DISTRIBUTION OF DRUG

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Presented By:-BHANDARI UMESH M. 1st Year M- Pharm.

Department of Pharmaceutics. RCPIPER, SHIRPUR

2015 - 16

1. Introduction.

2. Definition.

3. Steps in drug distribution

4. Different compartments of drug distribution.

5. Factor affecting distribution

6. Conclusion

7. References.

AGENDA

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• Drug disposition is divided into four stages designated by the 'ADME‘.

• Absorption from the site of administration

• Distribution within the body

• Metabolism is chemical conversion of one form to anather

• Excretion means irreversible loss of drug

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DRUG Absorption &distribution

Drug level

Adverse drug effect

Therapeutic effect

Metabolism &Excrition

Excrition

INTRODUCTION

Distribution

• After entry into the systemic circulation , either by intravascular injection or absorbsion of any extravascular site the drug is subjected to number of processes called as disposition process

• Disposition it may be defined as the process that tend to lower the plasma concentration of drug.

Distribution Elimination

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Drug Distributed

in body

Drug metabolized

Drug in plasma

Drug excretedFig. Inter –relationship between

different process of drug distribution

• “Reversible transfer of drug from one compartment to another compartment of the body”

• One of the compartment is always blood or plasma and another is extravascular fluids

• Drug molecules are distributed is throughout the body by systemic circulation of blood

• The process occurs by diffusion of free drug only until equibrilium achieved

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DEFINITION

Distribution play the very important role in – Onset of action.– Intensity of action.– Sometimes duration of drug action

Distribution of a drug is not Uniform throughout the body because different tissues receive the drug from plasma at different rates & to different extents.

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•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

STEPS IN DRUG DISTRIBUTION

Body compartment

Concentration Types of drugs

Total body water O.6 L/kg Small, water soluble alcohol and antipyrine.

Extracellular space 0.2L/kg Large, water soluble mannitol

Intravascular space o.4 L/kg Very large, strongly protein bound, heparin

Intestinal fluid 0.16 L/kg Highly lipid solubleDDT and thiopentone

Bones 0.04 L/kg Fluoride and lead8

DIFFERENT COMPARTMENTS OF DRUG DISTRIBUTION

• Lipid solubility

• Ionization at physiological pH

• Binding to plasma proteins

• Cardiac output

• Blood flow

• Capillary permeability

• Tissue volume

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DISTRIBUTION PROCESS IS DEPENDS ON

1. Tissue Permeability of Drugs• Physicochemical Properties of drugs• Physiological barriers to diffusion of drugs

2. Organ/tissue size and perfusion rate

3. Binding of drugs to tissue components.• Binding of drug to blood components• Binding of drug to extra cellular components

4. Miscellaneous

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FACTORS AFFECTING DISTRIBUTION OF DRUG

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Physicochemical properties of drugsMolecular size

pKa

Partition Coefficient of drug Physiological barriers to diffusion of DrugsSimple capillary endothelial barrier

Blood Brain Barrier

Blood – CSF Barrier

Blood Placental Barrier

TISSUE PERMEABILITY OF DRUGS

I) Molecular Size :

less then 500 to 600 Dalton easily pass capillary membrane to extra cellular fluid.

Large mol size Restricted to specialized transport system

ii) Degree of Ionization (pKa)

The degree of ionisation of a drug is an imp for tissue permeability

The pH of blood & ECF play imp role in ionisation & diffusion into the cell

Unionised drug rapidly permeate

The pH of Blood plasma and ECF is 7.4( constant )

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iii) PARTION COEFFICIENT

Polar and hydrophilic drugs are less likely to cross the cell membrane

Non-polar and hydrophobic drugs are more likely to cross the cell membrane

Lipoidal drug penetrate the tissue rapidly.One which has less ionization show better distribution.

Eg. Phenobarbital > salicylic acidBoth are having same partion coefficient but Phenobarbital have more unionised in blood pH

1) The simple capillary endothelial barrier

Capillary supply the blood to the most inner tissue

All drugs ionized or unionized molecular size less than 600 dalton 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 of complex

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Physiological barriers to diffusion of Drugs

2) BLOOD BRAIN BARRIER

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Endothelial cell

The brain capillaries consist of endothelial cells which are joined to one another by continuous tight intercelluar junction comprising is called BBB

Highly lipid soluble drug crosses the BBBEg. pentobarbital, Penicillin.

Fig. Difference between brain capillary and general capillary

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Three approaches to promote crossing the BBB by the drugs are:• Use of the permeation enhancers such as dimethyl sulfoxide

(DMSO).• Osmotic disruption of BBB with mannitol.• Use of dihydropyridine redox system as drug carriers.

3) BLOOD CEREBRAL SPINAL FLUID BARRIER

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Ephemndymal cell of

The CSF mainly formed by choroid plexus of the lateral ,The capillary endothelium that lines have open junction or gaps and drug flows freely to extracellular space between the capillary wall colloidal cellThe colloidal cell join to each other by tight junction and which forming the Blood CSF barrier

4) PLACENTA BARRIERAS

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The maternal and foetal blood vessels are separated by number of tissue layer made up from foetal trophoplast basement membrane and endothelial basement membrane which together and forming placenta barrier Highly lipidic drug or mole wt less than 1000 Dalton drug passesIn this process drug or nutrients transported by carrier mediated process

3).Binding of drug to tissue components

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Drug

A drug in the body can bind to several components such as the • Protein binding • Blood component

Protein binding : complex formation with protein is calledTwo types of binding

•Extracellular binding •Intracellular binding

Blood component : RBC drug binding is possible.

4). MISCELLANEOUS FACTORS Age:

a) Total body water

b) Fat content

c) Skeletal muscles

d) Organ composition

e) Plasma protein content

Pregnancy

Diet

Disease states

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VI) DIET :

A high diet in fat will increase the fatty acids level in circulation thereby affecting a binding of acidic drugs.

V) DISEASE STATES:

• Distribution characteristics of several drugs are altered in disease states.

• Eg.

In meningitis and encephalitis, the blood-brain barrier becomes more permeable and the polar antibiotics like penicillin-G, which do not normally cross it, gain access to the brain.

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APPARENT 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.

Apparent volume = amount of drug in the body/

of distribution plasma drug concentration

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.22

Vd = X/C

CONCLUSION

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Distribution of a drug is not Uniform throughout the body because different tissues receive the drug from plasma at different rates & to different extents.

Distribution study helps –

•To know interactions between drug and type of Compartment model • To achieve maximum bioavability

1. Brahmankar D.M. Jaiswal S.B., First edition, “Absorption of Drugs” Biopharmaceutics and Pharmacokinetics – A treatise, Vallabh Prakashan, Delhi 1995, page no. 98-113

2. Shargel L., Andrew B.C., Fourth edition “Physiologic factors related to drug absorption” Applied Biopharmaceutics and Pharmacokinetics, Prentice Hall International, INC., Stanford 1999.

3. Aulton M.E. Pharmaceutics “The Science of Dosage Form Design”, 2nd Ed.; Churchill Livingstone.

4. Ashok Kari1, Gandhu Sateesh1, Bharatha Suresh1, Bodavula Samba Siva Rao2*, Factors Effecting on Drug Distribution, THE PHARMA INNOVATION, at www.thepharmajournal.com, Vol. 1 No. 6 2012 Page no. 63-73

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REFERENCE

…..THANK YOU….

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