drug distribution.ppt
TRANSCRIPT
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
10
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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
erf
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Mod
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perf
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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
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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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