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Distribution
This document discusses factors that affect drug distribution in the body. It begins by explaining how drugs diffuse from capillaries into interstitial spaces. It then discusses various physiological barriers drugs must cross, including the capillary endothelial barrier, cell membrane barrier, blood-brain barrier, blood-CSF barrier, and blood-placental barrier. The document outlines several factors that influence drug distribution, such as a drug's physicochemical properties, tissue permeability, organ perfusion rates, binding to tissue components, and patient-specific factors like age, pregnancy, and disease states. It also covers concepts of volume of distribution and drug-protein binding interactions.
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Distribution
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- 2. Contents Introduction Tissuepermeability of drugs Barrier to distribution of drugs Factors affecting drug distribution Physico-chemical properties of drugs Volume of distribution Drug-protein binding Factors affecting drug-protein binding Significance of drug protein binding 2
- 3. Introduction Diffusion ofdrug from capillaries to interstitial spaces 3
- 4. Steps in drugdistribution Blood to ECF Capillary wall- rapid ECF to tissue Cell membrane Rate of perfusion Membrane perfusion 4
- 5. Factors affecting drugdistribution Tissue permeability of drug Organ/tissue size and perfusion rate Binding of drug to tissue components Miscellaneous factors 5
- 6. Factors affecting drugdistribution Tissue permeability of drug Physicochemical properties of drug Physiological barriers 6
- 7. Factors affecting drugdistribution Physicochemical properties of drug Capillary membrane Molecular weight < 500 – 600 daltons cross Cell membrane Molecular size < 50 dalton through pores Degree of ionisation- pH of ECF & ICF (7.4), pKa of drug Unionised and lipophilic drug cross cell membrane barrier Phenobarbital and SA same Ko/w but former is ionised less at blood pH shows rapid distribution. Thiopental- lipophilic, unionised- Fast distribution (BBB/Fat Biphasic distribution) Penicillins- polar, water soluble and ionised Systemic Acidosis / Alkalosis (altered distribution of drugs) 7
- 8. Factors affecting drugdistribution Physiological barriers Simple capillary endothelial barrier Simple cell Membrane barrier Blood-brain barrier Blood – CSF barrier Blood-placental barrier Blood-tests barrier 8
- 9. Factors affecting drugdistribution Physiological barriers Simple capillary endothelial barrier Simple cell Membrane barrier 9 Blood ECF ICF Drug size < 50 dD D D D P D D D D D Lipophilic Drug Size 50-500 d Polar/ ionised size > 50 d D Bulk flow Passive Active D + + - Capillary barrier Cell membrane barrier
- 10. Blood Brain Factors affecting drugdistribution Physiological barriers Blood-brain barrier 10 ECF Glial cells Basement Memb. Astrocytes Pericytes Capillary endothelium Tight intercellular Junctions
- 11. Factors affecting drugdistribution Physiological barriers Blood-brain barrier Intanasal drug direct passage to brain Passive diffusion- drugs Active transport - nutrients Thiopental Phenobarbital Penicillin Dopamine- levodopa Different approaches DMSO, osmotic disruption, dihydropyridine redox system 11
- 12. Factors affecting drugdistribution Physiological barriers Blood – CSF barrier 12 Blood CSF Tight Junction Chroid plexus Capillary endothelium ECF
- 13. Factors affecting drugdistribution Physiological barriers Blood-placental barrier 13 Mother Fetus Polar drug Non-polar drug Non-polar drug Polar metabolite Polar metabolite
- 14. Factors affecting drugdistribution Blood-placental barrier Factors Placental blood flow increased delivery of drug to placental membrane Molecular size of drug decreased transfer as size increases impermeable to drugs MW>1000 permeable to drugs MW<600 Lipid solubility of drug increased transfer as lipid solubility increases pKa of drug ion trapping on either side 14
- 15. Factors affecting drugdistribution Permeability rate limited Drug is ionic, polar or water soluble Physiological barriers 15
- 16. Factors affecting drugdistribution Organ/ Tissue Size and perfusion rate Perfusion rate limited Drug highly lipophilic High permeability Rate limited- Blood flow Rate limited- Perfusion to tissue Perfusion rate Volume of blood that flows per unit time per unit volume of the tissue Highly perfused tissue: lung, kidney, liver, heart, brain Moderately perfused tissue: muscles, skin Poorly perfused tissue: Fat, bone 16
- 17. Factors affecting drugdistribution Organ/ Tissue Size and perfusion rate Extent of distribution depend on tissue size Example: Thiopental (biphasic distribution) Initially- Brain Then- fats (adipose tissue) 17
- 18. Factors affecting drugdistribution 18 Tissue Percent Body Weight Percent Car diac Output Blood Flow (ml/100 g tissue/min) Adrenals 0.02 1 550 Kidneys 0.4 24 450 Thyroid 0.04 2 400 Liver 2.3 27 - Hepatic 2.0 5 20 Portal 20 75 Portal-drained viscera 2.0 20 75 Heart (basal) 0.4 4 70 Brain 2.0 15 55 Skin 7.0 5 5 Muscle (basal) 40.0 15 3 Connective tissue 7.0 1 1 Fat 15.0 2 1
- 19. Factors affecting drugdistribution Age Infants TBW and fat is greater Skeleton muscles and albumin content are less BBB poorly developed Elderly Fat is greater Skeleton muscles and albumin content less 19
- 20. Factors affecting drugdistribution Pregnancy Uterus, placenta and foetus increases volume available for distribution Plasma and ECF increased Albumin content decreased Obesity High adipose tissue content- lipophilic drugs distributed well High fatty acid contents- altered binding of acidic drugs Diet Fat increases free fatty acid levels which alters binding of acidic drugs to albumin 20
- 21. Factors affecting drugdistribution Disease state Altered albumin content Altered perfusion rate Altered tissue pH Meningitis increases permeation of polar drugs to brain Drug interactions 21
- 22. Volume of distribution TBW: 42L Volume of distribution Apparent volume of distribution 22
- 23. Protein Binding ofDrugs Phenomenon of complex formation of drug with protein Mechanisms of protein binding Hydrogen bonds Hydrophobic bonds Ionic bonds Van der Wall’s forces 23
- 24. Protein Binding ofDrugs Binding of drugs to blood component Plasma protein- drug binding Blood cell- drug binding 24
- 25. Protein Binding ofDrugs Binding of drugs to blood component Plasma protein- drug binding Albumin > alpha acid glycoproteins > lipoproteins > globilins Binding of drug to HSA Molecular Wt – 65000 Concentration- 3.5 to 5 g% Variety of drugs bind to albumin Endogenous material like – fatty acids, bilirubin, tryptophans Four binding Sites Site I (Warfarin)- NSAIDS, Phenytoin, bilirubin, Sodium valproate 25
- 26. Protein Binding ofDrugs Binding of drugs to blood component Plasma protein- drug binding Binding of drug to HSA Four binding Sites Site I (Warfarin)- NSAIDS, Phenytoin, bilirubin, Sodium valproate, etc Site II (diazepam)- ibuprofen, tryptophan, ketoprofen, etc Site III (digitoxin) Site IV (tamoxifen) 26
- 27. Protein Binding ofDrugs Binding of drugs to blood component Plasma protein- drug binding Binding of drug to AAG Molecular Wt- 44000 Concentration- 0.44 to 0.1 g% Basic drugs: Imipramine, lidocaine, amitriptyline, etc. 27
- 28. Protein Binding ofDrugs Binding of drugs to blood component Plasma protein- drug binding Binding of drug to Lipoproteins Molecular Wt- 200000 to 3400000 Concentration- variable Basic lipophilic drugs: Chlorpromazine etc. 28
- 29. Protein Binding ofDrugs Binding of drugs to blood component Plasma protein- drug binding Binding of drug to Globulins Alpha 1 globulin: transcortin Steroids Alpha 2 globulin: ceruloplasmin Vitamin A, D, E, K and cupric ions Beta 1 globulin: transferrin Ferrous ions Beta 2 globulin Carotinoids Gamma globulin Antigens 29
- 30. Protein Binding ofDrugs Binding of drugs to blood component Binding of drug to blood cells RBC (95%) components: Hemoglobin MW- 64500, Concentration 21 to 15 g% Phenytoin, pentobarbital, phenothiazines Carbonic anhydrase Acetazolamide, chlorthalidone Cell membrane Imipramine, chlorpromazine 33
- 31. Protein Binding ofDrugs Binding of drugs to tissues Tissue binding increases apparent Vd Tissue binding increases biological half life of drug Factors affecting tissue binding Lipophilicity Structure of drug Perfusion rate pH difference 34
- 32. Protein Binding ofDrugs Binding of drugs to tissues Liver: Paracetamol- hepatotoxicity Lungs: imipramine, chlorpromazine Kidney: Matallothionin (protein) bind to heavy metals Skin: Melanin- chloroquine, phenothiazines Eyes: Melanin- chloroquine, phenothiazines- retinopathy Hairs: Arsenicals, chloroquine, phenothiazines Bones: Tetracyclines Fats: Lipophilic drugs Nucleic Acids: chloroquine and quinacrine 35
- 33. Protein Binding ofDrugs 36 Parameter Protein- drug binding Tissue- drug binding Binding Weak bonds & thus reversible Covalent bonds & thus irreversible Vd Small Large Half Life Short Long Toxicity No Common DI Displacement No Binding Competitive Non Competitive
- 34. Factors affecting drug-Protein binding Drug related Physicochemical characters of drug Concentration of drug in body Drug binding affinity towards binding component Protein/ tissue Physicochemical characters of protein or binding agent Concentration of protein in body Number of binding sites on binding agent Drug interactions Patient 37
- 35. Factors affecting drug-Protein binding Drug related Protein/ tissue Drug interactions Competition between drugs for the binding sites Competition between drugs and normal body constituents for the binding sites Allosteric changes in protein molecules Patient Age Inter-subject variation Disease state 38
- 36. Factors affecting drug-Protein binding Drug related Physicochemical characters of drug Lipophilicity- localized in tissues Thiopental- adipose tissues Acidic drugs- HAS Penicillins, sulphonamides Basic drugs- AAG Imipramine Neutral, unionised- lipoproteins 39
- 37. Factors affecting drug-Protein binding Drug related Concentration of drug in body Therapeutic concentration of lidocaine can saturate AAG Drug concentration unable to saturate HSA Drug binding affinity towards binding component Lidocaine has greater affinity for AAG than for HAS Digoxin- protein of cardiac muscles Iophenoxic acid- plasma proteins (t1/2 2.5 years) 40
- 38. Factors affecting drug-Protein binding Protein/ tissue Physicochemical characters of protein or binding agent Lipoproteins and adipose tissue bind to lipophilic drugs Concentration of protein in body Albumin high percent Number of binding sites on binding agent Albumin-Four binding sites 41
- 39. Factors affecting drug-Protein binding Drug interactions Competition between drugs for the binding sites Warfarin + Phenylbutazone Competition between drugs and normal body constituents for the binding sites Free fatty acids- drugs- HSA Bilirubin - HSA Allosteric changes in protein molecules 42
- 40. Factors affecting drug-Protein binding Patient Related factors Age Neonates: Low albumin content Young infants: Greater binding Elderly: Low albumin content, High levels of AAG Inter-subject variation Disease states Hypoalbuminaemia: aging, CCF, trauma, burns, inflammatory states, renal and hepatic disorders, pregnancy, surgery, etc Hyperlipoproteinaemia: hypothyroidiosm, obstructive liver disease, alcoholism etc 43
- 41. Factors affecting drug-Protein binding Disease States Conditions Change in concentration Albumin hepatic cirrhosis burns nephritic syndrome pregnancy a-glycoprotein myocardial infarcts surgery trauma rheumatoid arthritis 44
- 42. Significance of Proteinbinding Patient Related Factors Absorption Systemic solubility of drugs Distribution Tissue binding Elimination Displacement interactions and toxicity Diagnosis Therapy and drug tageting 45
- 43. Bibliography D. M.Bramhankar and S. B. Jaiswal. Biopharmaceutics and Pharmacokinetics A Treatise. Delhi;Vallabh Prakashan. 2010 Jambhekar SS, Breen PJ. Basic Pharmacokinetics. London; Pharmaceutical Press. 2009. Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics and Pharmacokinetics. McGraw Hill. 2007. 46