DISTRIBUTION

DISTRIBUTION : 

DISTRIBUTION By, Chinmayi Ramachandran

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Distribution is defined as the reversible transfer of a drug between one compartment and another. Process is carried out by the circulation of the blood. One compartment is blood and the other will be EV fluids or body tissues. Distribution is a passive process and the driving force is the concentration gradient between the blood and the EV tissue. Drug diffuses only until equilibrium is reached. Distribution of drug is not uniform throughout the body because different tissues receive the drug from the plasma at different rates and to different extends.

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Difference in the drug distribution among the tissues arise as a result of a number of factors: 1. Tissue permeability of the drug Physicochemical properties of the drug – molecular size, degree of ionization and partition coefficient Physiological barriers to diffusion of drugs 2. Organ/tissue size and perfusion rate 3. Binding of drugs to the tissue components Binding of drugs to the tissue components Binding of drugs to the EV tissue proteins 4. Miscellaneous factors – age, pregnancy, obesity, diet, disease state, drug interactions etc..

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TISSUE PERMEABILITY OF DRUGS the two major rate determining steps in the distribution of drugs are: Rate of tissue permeability Rate of blood perfusion. If the blood flow to the entire body tissues were uniform, differences in the degree of distribution between tissues will indicate the differences in the tissue permeability of drugs. So the process is tissue permeability rate limited.

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Physicochemical properties of the drugs….. Drug distribution is mainly affected by the degree of ionization, partition coefficient and molecular size. Drugs having molecular weight less than 500-600 Daltons easily cross the capillary membrane to diffuse into the EC fluids. Penetration of drugs from the EC fluid into the cells is a function of molecular size, ionization constant and lipophilicity of the drug. Small water soluble molecules and ions of size below 50 Daltons enter the cell through the aqueous filled channels.

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The pH of the blood and the EV fluid also play a role in the ionization and diffusion of drugs into the cells. All drugs that ionize at plasma pH i.e. polar hydrophilic drugs cannot penetrate the lipoidal cell membrane. So tissue permeability is the rate limiting step in the distribution of such drugs. Only unionized drugs which are generally lipophilic can rapidly cross the cell membrane. In case of polar drugs where permeability is the rate limiting step in the distribution, the driving force is the effective partition coefficient of drug.

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Physiologic barriers of distribution of drugs…. Some of the important physiological barriers are: Simple capillary endothelial barrier Simple cell membrane barrier Blood brain barrier Cerebrospinal fluid barrier Placental barrier Blood testis barrier

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The simple capillary endothelial barrier…. All drugs ionized or unionized with a molecular size less than 600 daltons, diffuse through the capillary endothelium and into the interstitial fluid. Only drugs bound to the blood components are restricted. The simple cell membrane barrier…. Entry into cells of most tissues is limited by its permeability through the membrane that lines such cells.

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Blood brain barriers…(BBB) The capillaries in the brain are highly specialized and less permeable to water permeable drugs. The brain capillaries consists of endothelial cells, joined to one another by continuous tight intercellular junctions called as BBB. Special cells called as astrocytes form a solid envelop around the brain capillaries. Since the BBB is lipoidal in nature, it allows the drugs having high o/w partition coefficient to diffuse passively. Moderately lipid soluble and partly ionized molecules penetrate at a slow rate.

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Polar natural substances such as sugars and amino acids are transported to the brain actively. Structurally similar foreign molecules can also penetrate the BBB by the same mechanism. This selective permeability of lipid soluble moieties through the BBB helps to treat CNS disorders. Parkinsonism occurs due to the depletion of dopamine in the brain, cannot be treated by the administration of dopamine as it does not cross the BBB. Levodopa can cross BBB where it metabolized to dopamine and produces necessary action. Three approaches to promote crossing the BBB by the drugs are:

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Use of the permeation enhancers such as dimethyl sulfoxide Osmotic disruption of BBB with mannitol Use of dihydropyridine redo system as drug carriers.

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Blood cerebrospinal fluid barrier…. The CSF is formed by the choroid plexus and is similar in composition as ECF of brain. The capillary endothelium that lines the choroid plexus have open junctions or gaps. So the drugs can easily flow into the EC space between the capillary wall and the choroid cells. Choroid cells have tight junctions forming the blood-CSF barrier. Only highly lipophilic drugs can cross the blood CSF barrier. A drug that enters the CSF cannot achieve a high concentration , as the bulk flow of CSF continuously remove the drug.

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Mechanisms for diffusion of drugs into the CNS and CSF are similar, the degree of uptake may vary significantly. Placental barrier….. The maternal and the fetal blood vessels are separated by tissue layers made of fetal trophoblast basement membrane and the endothelium which together forms the placental barrier. Drugs having molecular weight less than 1000 Daltons which are lipid soluble can cross the barrier by simple diffusion. This is not an effective barrier as BBB. Nutrients for fetal growth are transported by carrier mediated process.

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Immunoglobulins are transported by endocytosis. Drugs affects the fetal organ development and the physiological functions. It is better to avoid all drugs during pregnancy.

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Blood testis barrier….. This barrier is located at sertoli-sertoli cell junction. It is the tight junctions between the neighboring sertoli cells that act as the blood testis barrier. This barrier restricts the passage of drugs to spermatocytes and spermatids.

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TISSUE SIZE AND PERFUSION RATE. Distribution is permeability rate limited when: The drug under consideration is ionic, polar or water soluble. The highly selective physiological barriers restrict the diffusion of such drugs into the cell. Distribution is perfusion rate limited when: The drug is highly lipophilic The drug diffuses through a highly permeable membrane such as those of capillaries and muscles. Greater the blood flow, faster the distribution.

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Perfusion rate is the volume of blood that flows per unit time per unit volume of the tissue (ml/min/ml of the tissue.) The extend to which a drug is distributed in a particular tissue depends upon the size of the tissue and the tissue blood partition coefficient of the drug. BINDING OF DRUGS TO THE TISSUE COMPONENTS A drug in the body can bind to several components such as plasma proteins, blood cells and hemoglobin, extra vascular proteins and other components.

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MISCELLANEOUS FACTORS AFFECTING DRUG DISTRIBUTION. Age Total body water is much greater in infants. Fat content is higher in infants and elderly. Skeletal muscles are lesser in infants and in elderly. Organ composition – BBB is poorly developed in infants, so greater penetration of drugs in the brain. Plasma protein content – low albumin content in both infants and in elderly. Pregnancy The growth of uterus, placenta and fetus increases the volume available for the distribution of drugs. Plasma and ECF volume ↑ and albumin content ↓.

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Obesity The high adipose tissue content can take up a large fraction of lipophilic drugs even the perfusion is low. Diet A diet high in fats will increase the free fatty acid levels in circulation and affects the binding of acidic drugs such as NSAICs to albumin. Disease state Alteration in drug distribution during disease states may be due to: Altered albumin and other drug binding protein concentration. Reduced perfusion to organs Altered tissue pH.

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In meningitis and encephalitis, the BBB becomes more permeable and polar antibiotics like penicillin and ampicillin can easily cross it. Drug interactions. DI that affects distribution are due to differences in the plasma protein or tissue binding of drugs. There can be displacement interactions i.e. competition between drugs for the binding sites, or competition between drugs and normal body constituents. Drug or its metabolites can alter the protein structure thereby modifying its binding structure.

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VOLUME OF DISTRIBUTION. There is a constant relation between the concentration of drug in the plasma (C) and the amount of drug in the body (X) X α C X = VdC Vd = proportionality constant ,apparent volume of distribution. It is defined as the hypothetical volume of body fluid into which a drug is dissolved or distributed. Vd = X/C Expressed in liters or liters/kg body weight.