Drug Distribution

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WELCOME:

WELCOME WELCOME

DRUG DISTRIBUTION:

DRUG DISTRIBUTION Harish rathi M. Pharm. 2 nd Sem Department of Pharmaceutics Maharishi Arvind Institute of Pharmacy JAIPUR-302020, Rajasthan India Cell No: 0091 9413183795 E-mail: harishrathi1986@gmail.com 2

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Supervised by: Presented By: Mr. Mahesh sir Harish Rathi Lecturer M. Pharm. 2nd Sem.(2010-11) Department of Pharmaceutics MAHARISHI ARVIND INSTITUTE OF PHARMACY JAIPUR

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Contents Introduction Volume of distribution Factors affecting on drug distribution References 4

Introduction:

Introduction Once a drug has gained excess to the blood stream, the drug is subjected to a number of processes called as Disposition Processes that tend to lower the plasma concentration. Distribution which involves reversible transfer of a drug between compartments. Elimination which involves irreversible loss of drug from the body. It comprises of biotransformation and excretion. 5

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Drug Distribution refers to the Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (for example, fat, muscle, and brain tissue). 6

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As the Pharmacological action of a drug depends upon its concentration at the site of action Distribution plays a significant role in the Onset, Intensity, and Duration of Action. 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. 8

Volume of Distribution:

Volume of Distribution The Volume of distribution (V D ) , also known as Apparent volume of distribution , is used to quantify the distribution of a drug between plasma and the rest of the body after oral or parenteral dosing. It is called as Apparent Volume because all parts of the body equilibrated with the drug do not have equal concentration. It is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration. 9

Redistribution:

Redistribution Highly lipid soluble drugs when given by i.v. or by inhalation initially get distributed to organs with high blood flow, e.g. brain, heart, kidney etc. Later, less vascular but more bulky tissues (muscles,fat) take up the drug and plasma concentration falls and drug is withdrawn from these sites. If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of the drug action. Greater the lipid solubility of the drug, faster is its redistribution. 10

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The real volume of distribution has physiological meaning and is related to the Body Water. 11

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The volume of each of these compartments can be determined by use of specific markers or tracers. The intracellular fluid volume can be determined as the difference between total body water and extracellular fluid. Physiological Fluid Compartments the Markers Used Approximate volume (liters) Plasma Evans Blue, Indocyanine Green 4 Extracellular fluid Inulin , Raffinose , Mannitol 14 Total Body Water D 2 O, Antipyrine 42 12

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Drugs which bind selectively to Plasma proteins e.g. Warfarin have Apparent volume of distribution smaller than their Real volume of distribution. The Vd of such drugs lies between blood volume and total body water i.e. b/w 6 to 42 liters. Drugs which bind selectively to Extravascular Tissues e.g. Chloroquine have Apparent volume of distribution larger than their Real volume of distribution. The Vd of such drugs is always greater than 42 liters. 13

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Tissue Permeability of the Drug a. Physiochemical Properties of the drug like Molecular size, pKa and o/w Partition coefficient. b. Physiological Barriers to Diffusion of Drugs. Organ / Tissue Size and Perfusion Rate Binding of Drugs to Tissue Components (Blood components and Extravascular Tissue Proteins) Miscellaneous Factors Age, Pregnancy, Obesity, Diet, Disease states, and Drug Interactions… Differences In Drug Distribution Among Various Tissues Arises Due To a Number of Factors: 14

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Tissue Permeability of the Drugs depend upon: Rate of Tissue Permeability, and Rate of Blood Perfusion. The Rate of Tissue Permeability, depends upon Physiochemical Properties of the drug as well as Physiological Barriers that restrict the diffusion of drug into tissues. Physiochemical Properties that influence drug distribution are: Molecular size, pKa , and o/w Partition coefficient. 15

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Drugs having molecular wt. less than 400 daltons easily cross the Capillary Membrane to diffuse into the Extracellular Interstitial Fluids. Now, the penetration of drug from the Extracellular fluid (ECF) is a function of :- Molecular Size: Small ions of size < 50 daltons enter the cell through Aq. filled channels where as larger size ions are restricted unless a specialized transport system exists for them. Ionisation : A drug that remains unionized at pH values of blood and ECF can permeate the cells more rapidly. Blood and ECF pH normally remains constant at 7.4, unless altered in conditions like Systemic alkalosis/acidosis. 16

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Lipophilicity : Only unionized drugs that are lipophilic rapidly crosses the cell membrane. e.g. Thiopental, a lipophilic drug, largely unionized at Blood and ECF pH readily diffuses the brain where as Penicillins which are polar and ionized at plasma pH do not cross BBB. Effective Partition Coefficient for a drug is given by: Effective K o/w = X Fraction unionized at pH 7.4 K o/w of unionized drug 17

PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIER :

PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIER A stealth of endothelial cells lining the capillaries. It has tight junctions and lack large intra cellular pores. Further, neural tissue covers the capillaries. Together , they constitute the BLOOD BRAIN BARRIER. Astrocytes : Special cells / elements of supporting tissue are found at the base of endothelial membrane. The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid (CSF) maintained by the choroid plexus in the central nervous system (CNS). 18

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Since BBB is a lipoidal barrier, It allows only the drugs having high o/w partition coefficient to diffuse passively where as moderately lipid soluble and partially ionized molecules penetrate at a slow rate. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) and large or hydrophillic molecules into the CSF, while allowing the diffusion of small hydrophobic molecules (O2, CO2, hormones). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins. :

Since BBB is a lipoidal barrier, It allows only the drugs having high o/w partition coefficient to diffuse passively where as moderately lipid soluble and partially ionized molecules penetrate at a slow rate. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) and large or hydrophillic molecules into the CSF, while allowing the diffusion of small hydrophobic molecules (O 2 , CO 2, hormones). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins. 20

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Various approaches to promote crossing BBB: Use of Permeation enhancers such as Dimethyl Sulfoxide. Osmotic disruption of the BBB by infusing internal carotid artery with Mannitol. Use of Dihydropyridine Redox system as drug carriers to the brain ( the lipid soluble dihydropyridine is linked as a carrier to the polar drug to form a prodrug that rapidly crosses the BBB ) 21

PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER :

PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER Placenta is the membrane separating Fetal blood from the Maternal blood. It is made up of Fetal Trophoblast Basement Membrane and the Endothelium. Mean thickness in early pregnancy is (25 µ) which reduces to (2 µ) at full term. 22

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Many drugs having mol. wt. < 1000 Daltons and moderate to high lipid solubility e.g. ethanol, sulfonamides, barbiturates, steroids, anticonvulsants and some antibiotics cross the barrier by simple diffusion quite rapidly . Nutrients essential for fetal growth are transported by carrier mediated processes. 23

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Blood – Cerebrospinal Fluid Barrier: The Cerebrospinal Fluid (CSF) is formed mainly by the Choroid Plexus of lateral, third and fourth ventricles. The choroidal cells are joined to each other by tight junctions forming the Blood – CSF barrier which has permeability characteristics similar to that of BBB. Only high lipid soluble drugs can cross the Blood – CSF barrier. 24

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Blood – Testis Barrier: It has tight junctions between the neighboring cells of sertoli which restricts the passage of drugs to spermatocytes and spermatids. 25

Organ / Tissue Size and Perfusion Rate :

Organ / Tissue Size and Perfusion Rate Perfusion Rate is defined as the volume of blood that flows per unit time per unit volume of the tissue. Greater the blood flow, faster the distribution. Highly perfused tissues such as lungs, kidneys, liver, heart and brain are rapidly equilibrated with lipid soluble drugs. The extent to which a drug is distributed in a particular tissue or organ depends upon the size of the tissue i.e. tissue volume. 26

Miscellaneous Factors:

Miscellaneous Factors 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. Obesity: In Obese persons, high adipose tissue content can take up a large fraction of lipophilic drugs. Pregnancy: During pregnancy the growth of the uterus, placenta and fetus increases the volume available for distribution of drugs. Disease States: Altered albumin or drug – binding protein conc. Altered or Reduced perfusion to organs /tissues Altered Tissue pH 27

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28 Age: Differences in distribution of a drug in different age groups are mainly due to : Fat content Skeletal muscles Organ composition Plasma protein content Total body water

REFERENCES:

REFERENCES Swarbrick, James, Encyclopedia of Pharmaceutical Technology, Edn-Third , pg: 208- 228 Brahmankar, D.M., Jaiswal, S.B., Biopharmaceutics & Pharmacokinetics A Treatise, Vallabh Prakashan, Edn-2009, pg : 98-110 Gibaldi, M. , Pharmacokinetics, Marcel Dekker Inc., New York, 1982 , Edn - 2 nd , pg – 44 – 48 Rani,S., Hiremath,R., Text–Book of Biopharmaceutical and Pharmacokinetics, Prism Books Pvt. Ltd., Edn-2000 , pg: 28- 32 Aulton, E., Michael, The Design and Manufacture of medicines, Churchill Livingstone Elsevier, Edn-Third, pg: 270-293 29

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THANK YOU 30