Drug distribution -Pharmacology class for second year MBBS students

Pharmacology and Toxicology- ppt related to drug distribution

1. Dr. Ravi Mundugaru Associat e Professor Dept. of Pharmacology AIMS, BG Nagara Drug distribution

2. Pharmacokinetics (PK) Excretion Movement of Drug in, through and out of the body

3. Brain Rest of the body tissues

4. Total body composition (70kg man) Total body fluid (42L ) Intracellular fluid (28L) + Extra cellular Fluid (14L) Plasma (4-5L) + Interstitial fluid (8-10L)

5. Drug Distribution Drug Distribution is defined as the Reversible transfer of drug between one compartment (blood) to another (extra vascular tissue like fat, muscles and brain) Movement of drug from the central compartment (blood) to peripheral compartments (tissues) where the drug is present.

6. Factors influencing the drug distribution lipid solubility , I onization, Molecular size , binding to plasma proteins , tissue proteins rate of blood flow and special barriers

7. Physiological barriers Capillary endothelial barriers Blood brain barrier Placental barrier

8. Physiological barriers C apillary endothelial barrier Capillaries supply the blood to the most inner tissue All drugs ionized or unionized, molecular size less than 600D diffuse through the capillary endothelium to interstitial fluid Only drugs that bound to that blood components can’t pass through this barrier because of larger size

9. Biological membrane structure

10. Efflux transporters like P- gp and OATP, MAO, Cholinesterase enzymes present in BBB Inflammation of meninges - permeability

11. Placental Barrier

12. The Placental barrier

13. Role of plasma proteins in drug distribution

14. Clinical relevance of Plasma protein binding Most drugs possess physiochemical affinity for plasma proteins and get reversibly bound to these. Albumin (only acidic drugs) - Barbiturates, Benzodiazepines, NSAIDs, warfarin , tetracycline's, Phenytoin, Penicillins α- Acid glycoprotein (only basic drugs ) - Lignocaine, Propranolol, prazosin , methadone, Quinidine, varapamil

15. Importance of Plasma proteins Extent of protein binding depends on the individual compounds and its chemical structure Example: Percentage binding to Albumin by Benzodiazepines Flurazepam (10%) Alprazolam (70%) Lorazepam (90%) Diazepam ( 99%)

16. Importance of Plasma proteins Increasing concentration of the drug can progressively saturate the protein binding sites;

17. Importance of Plasma proteins Highly plasma protein bound drugs are largely restricted to the vascular compartment. Bound fraction of drugs are not available for action. ( Temporary storage of drugs) High degree of protein binding generally makes the drug long acting ( Because bound form not available for metabolism and excretion ) - Poison condition cannot remove by hemodialysis

18. Importance of Plasma proteins One drug can bind to many site on the albumin molecule. Conversely more than one drug can be bind to the same site of albumin. Leads to displacement interaction Hypoalbuminemia binding capacity is reduced – Increased concentration of free drugs – Toxicity Ex: Phenytoin and T oresemide ( Ex: Pregnancy- Propranolol binding increased and in Acute inflammation – α - Acid glycoprotein increases )

19. Perfusion rate T he volume of blood that flows per unit time per unit volume of the tissue (ml/min/ml) Perfusion rate - limited when -Drug is highly lipophilic - Membrane across which the drug is supposed to diffuse Above both the cases Greater the blood flow , Faster the distribution

20. Apparent volume of distribution (V) 1000mg of drug is injected i.v. produces steady state plasma concentration of 50mg/L, apparent volume of distribution is 20L

21. Drugs with various Volume of distribution Warfarin - 0.15L/kg - for 70 kg person = 10.5L Diclofenac - 0.15L/Kg Streptomycine - 0.25L/kg = 17.5 L Gentamycine – 0.25L/kg Digoxin - 6L/kg = 420L Morphine – 3.5L/kg = 245L

22. Tissue storage Drugs also accumulate in the specific organs by active transportation or get bound to specific tissue proteins Larger volume of distribution and longer duration of action Some drugs may exert local toxicity Ex : Tetracycline in Bone and teeth Chloroquine in retina Streptomycin in vestibular apparatus Some drugs specifically binds to cell organelles Tetracycline's to mitochondria, Chloroquine to nuclei

23. Factors governing volume of drug distribution Lipid water partition coefficient of the drug pH of different regions of the body and pKa value of the drug Degree of plasma protein binding Affinity for different tissues Fat : lean body mass ratio, Which can vary with age, sex obesity Diseases like CHF, uremia, cirrhosis

24. Problem directed study A 60 Y old woman complained of weakness, lethargy and easy fatigability. Investigation showed that she had iron deficiency anemia ( Hb 8g/dl). She was prescribed capsule ferrous fumerate 300mg/twice daily. She returned after one month with no improvement in symptoms. Her Hb level was unchanged. On enquiry she revealed that she felt Epigastric distress after taking the iron capsules and had started taking antacid tablets (to prevent gastritis) along with the capsules. What could be the possible reasons for her failure to respond to the oral iron medication?