The document discusses drug distribution, defining it as the process by which drugs leave the bloodstream and enter body tissues. It covers factors affecting distribution, such as drug size, lipophilicity, and protein binding, as well as the concept of volume of distribution and its significance for dosing. Key insights include that distribution is uneven across body compartments and demonstrates how various physiological and pathological conditions can influence the pharmacokinetics of drugs.

1. DRUG DISTRIBUTION
DR AWAIS IRSHAD
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2. ELIMINATION
METABOLISM
DISTRIBUTION OF DRUGS
ADMINISTRATION
PHARMACOKINETICS
ABSORBTION
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3. Presentation Outline
Definition Of Drug Distribution.
Factors affecting drug distribution.
Volume Of Distribution.
Binding of Drug with Plasma proteins.
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4. Drug Distribution
A process by which drug
reversibly leaves blood
stream & enters
interstitium and/or cells of
tissues like muscle, fat &
brain tissue .
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Vd - amount of fluid in
which administered drug
DOSE is distributed

5. Distribution….. Where do the drugs go after absorption?
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Pharmacological action of drugs
depend upon its conc at site of
action
Drug Distribution

7. Primary Kinetic parameters
VOLUME OF DISTRIBUTION
Where the drug is distributed over.
In obese persons is high for fat
soluble drugs.
Vital to calculate dose & frequency
CLEARANCE
Clearance of creatinine is 120 ml / min.
It is the volume of plasma that is
completely cleared of drug in unit time.
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8. 0
50
100
150
0 5 10 15 20 25 30
Time (h)
Concentration
mg/l
Threshold concentration
desired effect
Threshold concentration
toxic effect
Duration of action
Knowledge of the pharmacokinetics of drugs is necessary for designing proper dosing schemes!
Pharmacokinetics –
Distributionof drugs
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9. Volume Of Distribution
 Consider human body as a vessel filled with
Plasma (volume).
Volume of distribution (Vd) relates the amount of
drug in the body to the concentration of drug(C) in
blood or plasma.
 Vd =
is constant for most of compounds.
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9
Amount of drug in body
Drug in plasma - C
(Katzung)
Body Composition:
40% - Mass.
60% - Water
ECF & ICF
Plasma Volume
Interstitial fluid
Drug Protein bound OR FREE
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10. Pharamcology FAZAIA RUTH PFAU MEDICAL COLLEGES 10
Volume of distribution (Vd) of drug
Calculation of Vd:
ion
concentrat
Plasma
Dose

Vd

11. Volume of distribution.
(Extent of drug in plasma after giving a dose)
Vital to calculate the dose of a drug & its frequency
Vd = Amount of drug in body (Dose in mg)
amount of drug in plasma(Conc in plasma)
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Vd = 120 mg = 6 Low
20 mg/L
• Distributed in blood.
• Large charged molecules.
Vd = 120 mg = 120 High
1 mg/L
• Drug protein bound in plasma
• Fat soluble stuck in fatty tissues

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No body is big enough to have a
capacity of 2400 L, hence it is
imaginary.

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Drug Distribution
Some drugs remain in plasma only (can’t cross the capillary membrane)
Some drugs remain in the ECF (plasma & interstitial fluid) as they can
cross the capillary membrane but can’t cross the cell membrane
Some drugs can be distributed in the whole body fluid (both ECF & ICF)
as they can cross the all membranes of the body
Some drugs have great affinity to some tissues & remain conc on that
tissue and gives low plasma conc.
Drugs seldom remain at same conc throughout body, HENCE
distribution of drug into whole body is not equal.

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Volume of distribution (Vd) of drug
•It does not represent volume in a
particular body fluid compartment,
instead it is an apparent volume that
represent relationship between dose of a
drug and resulting plasma concentration
•For this reason it is called as “Apparent
volume of distribution”
The volume of fluid into which
a drug appears to be
distributed or diluted is called
the volume of distribution
Why appears to be
distributed?
Why not real?

15. 0
0
Time
Time
Amount
in
blood
Amount
in
blood
Blood
Blood
Rapid intravenous
injection
Rapid intravenous
injection
NO elimination
Elimination follows
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16. Blood
Blood
Extra vascular volume
Extra vascular volume
Amount
in
blood
Amount
in
blood
0
0 Time
Time
Rapid intravenous
injection
Rapid intravenous
injection
NO elimination
Elimination follows
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18. Effect of drug size and lipophilicity on Vd (example)
interstitial space
blood vessel
cells
endothelium
Large, readily water soluble or charged compounds remain in blood plasma:
example heparin (strongly neg. charged and large, 3-20 kDa)
Vd = plasma volume = plasma volume =
± 0.05 l/kg (`normal´ male) or 0.04 l/kg (`normal´ female)
Pharmacokinetics
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19. Effect of drug size and lipophilicity on Vd (example)
Interstitial space
blood vessel
cells
endothelium
Small very water soluble/ heavily charged/ highly polar substances
remain in the extracellular fluid: example theophyllin
Vd = plasma volume + interstitial volume =
± 0.2 l/kg (`normal´ male) or ± 0.17 l/kg (`normal´ female)
Pharmacokinetics
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20. Effect of drug size and lipophilicity on Vd (example)
Interstitial space
blood vessel
cells
endothelium
Small, quite lipophilic substances will distribute over the entire
body water: example alcohol Vd = total (exchangable) water
volume = intracellular + extracellular volume =
± 0.55 l/kg (`normal´ male) or ± 00.450 l/kg (`normal´ female)
Pharmacokinetics
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21. Effect of drug size and lipophilicity on Vd (example)
interstitial space
blood vessel
endothelium
Very lipophilic substances will accumulate in fat tissue: like DDT
fat tissue
cells
Vd MAY EXCEED total body volume many times!!!! Also in case of (tissue)
binding of substances, this may occur. For this reason the term APPARENT
volume of distribution has been introduced.
Pharmacokinetics
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22. Vd vs. plasma conc. of drug
Less plasma concentration of a drug
means more distribution……
means greater Vd
Greater plasma concentration of a drug
means less distribution……
means smaller Vd
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23. Factorswhichaffectsthe drug distributions
 1) Tissue permeability of drug
a. physicochemical property – i) molecular size
ii) pKa
iii) o/w partition coefficient
b. physiological barriers
 2). Organ tissue size and perfusion rate
 3). Binding of drug to tissue components
a. with blood components
b. with extravascular tissue proteins
4). Miscellaneous factors
a. age
b. Pregnancy
d. Obesity
e. Diet
f. Disease states
g. Drug interaction
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24. Tissue permeability of drug
 Physicochemical property:
I) Molecular Size;
 Mol wt less then 500 to 600 Dalton easily pass capillary membrane to extra
cellular fluid.
 From extra cellular fluid to cross cell membrane through aqueous filled
channels need particle size less then 50 Dalton with hydrophilic property .
 Larger size were restricted unless specialized transport system is exists
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25. Physicochemical property
Degree of ionization (pKa)
The pH at which half of a drug is unionized is called pKa
A weak acid becomes unionized in a strong acidic environment.
A weak acid becomes ionized in a neutral or basic environment.
&
A weak base becomes unionized in a strong basic environment.
A weak base becomes ionized in a neutral or acidic environment.
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26. Physicochemical property: Permeability
Polar and hydrophilic drugs are less likely to cross the cell membrane
☺ Nonpolar and hydrophobic drugs are more likely to cross the cell membrane
Lipid soluble drugs (non-ionized) can cross easily the membranes & available
everywhere
Water soluble drugs (ionized) can’t cross the cell-membrane, and so remains in mostly
ECF
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Drug Distribution
Importance of PPB of the drugs
Bound drugs are inactive
Bound drugs can’t cross the membranes
Bound drugs are not metabolized
Bound drugs are not excreted

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Drug Distribution
Plasma-protein binding (PPB)
When the drugs appear in the circulation,
A fraction of drug molecules bind with plasma protein & another
fraction remain free.
In general, binding is reversible and obeys the law of mass action
There is always an equilibrium between bound & free drug
concentration. When free drug concentration is decreased then bound drugs
become free and maintains the equilibrium
Diazepam: 99% bound, 1% free Morphine: 35% bound, 65% free

29. Plasma Protein Binding [PPB]
ACIDIC DRUGS
High affinity & low capacity
Two particular sites of the albumin molecule
bind acidic drugs with high affinity (strongly)
BASIC DRUG
Low affinity & high capacity
Basic drugs bind with alpha1-acid
glycoprotein & Lipo protein
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 CLASS I DRUGS
o Low dose/capacity
ratio e.g.
Tolbutamide
 CLASS II DRUGS
o High dose/capacity
ratio e.g.
Sulphonamide

30. Drug Displacement
Class I drugs are displaced by Class II drugs.
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Most drug molecules are
bound to albumin and
the conc. Of free drug
is less
Most Albumin contains bound
drug and the conc. Of free
drug is significant
Displacement of Class I drug
occurs when a Class II
Drug is administered
simultaneously
Class I Drug Class II Drug Displacement

31. Warfarin
When it is administered
alone and absorbed into
the blood stream……
75% PPB, 25% Free
3 of 4 of it binds to
albumin and 1 of 4 is free
in the blood for effect
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32. Aspirin
When aspirin is
administered alone and is
absorbed into the blood
75% PPB, 25% Free
3 of 4 of it binds to
albumin and 1 of 4 is free
in the blood for effect
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33. But if warfarin and aspirin are administered
together………..
They compete for binding on albumin.
May be 2 bound and 2 free of each drug
The amount of drug available to produce a
therapeutic response increases from 1 to 2
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(chance of toxicity) May be a doubling of therapeutically
effective dose
Thus taking two highly protein bound drugs together can
increase the therapeutic effectiveness of both

34. Relationship Of Drug Displacement to Vd
The impact of drug displacement from albumin depends on Vd.
If the Vd is large, drug displaced from albumin distributes to
periphery and change in free-drug concentration in plasma is not
significant.
If the Vd is small the newly displaced drug does not move into the
tissues as much and the increase in free drug concentration is more
profound.
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35. Regional blood flow
More blood flow…more distribution
Drugs distribute….
to tissues with a high blood flow (heart, lungs, brain) most rapidly
then to those with a moderate blood flow (muscle) and
finally to those with a poor blood flow (fat, tendons, cartilage)
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36. Drug Distribution: Barriers
BLOOD-BRAIN BARRIER
is lipoidal thus drugs with high O/W partition
coefficient diffuse passively others passes
slowly. Only lipid soluble substances can cross
the BBB
Also unique mechanisms
A) permeation enhancers ;- dimethyl
sulfoxide
B) pro- drug approach ;- dopamine----
livodopa
BLOOD-PLACENTAL BARRIER
Both are separated by fetal trophoblast
basement membrane & endothelium .
Mol wt <1000 Dalton & moderate to high lipid
solubility drugs like….. sulfonamides,
barbiturates, steroids, narcotic and some
antibiotics ) cross the barrier by simple
diffusion rapidly
Only low molecular weight - Lipid Soluble
drugs permit to cross
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37. Pharamcology FAZAIA RUTH PFAU MEDICAL COLLEGES 37
Drug Distribution
Tissue binding
Some drugs have special affinity to some tissues, e,g,
brain, adipose tissue, kidneys, cornea, bone etc.
Tetracycline to bone
Phenobarbitone to brain
Chlorpromazine to eye
Chloroquine to kidneys

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Vd for basic drugs
Many basic drugs are
taken up by tissues and
thus have larger volume
of distribution
Amphetamine
Chloroquine

39. Distribution in body water compartments
Total Body
water
oLow molecular
weight drug
oHydrophobic
Extracellular
fluid
oLow molecular
weight drug
oHydrophilic
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 Plasma
o Very large
molecular
weight drug
o Binds
extensively to
plasma
proteins
 Other
sites
o In cells ,
fat ,
bone
o Act as
drug
reservoir

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Plasma compartment
Vd: around 5 L
Very high molecular weight drugs, or
drugs that are highly bind to plasma
proteins
Example: Heparin 4L (3-5)

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Extracellular fluid
Vd: between 4 and 14 L
Drugs that have a low
molecular weight but are
hydrophilic
Example
Atracuronium 11 L (8-15)

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Vd equal or higher than total body water
Diffusion to intracelullar fluid
Vd equal to total body water
◦Ethanol 38 L (34-41)
◦Alfentanyl 56 L (35-77)
Drug that binds strongly to tissues
Vd higher than total body water
◦Fentanyl: 280 L
◦Propofol: 560 L
◦Digoxin:385 L

43. Pharamcology FAZAIA RUTH PFAU MEDICAL COLLEGES 43
A) If Vd approximates
blood volume
 The drugs are mainly
limited to vascular
compartment
 Max amount cannot
cross the capillary
membrane
 They are highly protein
bound
 e.g. Warfarin, Heparin
B) If Vd approximates
extracellular fluid
volume
 They occupy the whole
extracellular space.
 Can cross the capillary
membrane
 But cannot easily cross
cell membranes to enter
the intracellular fluid
 e.g. Aspirin, Gentamicin
Interpretation volumes of distribution

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C) If Vd is close to total body
water
 They occupy the whole
extra and intracellular space
 The drugs are highly lipid
soluble.
 These drugs are able to
cross cell membranes to
enter the intracellular fluid
from extracellular space.
 e.g. Phenytoin, Ethanol
D) If Vd is greater than total body
water (>45L)
 Drugs are highly lipid soluble
 They enter into all cells easily
 Also bind extensively to tissue
proteins
 Accumulation in certain organs
 e.g. Digoxin, Chloroquine
Interpretation volumes of distribution

45. Physical & Chemical
Characteristics:
-small molecular weight drugs
-unionized drugs
-hydrophobic
Tissues in which cell
membrane is discontinuous
e.g. liver , spleen
Organ with blood flow Increased Tissue Affinity
Increase Drug Distribution
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46. Decrease drug distribution
Drugs with large
molecular weight
Tissues in which cells
have tight junctions
Drugs extensively
bound to plasma
proteins
Highly ionizable drugs
Pathological states e.g.
Uremia, Liver cirrhosis
Hydrophilic
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47. References:
Introductory clinical pharmacology by Sally.S.Roach
Pharmaceutical practice by Arthur .J. Winfield
Drug therapy in nursing by DianeS. Aschen brenner
Basic & clinical pharmacology Katzung 14 th edition
Lippincott’s pharmacology 6th edition.
Rang & Dale 9th edition
Clinical pharmacology 11th edition Peter Bennett
Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd edition
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