UNIT 2. Drug Distribution. S. SANGEETHA., M.PHARM., (Ph.d) Department of Pharmaceutics SRM College of Pharmacy SRM University
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1 UNIT 2 Drug Distribution S. SANGEETHA., M.PHARM., (Ph.d) Department of Pharmaceutics SRM College of Pharmacy SRM University
2 Contents Definition Factors affecting drug distribution a) Tissue permeability of the drug b) Organ/tissue size and perfusion rate c) Binding of drugs to tissue components d) Miscellaneous Volume of distribution Significance One compartment open model Non compartment method References
3 Definition Drug distribution is defined as the reversible transfer of drug between one compartment(blood) and another (extra vascular tissue)
4 Steps in drug distribution Permeation of free drug through capillary wall & entry in to ECF. Permeation of drugs from ECF to ICF through membrane of tissue cell. Rate limiting steps Rate of perfusion to the ECF Membrane permeability of the drug
5 Factors affecting distribution of drugs 1. Tissue permeability of drugs 2. Organ tissue size and perfusion rate 3. Binding of drug to tissue component. 4. Miscellaneous
6 Tissue permeability of drugs Physicochemical properties of the drug molecular size, pka and o/w partition co efficient. Physiological barrier to diffusion Simple capillary endothelial barrier Simple cell membrane barrier Blood Brain Barrier Blood CSF barrier Blood placental barrier blood testis barrier
7 Physicochemical properties of the drug: Molecular size: < d easily cross capillary membrane, water soluble molecules & ions of size < 50 d pass through aq. Filled channels. pka : ph of blood & ECF (7.4) play a role in degree of ionization, unionized drug diffuse rapidly. o/w partition co efficient: lipoidal drug penetrate the tissue rapidly. Among Drugs with same K0/w but diff in ionization of blood ph. The one which has less ionization show better distribution. E.g. Phenobarbital > salicylic acid
8 Physiological barrier to the diffusion: Simple capillary endothelial barrier: drugs with molecular size < 600 d easily diffuse. The simple cell membrane barrier : it is similar to the lipoidal barrier in the GI absorption of the drugs. B.B.B: highly specialized and less permeable to water soluble drugs. Brain capillary consist of endothelial cells which are joined one another by continuous tight intercellular junctions. Pericytes & astrocytes form a solid envelop around brain capillary & block intercellular passage.
9 Physiological barrier to the diffusion: A solute may enter to brain via: 1. Passive diffusion through the lipoidal barrier 2. Active transport of essential nutrients BBB crossing can be promoted by: 1. Use of permeation enhancer like DMSO. 2. Osmotic disruption of the BBB by infusing internal carotid artery with Mannitol 3. Use of dihydropyridine redox system as a drug carriers
10 Physiological barrier to the diffusion: Blood cerebrospinal fluid barrier: formed by the choroid plexus of the lateral, third & fourth ventricles. It is similar to ECF of brain. The capillary endothelium that line choroid plexus have open junctions or gaps and drugs can flow freely. The choroid cells are joined to each other by tight junctions forming the blood CSF barrier which has permeability characteristic similar to BBB. For any given drug, its conc in brain > in the CSF.
11 Physiological barrier to the diffusion: Blood placental barrier: The maternal & fetal blood vessels are separated by a number of tissue layers made of fetal trophoblast basement membrane &endothelium which together constitute the placental barrier. Drugs having molecular size less than 1000 d and moderate lipid solubility cross the placental barrier. E.g. ethanol, sulphonamide, barbiturate, Narcotic analgesic, anticonvulsant etc.
12 Physiological barrier to the diffusion: Blood testis barrier: Located not at the capillary endothelium level but at the sertoli sertoli cell junction. It is tight junction between neighboring sertoli cells that act as barrier. It restrict the passage of drugs to spermatocyte and spermatids.
13 Organ/Tissue size & perfusion rate Distribution is permeability related in following cases When the drug is ionic/polar/water soluble Where the highly selective physiology barrier restrict the diffusion of such drugs to the inside of cell. Distribution bill be perfusion rate limited When the drug is highly lipohilic When the membrane is highly permeable.
14 Perfusion rate : it is defined as the volume of the blood that flows per unit time per unit volume of the tissue. Unit: ml/min/ml Kt = perfusion rate / Kt/b Distribution half life = 0.693/Kt =0.693Kt/b/perfusion rate
15 Binding of drug to tissue components Binding of drugs to blood components o Blood cells o Plasma proteins Binding of drugs to extra vascular tissues
16 Binding of drugs to blood cells The major component of blood is RBC The RBC comprises of 3 components each of which can bind to drugs: hemoglobin carbonic anhydrase cell membrane
17 Binding of drugs to plasma proteins Plasma protein drug binding: The binding of drug to plasma protein is reversible The extent or order of binding of drugs to various plasma proteins is: Albumin >α 1 Acid Glycoprotein> Lipoproteins > Globulins
18 Binding of drug to Human serum Albumin: Most abundant plasma protein with large drug binding capacity Both endogenous compounds and drugs bind to HSA Four different sites on HSA: Site I: warfarin and azapropazone binding site Site II: diazepam binding site Site III: digitoxin binding site Site IV: tamoxifen binding site
19 Binding of dugs to α 1 Acid Glycoprotein: it binds to basic drugs like imipramine, amitryptyline, lidocaine Binding of dugs to lipoproteins: a drug that binds to lipoproteins does so by dissolving in the lipid core of the protein and thus its capacity to bind depends upon its lipid content. binding of drugs to lipoproteins is non competitive
20 Miscellaneous factors Age: a) Total body water b) Fat content c) Skeletal muscles d) Organ composition e) Plasma protein content Pregnancy Obesity Diet Disease states
21 Volume of distribution The apparent volume of distribution is a proportionality constant relating the plasma concentration to the total amount of drug in the body. XαC X=Vd.C Vd=X/C Apparent volume =amount of drug in the body/ of distribution plasma drug concentration
22 Significance Apparent volume of distribution is dependent on concentration of drug in plasma. Drugs with a large apparent volume are more concentrated in extra vascular tissues and less concentrated intravascular. In certain pathological cases, the Vd for the drug may be altered if the distribution of the drug is changed.
23 One compartmental open model Vd=X/C Vd=X 0 /C o =i.v.bolus dose/concentration of drug in plasma
24 Non compartmental method for drugs given as i.v. bolus: Vd (area) =X0/K E (AUC) For drugs administered extravascularly: Vd (area) = FXo/K E (AUC)
25 References Applied biopharmaceutics and pharmacokinetics by Leon Shargel Clinical biopharmaceutics and pharmacokinetics by Gibaldi biopharmaceutics and pharmacokinetics by Brahmankar
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