500 to 600 Da easily cross the capillary membranes to penetrate into the extracellular fluids (except in CNS) because junctions between the capillary endothelial cells are not tight.

5.  However, passage of drugs from the ECF into the cells is a function of molecular size, degree of ionisation and lipophilicity of the drug.  A drug that is lipid soluble and unionised at blood and extracellular fluid pH permeates the cell more rapidly than a polar and ionised drug. 5

6.  According to the pH-partition hypothesis, basic drugs present in blood (pH 7.4) concentrate there (because basic drugs will be more unionised in plasma than that of acid fluid, so they will diffuse readily, but on entering the acid compartment they become ionised and get trapped). 6

7.  Conversely, acidic drugs attain high concentrations in the relatively more alkaline body fluids. For example. weak organic bases administered parenterally diffuse passively from blood (pH 7.4) into rumen fluid (pH 5.5 - 6.5) of cattle and sheep, where they become trapped by ionisation.  Similarly. weak bases tend to accumulate in milk since the pH of milk is slightly acidic (pH6.5 to 6.8) to the blood. 7

8. 2. Binding to Plasma and Tissue Proteins 8  Drugs are transported in the circulating blood in two forms: free form and bound to plasma proteins.  Free form of drugs is mostly dissolved in plasma water and is pharmacologically active, diffusible and available for metabolism and excretion.  Protein bound drugs are pharmacologically inactive, non-diffusible, and not available for metabolism or excretion as they cannot pass through capillaries and cell membranes because of their larger size.

9.  Plasma protein binding is an important phenomenon, which significantly affects distribution and pharmacological and therapeutic response of drugs. 9

10.  Plasma protein binding of drugs generally involves weak chemical bonds and is a reversible process.  Extent of binding is a characteristic of a drug and generally remains fixed for a drug within a wide range of concentration.  The binding of individual drugs ranges from very little (e.g. aminoglycosides) to very high (e.g. warfarin)

11.  In circulating blood, there is a constant ratio between the bound and free fractions of the drug. When the concentration of the free drug falls due to redistribution,metabolism or excretion, the free: bound ratio is maintained by dissociation of the bound form.  Thus plasma protein binding mainly serves as a reservoir, which supplies free drug whenever required.  Free drug Protein bound drug 11

12.  Common blood proteins which drugs bind to are albumin, lipoprotein, glycoprotein and globulins.  Acidic and neutral drugs generally bind to plasma albumin and basic drugs to glycoproteins.  Binding to other plasma proteins (e.g. lipoproteins and globulins) occurs to a much smaller extent. 12

13.  Some drugs may bind to blood components other than plasma proteins. Drugs like pentobarbital binds to haemoglobin, and chlorpromazine binds with the RBC membrane. 13

14. Significance of plasma-protein binding a. Plasma protein bound drugs are non- diffusible. Therefore, high plasma protein binding reduces the efficiency o f drug distribution. b. Plasma protein bound drugs are pharmacologically inactive. Therefore, heavily protein-bound drugs are generally less efficacious and less potent. 14

15. c. Protein-bound drugs do not undergo metabolism and excretion through glomerular filtration. d. Therefore, heavily protein-bound drugs generally have long plasma half- lives. 15

16. e. Protein-bound drugs may show drug displacement interactions. Therefore, if a drug is heavily protein-bound, has a narrow therapeutic index and show small volume of distribution, the displacement may significantly increase the biological activity and possible toxicity of the drug. 16

17. Drug displacement interactions: 17  : Drug displacement interactions occur between two or more drugs which bind to the same plasma protein site. If one drug is binding to such a site, then administration of second drug having higher affinity for the same site results in displacement of first drug from its binding site.

18.  . For example, administration of phenylbutazone to a patient on warfarin therapy results in displacement of warfarin from its binding site. Warfarin has high plasma protein binding of about 99% (remains confined to blood compartments) and has a narrow therapeutic index.  If just 1 % of warfarin is displaced by the phenylbutazone, the concentration of free warfarin will be doubled. This enhanced concentration of free warfarin may cause intense biological activity with severe haemorrhagic episodes, which may prove to be fatal. 18

19. Binding to tissue proteins  A drug may bind to one or more of the several tissue components and may get accumulated there.  A drug is said to be localised in tissue if its concentration in that tissue exceeds the concentration in plasma. 19

20.  Tissue-drug binding is important in distribution as it results in localisation of the drug at a specific site in the body.  Binding of drugs with tissues may be either reversible where it acts as storage site, or irreversible. 20

21.  The reversible tissue binding is not harmful, but the strong irreversible chemical binding often results in adverse effects and toxicity.  For example: binding of paracetamol and chloroform metabolites with liver results in hepatotoxicity, deposition of tetracyclines in dental tissues during odontogenesis in infants and children results in permanent brown-yellow discolouration of teeth. 21

22. 3. Blood Flow and Organ Size 22  In addition to the physico-chemical properties of drug and plasma protein binding, the drug distribution to a particular organ or tissue depends on the size of tissue (tissue volume) and tissue perfusion rate. Highly perfused tissues such as lungs, kidneys, liver, heart, adrenals and brain are rapidly equilibrated with lipid soluble drugs.

23.  Muscle and skin are moderately perfused, so they equilibrate slowly with the drug present in blood.  Adipose tissues, bones and teeth being poorly perfused take longer to get distributed with the same drug. 23

24. 4. Specialised Compartments and Barriers 24  Some organs/areas of the body are not readily accessible to drugs because their anatomic make- up poses permeability restriction to drugs.  Some of these compartments and barriers include blood-brain barrier, blood-CSF barrier and placental barrier.

25. Blood-brain barrier: 25  The capillary endothelial cells in brain have tight junctions and lack pores or gaps. Surrounding the tight and overlapping endothelial layer is a continuous basement membrane.  The basement membrane in turn is enveloped by a perivascular foot process' formed by astrocyte cells which encircle about 85% of the surface areas of brain capillaries . Together these layers add up to a formidable non- polar barrier called the blood-brain barrier (BBB ).

26.  There are certain specific sites in brain like chemoreceptor trigger zone (CTZ) and posterior lobe of hypothalamus where the BBB does not exist, and at these sites brain may be exposed to some lipid insoluble and polar drugs also.  In newly born and old animals, the blood-brain barrier is generally less effective, allowing increased passage of water soluble and polar compounds into the brain. 26

27. Blood-cerebrospinal fluid barrier: 27  Overall, the blood-CSF barrier has permeability characteristics similar to those of BBB (i.e. allows only lipid soluble drugs to enter the CSF), but unlike brain a drug that enters the CSF slowly generally fails to achieve high concentration there because the bulk flow of CSF continuously removes the drug.  Therefore for a given drug, its concentration in brain is always higher than that in the CSF.

28. Placental barrier: 28  The characteristics of this lipid barrier are generally the same as of blood-brain barrier.  Lipid soluble drugs pass freely into foetal circulation by diffusion and water-soluble drugs or essential nutrients cross the placental barrier by carrier mediated transport system.

29.  Care must be taken while administration of all types of drugs during pregnancy because of the uncertainty of their harmful effects on developing foetus.  Other barriers: The prostrate, testicles and globe of eyes contain barriers which prevent easy drug penetration to tissues. 29

30. 5. Availability of Specialised Transport System 30  Some drugs are concentrated in some specific tissues as a result of their active uptake by specialised transport systems present in such tissues.  For example, iodine is actively concentrated into the thyroid cells.

31. 6. Disease States 31  Distribution characteristics of several drugs are altered in disease states.  In meningitis and encephalitis, the blood- brain barrier becomes more permeable and the polar antibiotics like penicillin-G, which do not normally cross it, gain access to the brain.

32.  In hypoalbuminaemia, plasma protein binding of drugs may be reduced and high concentration of free drugs may be attained.  In congestive heart failure or shock, the perfusion rate to the entire body decreases that adversely affects distribution of drugs. 32

33. 7. Physiological Factors 33 that perfusion rate to fats is low.  In infants, the blood-brain barrier is poorly developed and cerebral blood flow is more, all of which provide greater penetration of drugs in the brain.  In geriatric (Of or relating to the aged or to characteristics of the aging process) animals, the protein contents are low and blood-brain barrier is not efficient. which alter distribution pattern of certain drugs.  In obese animals. the high adipose tissue can take up a large fraction of lipophilic drugs despite the fact

34. Drug Distribution  Oral Administration