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Drug Distribution:

Drug Distribution Dr.S.P.Dhanya Assistant Professor Dept of Pharmacology Govt TDMC

Drug disposition:

Drug disposition Distribution- reversible transfer of a drug between compartments. Elimination- irreversible loss of drug from the body. It comprises of biotransformation and excretion.

Distribution:

Distribution Scatter of drugs Delivery of drugs from the systemic circulation to the site of action

Factors affecting drug distribution:

Factors affecting drug distribution Lipid solubility Ionization Plasma protein binding Regional blood flow Fat : lean body mass ratio Disease

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Tissue Permeability of the Drug Physiochemical Properties of the drug like Molecular size, pKa and o/w Partition coefficient. Physiological Barriers to Diffusion of Drugs. Organ / Tissue Size and Perfusion Rate Binding of Drugs to Tissue Components Miscellaneous Factors Age, Pregnancy, Obesity, Diet, Disease states, and Drug Interactions

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Drug Distribution refers to the Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (for example, fat, muscle, and brain tissue)

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Passive Process driving force Concentration Gradient between the blood and Extravascular Tissues Diffusion of Free Drug until equilibrium

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LMW HYDROPHILIC Mannitol Gentaimicin

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HMW protein bound Insulin , heparin , warfarin

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LMW hydrophobic Digoxin Propranolol Morphine

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Vd equal to total water Ethanol, Alfentanyl Vd more than total water Drugs that bind strongly to tissues Fentanyl Propofol Digoxin

Aqueous humor:

Aqueous humor Chloramphenicol Prednisolone CSF - Aminosugars , sucrose Joint fluid -Ampicillin

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Albumin Large variety of drug,acidic α1 - a cid glycoprotein Basic drug - propranolol , imipramine lignocaine Lipoproteins Basic lipophilic drug chlorpromazine α 1 globulin α 2 globulin Steroid , thyroxine Cynocobalamine Vit . –A,D,E,K Plasma protein binding

Plasma Protein Binding :

Plasma Protein Binding Site 1 Site 2 Site 3 site4 Warfarin binding site Diazepam binding site Digitoxin binding site Tamoxifen binding site

Clinical importance:

Clinical importance Restricted Not available high PPB - not removed by haemodialysis Acts as a store Long acting Total- bound/unbound

One drug can bind to many sites many drugs can bind to same site :

One drug can bind to many sites many drugs can bind to same site A A B A

Displacement reactions:

Displacement reactions Competition If one of the drug (A) is bound to a site , then administration of the another drug (B) having high affinity for same binding site result in displacement of drugs (A) from its binding site interaction is known as displacement interaction .drug (A) - displaced drug drug (B) as the displacer

Displacement :

Displacement Site 1 Site 2 Site 3 site4 Indomethacin Salicylate Phenylbutazone tolbutamide Warfarin BLEEDING

Displacement :

Displacement Site 1 Site 2 Site 3 site4 Salicylate Phenylbutazone tolbutamide HYPOGLYCEMIA

Displacement :

Displacement Site 1 Site 2 Site 3 site4 Sulfonamide Vitamin K bilirubin kernicterus

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Age - Neonate – albumin content is low -increase conc. of free drug eg . Phenytoin , diazepam Elderly albumin content is lowered In old age acid glycoprotein level is increased

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Disease Influence on plasma protein Influence on protein drug binding Renal failure (uremia) albumin Decrease binding of acidic drug Hepatic failure albumin Decrease binding of acidic drug Inflammatory state (trauma , burn, infection ) AAG Increase binding of basic drug

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% Drug A Drug B BEFORE BOUND FREE 99 1 90 10 AFTER BOUND FREE 9 8 2 89 11 INCREASE IN FREE DRUG 100 10

Tissue binding of drug:

Tissue binding of drug Liver- Chloroquine,Digoxin Heart- Digoxin,Amiodarone Kidney- Chloroquine,Digoxin Retina- Chloroquine Bone and teeth- Tetracycline,Bisphosphonates Adipose tissue- Thiopentone

:

Physiological barrier to diffusion Simple capillary endothelial barrier Simple cell membrane barrier Blood Brain Barrier Blood –CSF barrier Blood placental barrier blood testis barrier

B.B.B :

B.B.B highly specialized less permeable to water soluble drugs Brain capillary - endothelial cells - continuous tight intercellular junctions. Pericytes & astrocytes -solid envelop around brain capillary & block intercellular passage.

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L L H H

A solute may enter to brain via: :

A solute may enter to brain via: Passive diffusion through the lipoidal barrier Active transport of essential nutrients

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Only lipid soluble unionized drugs can pass through BBB. Eg : diazepam Inflammation of meninges & brain increases permeability. Eg : penicillins BBB deficient at CTZ & some periventricular sites

Blood cerebrospinal fluid barrier: :

Blood cerebrospinal fluid barrier : formed by the choroid plexus of the lateral, third & fourth ventricles similar to ECF of brain 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.

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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 .

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PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER Placenta is the membrane separating Fetal blood from the Maternal blood.

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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 .

Apparent volume of distribution:

Apparent volume of distribution drugs distribute - several compartments Presume - body - single homogeneous compartment The volume that would accommodate all the drug in the body if the conc throughout was the same as in plasma is called the apparent volume of distribution, or V d .

Volume of Distribution:

Volume of Distribution An abstract concept Gives information on HOW the drug is distributed in the body Used to calculate a loading dose

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Volume of Distribution ( V d ) = Dose_____ Plasma Concentration Expressed as L

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Loading Dose Dose = Cp (Target) x V d

Important Concepts:

Important Concepts VD is a theoretical Volume and determines the loading dose Clearance is a constant and determines the maintenance dose CL = kVD CL and VD are independent variables k is a dependent variable

Significance :

Significance Apparent V d - dependent on conc in plasma. large apparent volume are more concentrated in extra vascular tissues- eg chloroquine pathological cases, the Vd for the drug may be altered if the distribution of the drug is changed.

Redistribution:

Redistribution Highly lipid soluble drugs i.v ./inhalation -distributed to organs with high blood flow, e.g. brain, heart, kidney etc. Later, less vascular but more bulky tissues (muscles, fat) take up the drug plasma concentration falls and drug is withdrawn from these sites. If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of the drug action. Greater the lipid solubility of the drug, faster is its redistribution. 49

Redistribution of drugs:

Redistribution of drugs Eg : thiopentone sodium Being highly lipid soluble, enters the brain rapidly- anaesthesia-rapidly diffuses out of brain enters muscles and fat-termination of action

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