1

M.M.U COLLEGE OF PHARMACY

RAMANAGARAM-571511SEMINAR ON

DRUG DISTRIBUTION & FACTORS AFFECTING

PRESENTED BY SUBMIT TOAZIM ARSHI VASEEHA BANU.T.S1ST M.PHARMA ASSISTANT PROFESSOR

DEPARTMENT OF PHARMACEUTICS

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DRUG DISTRIBUTION

Distribution Means Reversible Transfer of Drug(s)from One Location to Another within Body. Thedistribution of drugs from blood to tissue occurs atvarious rate and to various extent. Following factorDetermine the distribution pattern of drug suchas:- Affinity of drug Ability of drug to pass through tissue membrane Binding of drug to both plasma protein and tissue

component

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DRUG DISTRIBUTION PATTERNS

Distribution can be through of as following one of four types of patterns

4 3

2

1BLOOD

BODY WATERIN VARIOUS

ORGEN

SPECIFIC ORGEN TISSUE

E.g. Fat

General Organ E.g.Liver Muscle

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Distribution Patterns

1)The drug May remain largely with in the vascular system.

2)Some Low molecular weight water soluble compound such as Ethanol, & few sulphonamides become uniformly Distributed through the body water.

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Distribution Patterns

3) A few drug are concentrated specifically in 1 or more tissue that may or may not be site of action.

4) Most drug exhibit a non-uniform distribution in the body with the variations that is largely determination by their ability to pass through the membrane &their lipid/water solubility. The highest concentration are often present in Kidney, Liver,

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FACTORS AFFECTING DRUG DISTRIBUTION

Rate of distribution Extent of distribution

Rate of distribution Membrane permeability (Capillaries

Membrane permeability) Blood perfusion rate

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Membrane permeability (Capillary Membrane

permeability)

Membrane Permeability tends to restrict the transfer & distribution of drug once they are delivered to the tissues

The capillaries are typically lined with endothelium whose cells overlap,. Also, the junctions between cells are discontinuous. Capillary walls are quite permeableLipid soluble drugs pass through very rapidly.Water soluble compounds penetrate more slowly at a rate more dependent on their size.

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Membrane permeability (Capillary Membrane

permeability)

Low molecular weight drug pass through simple diffusionFor compound with molecular diameter above 100 Å transfer is slowFor drugs which can be ionized the drug's pKa and the pH of the blood will have a large effect on the transfer rate across the capillary membrane.

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There are two deviations to the typical capillary structure which result in variation from normal drug tissue

permeability

Permeability is greatly increased in the renal capillaries by pores in the membrane of the endothelial cells, and in specialized hepatic capillaries, known as sinusoids which may lack a complete lining. Pores in

membrane

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There are two deviations to the typical capillary structure which result in variation from normal drug tissue

permeability

On the other hand brain capillaries seem to have impermeable walls restricting the transfer of molecules from blood to brain tissue. Lipid soluble compounds can be readily transferred But the transfer of polar substances is severely restricted. This is the basis of the "blood-brain" barrier

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That means Membrane Permeability depend upon Physico-Chemical Properties such as molecular size, lipid solubility,

And Physiologic Barriers such as….

Simple capillary endothelial barrier

Simple cell membrane barrier

Blood Brain barrier Cerebrospinal barrier

Placenta barrier Blood-Testis barrier

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Simple capillary endothelial barrier

All the Drug, ionized or unionized with a molecular size 600 Dalton, diffuse through the endothelium and into the interstitial fluid. Only drugs bound the blood component are restricted because of the large molecular size of complex

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Blood Brain barrier

The brain capillaries consist of endothelial cell which are joined to one another by continuous tight intracellular junction comprising what is called as blood brain barrier.

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Cerebrospinal barrier

CSF is formed mainly by choroid plexus of the lateral, 3rd & 4th ventricles & similar in composition to the EHF of brain.

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Placenta barrier

The maternal & the fetal blood vessels are separated by number of tissue layer made of fetal trophoblast basement membrane & endothelium which together constitute the placental barrier.

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Blood perfusion ratePerfusion

Perfusion rate is define as volume of blood that flows/minute/tissue volume. Perfusion rate of tissue varies from approximately 10ml/min/ml for lungs to 0.025 ml/min/ml form muscle or fat.

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Organ Blood flow (ml/min)

Perfusion rate

(ml/min/ml)LUNGS 5000 10.2KIDNEY 1250 4.5LIVER 1350 0.8HEART 200 0.6BRAIN 700 0.5

MUSCLES 1000 0.025

SKIN 350 0.033

FAT 200 0.03

BONE 250 0.02

Blood perfusion rate in various organs

Hig

h p

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Mod

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Poor

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Total blood flow is greatest to brain, kidneys, liver, andmuscle with highest perfusion rates to brain,kidney, liver, and heart. It would be expected thattotal drug concentration would rise most rapidly inthese organs. Certain smaller organs such as theadrenals (1.2 - 5.5 ml/min/ml or 0.2 - 1% CO) and thyroid(2.4 - 4 ml/min/ml or 1 - 2% CO) also have large perfusion rates.

As an example; thiopental gets into the brain fasterthan muscle, whereas, penicillin gets into musclemore quickly than it gets into brain Thiopental is only partly ionized and passes into the brain or muscle easily. Perfusion limits the transport. Since brain has a higher perfusion rate the thiopental can transfer in and out more quickly

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Penicillin is quite polar thus slowly permeable. Permeability limited transfer is faster in muscle as muscle capillaries are less restrictive. Thus transfer of penicillin is faster in muscle than brain

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Extent of distribution

APPARENT VOLUME OF

DISTRIBUTION

DRUG BINDING TO ERYTHROCYTES

PLASMA PROTEIN BINDING TISSUE BINDING

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PLASMA PROTEIN BINDING

Binding of drug to plasma protein is most common 50% of the total proteins bind the

widest range of drugs. The acidic drugs commonly tend to bind with albumin

where as basic drug often bind to alpha and glycoprotein and lipoprotein.

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PROTEINS WITH POTENTIAL BINDING SITES FOR VARIOUS DRUGS

Acidic Drug Basic drugBinding site Albumins Globulins, α1,

α2, β1, β2, γ

Example Drug Bilirubin, Bile acids, Fatty

Acids, Vitamin C, Salicylates, Sulfonamides, Barbiturates,

Phenylbutazone, Penicillins, Tetracyclines, Probenecid

Adenisine, Quinacrine,

Quinine, Streptomycin, Chloramphenicol, Digitoxin,

Ouabain, Coumarin

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FACTOR INVOLVED

Groups on the protein molecules that are responsible for electrostatic interactions with drugs includethe —NH3

+ of lysine and N- terminal amino acidsthe —NH2

+— of histidine, the —COO- of glutamic acid residues

The initial electrostatic attraction is reinforced by van der Waal's forces and hydrogen bonding

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ExamplePhenyllbutazone and Salicylates displace tolbutamide to give an increased effect, hypoglycemiaThe displacement of warfarine by phenyl butazone leads to nearly 100 folds increase in free drug con. Which can result in clinical significant reaction.The value of the fraction of drug in plasma that is unbounded to plasma proteins, fu is given by

fu = Cu/C

FACTOR INVOLVED

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PERCENT UNBOUND FOR SELECTED DRUGS

Drug Percent Unbound (100 * fu)

Digoxin 77

Gentamicin 90

Theophylline 85

Phenytoin 11 - 13

Diazepam 3 - 4

Warfarin 0.5

Phenylbutazone 1 - 5

Dicumarol 1 - 3

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TISSUE BINDING

a) Specific protein in tissues

b) Accumulation in endocytotic vesicles (E.g. Gentamycin in renal proximal tube)

c) Binding to nucleic acid

d) Binding to Calciume) Accumulation in

lipid depots

ExampleThe con. Of

chloroquine in the liver is due to the binding of drug to DNA. Paracetamol bind irreversibly to liver tissue resulting hepatotoxicity

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APPARENT VOLUM OF DISTRIBUTION

The extent of distribution is indicated by apparent of distribution

Vd = AB = Amount of drug in body Cp Amount of drug in the plasmaThe volume of distribution varies from 7-

40,0001 per 70 kg body weightThe amount of drug in plasma VpCp

The amount of drug in plasma VdCp

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APPARENT VOLUM OF DISTRIBUTION

Fraction of drug in body plasma = Vd/Vp

Fraction of drug in body outside plasma = Vd –Vp Vd

Percent unbound in body = total body water X 100

Vu

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DRUG BINDING TO ERYTHOCYTES

Hemoglobin

Carbonic anhydrase

RBC membrane

Drug like phenytoine ..etc bind to hemoglobin

Drug like Acetazolamide, Chlorthalidone

Imipramine & Chlorpromazine

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Miscellaneous factor

Pregnancy

Age

Obesity

Diet

Drug interaction

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D.M.BRAHMANKAR, SUNIL B.JAISWAL P 76-90

Dr.SHOBHA RANI , P 138-150 Rowland, M. and Tozer, T.N, 1995 Clinical

Pharmacokinetics Concepts and Applications, 3rd ed., Williams & Williams. Media, PA

Shargel, L., Wu-Pong, S. and Yu, A.B.C. 2005 Applied Biopharmaceutics and Pharmacokinetics, 5th ed., McGraw-Hill, New York, NY

Niazi, S. 1979 Textbook of Biopharmaceutics and Clinical Pharmacokinetics, Appleton-Century-Crofts, New York, NY p101

REFERENCES

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Ritschel, W.A. and Kearns, G.L. 2004 Handbook of Basic Pharmacokinetics ... including Clinical Applications, 6th ed., American Pharmaceutical Association, Washington, DC, pp369-401

chignell, C.F. 1973 Ann. New York Acad. Sci., 226, p49, 53

Abernethy, D.R., Greenblatt, D.J, Divoll, M. et al. 1981 Alterations in drug distribution and clearance due to obesity, J.P.E.T., 217, p681-85

Rowland, M and Tozer, T.N. 1989 Clinical Pharmacokinetics, Lea & Febiger, Philadelphia, pp 260-270

These book available on http://www.boomer.org/c/p4/c18/c1802.html http://www.boomer.org/c/p1/Ch18/Ch1802.html

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THANKYOU