Biological process and events in drug targeting


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Contents: Cellular uptake & processing Transport across epithelial barrier Extravasation Lymphatic uptake Atit Pandey 2


CELLULAR UPTAKE AND PROCESSING: Following administration a drug frequently passes through various cell membranes and reach its target site Low molecular weight drugs enter or pass through cells by simple diffusion TDDS comprise macro molecules and are unable to enter the cells by simple processes Atit Pandey 3

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However, large particles are able to enter cell by active transport process such as Phagocytosis Endocytosis Pinocytosis Exocytosis Atit Pandey 4

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Endocytosis & Exocytosis:

Endocytosis & Exocytosis Both require Energy. Large particles are transported across the membrane in membrane bound vesicles. Atit Pandey 6


Endocytosis: The process where a cell absorb extracellular material by engulfing it with their cell membrane to form a vesicle which is then pinched off intracellularly. The particles does not pass through the membrane, it is simply engulfed and enclosed. Atit Pandey 7


Exocytosis The reverse process where materials are expelled or secreted from a cell. This is used to rid wastes and secreted substances (hormones) produced by the cell. It may be excretion or secretion . Atit Pandey 8

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Pinocytosis & Phagocytosis Both take the materials IN Atit Pandey 9

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PHAGOCYTOSIS (SOLID PARTICLES – CELL EATING) This is carried by specialized cells of mononuclear phagocyte system called phagocytes by absorption of specific blood component called ‘opsonins’ Phagocytic vacuole fuses with one or more lyosomes to form phagolysosomes . Digestion of particles occurs by lyosomal acid hydrolysis , making drug available to exert its effect. Atit Pandey 10


11 PINOCYTOSIS (LIQUID – CELL DRINKING) Pinocytosis (a form of endocytosis) allows a cell to engulf large molecules and fluid that may be present in the extracellular region. The cell membrane folds inwards , encloses the fluid or particle to be transported and then fuses to form a vesicle . The vesicle detaches from the membrane and moves to the interior of the cell . Atit Pandey

It is of two types: Fluid phase pinocytosis Receptor mediated pinocytosis :

It is of two types: Fluid phase pinocytosis Receptor mediated pinocytosis Fluid phase pinocytosis is non-specific & continuous process where macromolecules adheres to general cell surface site. Adsorptive pinocytosis or R eceptor mediated pinocytosis is a specific process where the macromolecules bind to specific cell receptor site. Atit Pandey 12

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Receptor-mediated pinocytosis is a particularly efficient form of pinocytosis. :

Receptor-mediated pinocytosis is a particularly efficient form of pinocytosis. A receptor on the surface of the cell binds to a molecule in the tissue fluid and the complex of binding molecule (ligand) and receptor is ingested . For example, this is how human cells take in the element iron, which is present in the tissue fluid bound to a protein called transferrin. Atit Pandey 14


2 . TRANSPORT ACROSS THE EPITHELIAL BARRIER: Oral, buccal, nasal, vaginal and rectal cavities are internally lined with one or more layers of epithelial cells. Depending on position and function in body, these cells vary. These cells are extremely cohesive . Absorption of low molecular weight drugs from oral route is well established. Atit Pandey 15

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Various transport process used frequently by drugs to cross epithelial barrier lining are Passive diffusion Carrier mediated. Endocytosis Additionally, polar molecules can diffuse through tight junction of epithelial cells i.e., paracellular route . Atit Pandey 16

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Molecules less than 10 kDa are absorbed from nasal epithelium into systemic circulation in sufficient amount without need of added materials. Larger molecules proteins (e.g., interferon, human growth hormone) requires both penetration enhancer & bioadhesives. This flux enhancers deleterious effect Nasal mucosa & mucociliary clearance. Atit Pandey 17

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cyclodextrins Overcomed by phospholipids. Phospholipids significant increase in absorption of macromolecules. biocompatible bioresorbable no or less threat of toxicity. Atit Pandey 18

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Penetration enhancers improves intestinal absorption of peptides & other macromolecular drugs. These includes: a) Chelators: e.g., EDTA, citric acid, salicylates etc. b) Surfactants: Natural Semi synthetic Synthetic c) Fatty acid & derivatives : e.g., oleic acid, sodium laurate, sodium caprate etc. Atit Pandey 19

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The different region of GIT shows different sensitivity to penetration enhancers. Following order of sensitivity is suggested: Rectum> colon> small intestine> stomach. Factors influencing the absorption of drugs from gastrointestinal tract are pH, enzymes, surface area, microflora and transit time. Atit Pandey 20

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EXTRAVASATION: For a drug to exert its therapeutic effects, it must move from the central circulation and interact with its extra vascular-extracellular or extra vascular-intracellular target. This process of transvascular exchange is called “extravasation.”

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Extravasation is governed by permeability of blood capillary walls. Rate of blood & lymph supply Physicochemical factors: molecular shape, size & charge Hlb characteristics. Atit Pandey 22

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Depending on the morphology & continuity of endothelial layer & basement membrane , blood capillaries are of three types: Continuous Fenestrated sinusoidal Atit Pandey 23

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Continuous capillaries – these are common and widely distributed in the body. They exhibit tight interendothelial junctions and an uninterrupted basement membrane. Fenestrated capillaries – these show interendothelial gaps of 8-20 nm at regular intervals. Sinusoidal capillaries – show 150 nm of interendothelial gaps. Basal membrane is absent in sinusoidal capillaries of liver and is discontinuous in spleen and bone marrow.

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LYMPHATIC UPTAKE: Following extravasation, the drug molecules can either reabsorb into the blood stream directly by the enlarged post capillary interendothelial cell pores found in most tissues or enter into the lymphatic system and then return with the lymph to the blood circulation. Drugs administered through subcutaneous, intramuscular, transdermal and peritoneal routes reach the systemic circulation by lymphatic system Atit Pandey 26

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LYMPHATIC CIRCULATION: is a path of minor importance in drug absorption into systemic circulation for two reasons: The lymph vessels are less accessible than the capillaries. The lymph flow is exceptionally slow. However, fats, fat-soluble vitamins & highly lipophilic drugs are absorbed through lymphatic circulation . Atit Pandey 27

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Advantage of lymphatic absorption of drugs: Avoidance of first pass effect . Compounds of high molecular weight (above 16,000) can be absorbed by lymphatic transport. Targeted delivery of drugs to lymphatic system as in certain case of cancer is possible. Atit Pandey 28

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Reticuloendothelial (RE) System :

Reticuloendothelial (RE) System Comprised of set of mononuclear phagocytic cells which originate from precursors in bone marrow, enter blood stream as monocytes and pass into various tissues where they differentiate into macrophages Macrophages are essential part of defense function An important function of macrophages is to engulf and remove circulating pathogens, tissue debris and damaged macromolecules Atit Pandey 31

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RES is also involved in formation of new R.B.C & W.B.C by destruction of older ones. Since macrophages are concentrated at site of inflammation such as tumors, drug targeting is thus achievable Atit Pandey 32


REFERENCES: Modern Pharmaceutics ( Gilbert s. banker, 4 th edition) Targeted drug delivery system (vyas & khar ) Biopharmaceutics & pharmacokinetics( Brahmankar ) Cell Biology (S.C Rastogi) Anatomy & physiology (k. sambulingam) Atit Pandey 33

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Thank you Atit Pandey 34

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