FACTORS AFFECTING D.D (MURARI)

FACTORS AFFECTING DRUG DISTRIBUTION:

FACTORS AFFECTING DRUG DISTRIBUTION PRESENTED BY: MURARI PAVAN M.PHARM (PHARMACEUTICS) GAUTHAM COLLEGE OF PHARMACY +919686852515

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What is distribution? Distribution:- It is the reversible transfer of a drug between one compartment to another. Reversible transfer of a drug between the blood and extra vascular fluids and tissues. Transfer of a drug between the blood and the extra-vascular fluids and tissues. It is a passive process, for which driving force is concentration gradient between the blood and the extra-vascular tissues.

Steps in drug distribution:

Steps in drug distribution Distribution of drug present in systemic circulation to extravascular tissue involves following steps 1. Permeation of free or unbound drug present in the blood through the capillary wall (occurs rapidly)and entry into the interstitial/extracellular fluid (ECF) 2. Permeation of the drug present in the ECF through the membrane of tissue cells and into the intracellular fluid.

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Distribution of a drug is not uniform throughout the body because different tissues receive the drug from plasma at different rates and to different extents. Differences in drug distribution among the tissue essentially arise as result of a number of factors:

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1)Tissue permeability of the drug Physiochemical properties of the drug Physiological barriers to diffusion 2)Organ / tissue size and perfusion rate 3) Binding of drugs to tissue components Binding of drug to blood components Binding of drug to extra vascular tissue proteins 4)Miscellaneous factors Age Pregnancy Obesity Diet Drug interaction FACTORS AFFECTING DRUG DISTRIBUTION

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1)Tissue permeability of drugs: The two major rate-limiting steps in the distribution of drugs are: Rate of tissue permeability, Rate of blood perfusion. The tissue permeability of a drug depends upon the physicochemical properties of the drugs as well as the physiologic barriers that restrict diffusion of the drug into tissues. Important physicochemical properties that influence drug distribution are molecular size, degree of ionization and partition coefficient.

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The degree of ionization of a drug is an important determinant in its tissue permeability. The pH of the blood and the extravascular fluid also play a role in the ionization and diffusion of drugs into the cells. A drug that remains unionized at these pH values can permeate the cells relatively more rapidly.

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Situations that results in alteration of blood pH affect such a pattern; for example, acidosis results in decreased ionization of acidic drugs and thus increased intracellular drug concentration and pharmacologic action. Eg : thiopentone , a nonpolar , lipophilic drug, largely unionized at plasma ph, readily diffuses into the brain barrier penicillin which are polar, water soluble and ionize at plasma ph do not cross the blood brain barrier

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Physiologic Barriers to Distribution of Drugs Some of the important simple and specialized physiologic 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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Effect of Diffusion Barriers on Distribution Most capillaries have pores between the endothelial cells lining the capillaries. These pores allow rapid diffusion of most drugs into the interstitial space. In the brain capillaries, the endothelial cells are closely connected by “tight junctions” and do not have pores between the endothelial cells. In capillaries with tight junctions, drug molecules must diffuse across the endothelial cells rather than between them. Only lipophilic drugs rapidly diffuse across the endothelial cells of capillary beds with tight junctions, whereas hydrophilic drugs are excluded.

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1. 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. 2. The simple cell membrane barrier: Once a drug diffuses from the capillary wall into the extracellular fluid, its further entry into cells of most tissues is limited by its permeability through the membrane that lines such cells.

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3.Blood – Brain barrier (BBB): The brain capillaries consists of endothelial cells which are joined to one another by continuous tight intercellular junctions comprising of blood-brain barrier. Since the BBB is a lipoidal barrier, it allows only the drugs having high o/w partition coefficient to diffuse passively whereas moderately lipid soluble and partially ionized molecules penetrate at a slow rate. The effective partition coefficient of thiopental, a highly lipid soluble drug is 50 times that of pentobarbital and crosses the BBB much more rapidly. Polar natural substances such as sugars and amino acids are transported to brain actively. Thus, structurally similar foreign molecules can also penetrate the BBB by the same mechanism. Most antibiotics such as penicillin's which are polar, water – soluble and ionized at plasma pH, do not cross the BBB under normal circumstances .

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Three different approaches have been utilized successfully to promote crossing the BBB by drugs: Use of permeation enhancers such as dimethyl sulfoxide(DMSO) Osmotic disruption of the BBB by infusing internal carotid artery with mannitol Use of dihydropyridine redox system as drug carriers to the brain

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eg - Volatile anaesthetics like chloroform , ultra short acting barbiturate like thiopental , narcotic analgesic like morphine & heroin , dopamine precursor like 1-dopa , sympathomimetics like amphetamine & ephedrine and drugs like diazepam and propranolol can pass the BBB While polar compound like dopamine, serotonin & streptomycine and quaternary substance like d- tubocurine & hexamethonium, neostigmine & acetylcholine fails to penetrate theBBB.

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4. Blood-Cerebrospinal fluid barrier: The cerebrospinal fluid (CSF) is formed mainly by the choroid plexus of the lateral, third and fourth ventricles and is similar in composition to the ECF of brain. The capillary endothelium that lines the choroid plexus have open junctions or gaps and drugs can flow freely into the extracellular space between the capillary wall and the choroidal cells. However, the choroidal cells are joined to each other by tight junctions forming the blood-CSF barrier which has permeability characteristics similar to that of the BBB.

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As in the case of BBB, only highly lipid soluble drugs can cross the blood-CSF barrier with relative ease whereas moderately lipid soluble and partially ionized drugs permeate slowly. A drug that enters the CSF slowly cannot achieve a high concentration as the bulk flow of CSF continuously removes the drug. For a given drug, its concentration in the brain will always be higher than that in the CSF. Although the mechanisms for diffusion of drugs into the CNS and CSF are similar, the degree of uptake may vary significantly. In some cases, CSF drug concentration may be higher than its cerebral concentration.

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5. Placental Barrier: The maternal and the fetal blood vessels are separated by a number of tissue layers made of fetal trophoblst basement membrane and the endothelium which together constitute the placental barrier. The human placental barrier has a mean thickness of 25 microns in early pregnancy that reduces to 2 microns at full term which however dose not reduce its effectiveness. Many drugs having molecular weight less than 1000 daltons and moderate to high lipid solubility e.g. ethanol, sulfonamides, barbiturates, gaseous anesthetics, steroids, narcotic analgesics, anticonvulsants and some antibiotics, cross the barrier by simple diffusion quite rapidly. The placental barrier is not as effective a barrier as BBB.

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6. Blood-Testis Barrier: This barrier is located not at the capillary endothelium level but at sertoli-sertoli cell junction. It is the tight junction between the neighboring sertoli cells the act as the blood-testis barrier. This barrier restricts the passage of drugs to spermatocytes and spermatids.

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2)Organ/Tissue size and perfusion rate: Distribution is permeability rate-limiting in the following cases: when the drug under consideration is ionic, polar or water soluble, where the highly selective physiologic barriers restrict the diffusion of such drugs to the inside of the cell

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Distribution will be perfusion rate limiting when: The drug is highly lipophilic The membrane across which the drug is supposed to diffuse is highly permeable such as those of the capillaries and the muscles. If K t/b is the tissue/blood partition coefficient of drug then the first-order distribution rate constant, K t , is given by following equation: The tissue distribution half-life is given by equation:

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The extent to which a drug is distributed in a particular tissue or organ depends upon the size of the tissue and the tissue/blood partition coefficient of the drug. Thiopental - a lipophilic drug has a high tissue/blood partition coefficient towards the brain and still higher for adipose tissue. Since the brain is a highly perfused organ, following i.v . injection, thiopental readily diffuses into the brain showing a rapid onset of action. Adipose tissue being poorly perfused , takes longer to get distributed with the same drug.

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3)Binding of drugs to tissue components: A drug in the body can bind to several components such as the plasma proteins, blood cells and hemoglobin and extra vascular proteins and other tissues.

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4)MISCELLANEOUS FACTORS: a) Age : Differences in distribution pattern of a drug in different age groups are mainly due to differences in: Total body water is much greater in infants, Fat content is also higher in infants and elderly, Skeletal muscles are lesser in infants and in elderly, Organ composition – the BBB is poorly developed in infants, the myelin content is low and cerebral blood flow is high, hence greater penetration of drugs in the brain, Plasma protein content - low albumin content in both infants and in elderly,

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b) DRUG INTERACTIONS Drug interactions that affect distribution are mainly due to differences in plasma protein or tissue binding of drugs c) PREGNANCY The fetus represents a separate compartment in which a drug can distribute. The plasma and the ECF volume also increase but there is a fall in albumin content . d) OBESITY In obese persons, the high adipose tissue content can take up a large fraction of lipophilic drugs despite the fact that perfusion through it is low.

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e)Diet: A diet high in fats will increase the free fatty acid levels in circulation thereby affecting binding of acidic drugs such as NSAIDs to albumin. f) Disease States: A number of mechanisms may be involved in the alteration of drug distribution characteristics in disease states: Altered albumin and other drug-binding protein concentration, Altered or reduced perfusion to organs or tissues Altered tissue pH An interesting example of altered permeability of the physiologic barriers is that of BBB. In meningitis and encephalitis, the BBB becomes more permeable and thus polar antibiotics such as penicillin G and ampicillin which do not normally cross it, gain assess to the brain. In a patient suffering from CCF the perfusion rate to the entire body decreases affecting distribution of all drugs.

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