INTRO & chapt 1 vMECHANISM OF ABSORPTION.pptx

biopharmaceutics chapt 1

1. U The p r o c e ss ad m i n i s tr a t ion The movement of drug between one compartment and the other (generally blood and the extravascular tissues) is referred to as drug distribution . INT R O D C TI O N Biopharmaceutics is defined as the study of factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimise the therapeutic efficacy of the drug products. Bioavailability is defined as the rate and extent (amount) of drug absorption. Any alteration in the drug’s bioavailability is reflected in its pharmacological effects. of m o v e m e n t of d r ug f r om its s i te of to s y s t e m ic circulationis called as absorption.

2. to s u it m axi m u m t h erap e ut i c Elimination is defined as the process that tends to remove the drug from the body and terminate its action. Elimination occurs by two processes— biotransformation (metabolism), which usually inactivates the drug, and excretion which is responsible for the exit of drug/metabolites from the body. Pharmacokinetics is defined as the study of time course of drug ADME and their relationship with its therapeutic and toxic effects of the drug The use of pharmacokinetic princi les in optimising the drug i nd i v i d u al pat i e n t dosage a c h i ev i ng utility is clinical pharmacokinetics.

3. h Absorption : Process by which drug enters the body . Absorption : is the process of movement of unchanged drug from the site of administration to systemic circulation . Distribution : Dispersion of drugs throug out the fluids and tissues of the body. Metabolism : Irreversible transformation of parent drug compounds into daughter metabolites. Excretion: Elimination of drug metabolites from the body.

4. Plots showing significance of rate and extent of absorption in drug therapy LastBenchPharmacist.blogspot.com Absorption Gastrointestinal Absorption Of Drugs Drug absorption - process of movement of unchanged drug from the site of administration to systemic circulation. Process of movement of unchanged drug f om the site of administration to the site of measurement i.e. plasma.

5. Me c h a n is m s of Dru g Abs o r p ti on 9 There th r ee bro a d ca t ego r i e s a r e T r a n sce ll u l a r / intracel l ula r tr a nsp o rt Pas s ive T r a n s p o r t P r ocess e s Pa s siv e diff u sion P o r e tr a nsp o rt I o n- p a ir tr a nsp o rt Faci l ita t ed or med i a t ed dif f usion Ac t ive tr a nsp o rt p r o ces s es Primary Secondary S y mp o rt ( Co- tr a n s por t ) A n tip o rt ( Co un t er tr a nsp o rt) Paracellular / IntercellularTransport Permeation through tight junctions of epithelialcells Persorption V es i cu l a r o r C o rpuscular T r a n s p o r t (End o cy to si s ) Pinocytosis Phagocytosis

6. d T h e th re e b r o a d ca t e go r i e s ar e 1 . T ransc e l lular / i ntrace l lular t r a n sp o rt : is defined as the passage of drugs across the GI epithelium. 3 steps involve Permeation of GI epithelial cell membrane Movement across the intracellular space (cytosol). Permeation of the lateral or basolateral membrane. T h e var i o u s t r ans c e l lul a r t r ansp o r t pr o c e s se s in v ol v ed A. Passive Transport Processes – Not require energy Further classified into following types – Passive diffusion. Pore transport. Ion-pair transport. Facilitated- or mediated-diffusion. in dr u g absorption a r e – 1

7. Mechanism of D s T r a n s c e l l u l a r / I n t r a C ell u l ar T r a n s po r t Passive T r an s p o rt Process Active T r ans p ort Process Permeation t h r ough Tig h t Junctions of Epi t he l ial Cel l s D ru g Abs o rpt ion Mechani s m of Drug Absorption Paracellular / Intercellular Transport V e s i cu la r T r a n s p or t / Endocytosis Persorption Pinocytosis Phagocytosis

8. T P ass i v e Dif f usion P o r e T r a n s p o r t Primary Active Transport P ass i v e r a n s p o r t Process I o n - P a i r T r a n s p o r t F aci l i t a t ed Diffusion S e c onda r y Acti v e T r a n s p o r t S y m port Antiport

9. P as s i v e dif f usi o n Characteristics Common Occurs along concentration gradient Non selective Not saturable Requires no energy No carrier is needed Depends on lipid solubility Depends pka of drug - pH of medium

10. Passive diffusion is best expressed by Fick’s first law of diffusion The drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained & the rate of diffusion is dir e c t l y p r o p o r ti o n a l c o n ce nt r a t i o n g ra di e n t membrane . t o th e acr o s s the dQ dt = D A K m/w h (C git – C)

11. m u dQ/dt = rate of drug diffusion (a ount/time) D = diffusion coefficient of the dr g A= surface area of the absorbing membrane for drug diffusion K m/w = partition coefficient of drug between the lipoidal membrane & the aqueous GI fluids (C GIT – C) = difference in the concentration of drug in the GI fluids & the plasma (Concentration Gradient) h = thickness of the membrane

12. e larger volume of body fluids Hence, The concentration of drug at absorption sit concentration in the plasma The passively absorbed drug enters blood, rapidly swept away & distributed into a C GIT is maintained greater than the Such a condition is called as sink condition for drug absorption. Under usual absorption conditions, D, A, K m/w & h are constants, the term DAK m/w /h can be replaced by a combined t h r o ug h a constant P called as permeability coefficien Permeability - ease with which a drug can permeate or diffuse membrane. Due to sink conditions, the C is very small in comparison to C GIT. Equation II is an expression for a first order process. Thus, passive diffusion follows first order kinetics

13. u w y Pore Transport □ It is also called as convective transport , b lk flow or filtration . □ The driving force is hydrostatic pressure or the osmotic d i f fere n c e s a c ross the membrane. □ The process is important in the absorption of low molecular weight (less than 100), generally water-soluble drugs through narro , aqueous-filled channels ex: urea, water and sugars. □ Chain-like or linear compounds of molecular weight up to 400 Daltons can be absorbed by filtration. For example , the straight- chain alkanes. □ Drug permeation through water-filled channels is importance in renal excretion, removal of drug from the cerebrospinal fluid and entr of drugs into the liver.

14. a n = d c N. R 2 . A . ∆C dt (η) (h) e  Pore tr nsport It involves the passage of ions through Aq. Pores (4-40 A ) Absorption of low mol. Wt. (less than 100), Low molecular size (smaller than the diameter of the pore) & generally water-soluble drugs through narrow, aqueous filled channels or pores in the membrane structure e.g. urea, water & sugars Hydrostatic or the osmotic pressure differe ce is the driving force The rate of absorption via pore transport depends on the number & size of the pores, & given as follows: wher , dc = rate of the absorption. d t N = numb e r o f p o r e s , R = r a diu s o f p o r e s ∆C = concentration gradient, η = viscosity of fluid in the pores

15. I o n-P ai r T m s ransport □ Absorption of drugs like quaternary ammonium compounds (Examples are benzalkonium chloride, benzethoniu chloride) and sulphonic acids ( sulfonic acid ), w h i c h io n i s e u n der a l l pH co nd i t ion , is io n - p a i r t r ansp o r t . □ Despite their low o/w partition coefficient values, such agents penetrate the membrane by forming reversible neutral complexes with endogenous ions of the GIT like mucin. □ Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. Such a phenomenon is called as ion-pair transport . □ Propranolol, a basic drug that forms an ion pair with oleic acid, is absorbed by this mechanism.

16. Ion-pair transport of a cationic drug

17. R It is another absorption of condition. e ION P A I R T A NSP O R T m e ch a nis m i s a b le t o e x pla i n the su ch dru gs wh i c h ioni z e a t all pH Transport of charged molecules due to the formation of a neutral complex with another charg d molecule carrying an opposite charge. Drugs have low o/w partition coefficient values, yet these penetrate the membrane by forming reversible neutral complexes with endogenous ions. e.g. mucin of GIT. Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. .

18. d o Facilitate Diffusion / Carrier-Mediated Transport □ It is a carrier-mediated transport system that operates down the concentration gradient ( downhill transport ) but at a much a faster rate than can be accounted by simple passive diffusion. The driving force is concentrati n gradient (hence a passive process). Since no energy expenditure is involved, the process is not inhibited by metabolic poisons that interfere with energy production.

19. d □ Since the system is structure-specific, rugs having structure similar to essential nutrients, called as false nutrients , are absorbed by the same carrier system.

20. e m Carrier-Mediated Transport □ Some polar drugs cross the membrane more readily than can be predicted from their concentration gradient and partition coefficient values. Like monosaccharides, amino acids and vitamins will be poorly absorbed. □ The mechanism is involved is carrier that binds reversibly or non-covalently with the solute molecules to be transported. This carrier-solute complex traverses across the membrane to the other side where it dissociates and discharges the solute molecule. □ The carrier then returns to its original sit to complete the cycle by accepting a fresh molecule of solute. Carriers in membranes are proteins (transport proteins) and may be an enzyme or some other component of the me brane.

21. B. Active Transport Processes This transport process req u ires energy in the f o r m of ATP to move dru g molecules from extracellular to intracellular . The s e a r e o f t w o types – □ Primary active transport □ Secondary active transport – this process is further subdivided into two – Symport (co-transport) Antiport ( counter-transport) The rate of absorption by active transport can be determined by applying the equation used for Michaelis - Menten kinetics: d c [C]. ( d c/d t ) m a x dt Km + [C]

22. Active Transport = d c [C]. ( d c/ d t ) m a x dt Km + [C] h M o r e i m p o r t a n t p r o ce s s than f ac ili t a t e d di f fusi o n The driving force is against the concentration gradient or uphill transport Energy is required in the work done by the barrier It can be inhibited by metabolic poisons that interfere with energy production A good example of competitive inhibition of drug absorption via active transport is the impaired absorption of levodopa when ingested with meals rich in proteins The rate of absorption by active transport can be determined by applying the equation used for Michaelis- Menten kinetics: K m = affinity constant of drug for t e barrier.

23. A c tive T ra n s p or t □ Thi s transport mechanism requires energy in the form ATP.Active tranport mechanisms are further subdivided into - □ Primary active transport – In this process, there is direct ATP requirement. Moreover, the process transfers only one ion or molecule and in only one direction, and hence called as uniporter e.g. absorption of glucose . 2 types of carrier protein are involve Ion transporters: i. organic anion ii. organic cation ABC transporters □ Secondary active transport – In these processes, there is no direct requirement of ATP i.e. it takes advantage of previously existing concentration gradient. The energy required in transporting an ion aids transport of another ion or molecule (co-transport or coupled transport) either in the same direction or in the opposite direction. Accordingly this process is further subdivided into – □ symport (co-transport ) – involves movement of both molecules in the same direction e.g. Na + -glucose symporter □ Antiport (counter-transport) – involves movement of molecules in the opposite direction e.g. H + ions using the Na + gradient in the kidneys.

24. m La s tBe n ch P harmaci s t.blogs p ot. c o

25. o h Paracellular/Intercellular Transport is defined as the tra nsport of drugs through the jun ctions between the GI epithelial cells . This pathway is of min r importance in drug absorption. The two paracellular transport mechanisms involved in drug absorption are – □ Permeation through tight junctions of epithelial cells – this process basically occurs through openings which are little bigger t an the aqueous pores. Compounds such as insulin and cardiac glycosides are taken up this mechanism. □ Persorption – is permeation of drug through temporary openings formed by shedding of two neighbouring epithelial cells into the lumen.

26. Endocytosis c It involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle ( corpuscular or vesicular transport ) which is then pinched off intracellularly. In endocytosis, there are three process : Phagocytosis Pino ytosis Transcytosis Vesicular/ Corpuscular Transport

27. Phagocytosis s Cell eating : adsorptive uptake of solid particulates Pinocytosis Cell Drinking : uptake of fluid solute Important in the aborption of oil soluble vitamins & in the uptake of nutrients. Transcytosis It is a phenomenon in which endocytic ve icle is transferred from one extracellular compartment to another

28. m S u m a r y The biological membranes pose a significant barrier to drug delivery The fluid mosaic model describes the plasma membrane as a flexible boundary of a cell Passive diffusion is best expressed by Fick’s first law of diffusion Pore transport involves the passage of ions through Aq. Pores (4-40 A ) Carrier mediated transport involves both active and facilitated diffusion

29. Passive transport Along co n ce nt r a t i o n gradient (From high to low) No c a rriers Not selective N o t sa tu r a b l e No energy Active transport Against concentration gradient (From low to high) Needs carriers Selective, saturable Energy is required

30. Active transport Carrier-mediated f ac ili t a t e d d i ff u sion Against concentration gradient (From low to high) Along concentration gradient (From high to low) NO Needs carriers Needs carriers Selective, saturable Selective, saturable Energy is required No energy is required