Pharmacokinetics : Drug Distribution -Dr Rahul Kunkulol's Power point preparations

Dr Rahul Kunkulol's Power point preparations

1. ADME

2. Distribution Dr. Rahul Kunkulol Asso. Professor Dept. of pharmacology RMC, Loni

3. Distribution The process by which the drug reversibly leaves the site of administration and is distributed through out the tissues of the body. 28 litres 10 lit 4 lit

4. Volume of Distribution Volume into which a drug appears to distribute with a concentration equal to its plasma concentration

5. Drugs appear to distribute in the body as if it were a single compartment. The magnitude of the drug’s distribution is given by the apparent volume of distribution ( V d ). Vd = Amount of drug in body ÷ Conc. in Plasma PRINCIPLE (Apparent) Volume of Distribution: Volume into which a drug appears to distribute with a concentration equal to its plasma concentration

6. Importance If drug does not cross capillary wall its Vd is equal to plasma i.e. approx. 3L Drugs with high PP binding less Vd and vice versa Vd more than body volume means drugs are widely distributed

7. Importance aVolume of distribution ( aVd ) Retention Examples < 5 L Vascular compartment Heparin, Insulin, Warrfarin Aprox.15 L Extracellular compartment Aspirin, Tolbutamide >20 L Throughout the body Or Penetration in various tissues Ethanol , Phenytoin, Digoxin, Phenobarb , Morphine

8. Reservoirs for drugs Plasma proteins Cellular reservoir Fat as reservoir Transcellular fluids Bones

9. Reservoirs for drugs Reservoirs Details Example Cellular High affinity for tissue proteins (lipoproteins or nucleoproteins) Skeletal muscles, heart Thyroid Liver Digoxin Iodine Chloroquine Fats Highly lipid soluble drugs Thiopentone sodium Transcellular Aqueous humor Joint fluid Chloramphenicol Ampicillin Bones - Tetracyclines , calcium

10. Plasma Protein Binding Plasma consists of ~ 90% water, ~ 8% plasma proteins ~2% other organic or inorganic species . Many drugs bind to the plasma proteins as they have low water solubility . Plasma protein binding limits distribution.

11. Plasma Protein Binding A drug that binds plasma protein diffuses less efficiently, than a drug that doesn’t. Albumin provides most of the available ‘sites’ for absorption, particularly of acidic drugs . Warrfarin , Sulphonamides, Penicillins  -globulin and an acid glycoprotein can can become important in binding basic drugs . Quinine, Imipramine, Lidocaine

12. Clinical importance Highly protein bound drugs low Vd Highly protein bound drugs are difficult to remove by dialysis PPB is capacity limited and saturable process. Example: Liver diseases, ureaemia : Hypoalbuminemia --therapeutic dose may become toxic More than one drug can bind to the same site on albumin and can lead to displacement interactions.

13. Protein Binding Drug Displacement Plasma Tissue Drug A protein bound Drug A free Drug A free Drug B Drugs A and B both bind to the same plasma protein

14. 100-fold increase in free pharmacologically active concentration at site of action. NON-TOXIC TOXIC Alter plasma binding of chemicals 1000 molecules % bound molecules free 99.9 90.0 100 1

15. 17 Displacement interaction and toxicity Displacement Interactions Drug A Drug B % DRUG BEFORE DISPLACEMENT BOUND FREE 99 1 90 10 % DRUG AFTER DISPLACEMENT BOUND FREE 9 8 2 89 11 % INCREASE IN FREE DRUG CONCENTRATION 100 10 Interaction is significant if drug bind more than 95%

16. Protein Binding Interactions Importance has been over emphasized. Most interactions can be better explained by other mechanisms Increased availability of free drug which is displaced from plasma proteins, but compensatory mechanisms maintain free drug concentration Only important in interpretation of total drug concentrations e.g. phenytoin / VPA

17. Physiological barriers to drug distribution Blood brain barrier Blood CSF barrier Placental barrier

18. Blood Brain Barrier characteristics : 1. No pores in endothelial membrane 2. Transporter in endothelial cells 3. Glial cells surround endothelial cells 4. Less protein concentration in interstitial fluid

19. Distribution Extent depends on Blood flow Size, M.W. Of molecule Lipid solubility and ionization Plasma protein binding Tissue binding