Absorption of drug

1. Lok RajBhandari

2. Pharmacokinetics :
It determines how much of an administered
dose will reach its sites of action.
There are four phases of P.K
Absorption
Distribution
Metabolism
Excretion

3. Absorption
Absorption is the transfer of a drug from its site of administration to blood
stream
Factors affecting drug absorption:
1. Rate of Dissolution:
2. Particle size
3. Physical states
4. Lipid solubility
5. Formulation
6. pH & Ionization
7. Gastrointestinal transit time
8. Area of the absorbing surface
9. Blood flow
10.Metabolism of drugs
11. Disease states

4. 1. Rate of Dissolution:
1. Drugs in formulation that allow rapid dissolution have faster onset
than drugs formulated for slow dissolution
2. Particle size:
1. Smaller the particles size greater is the rate of absorption
1. Physical states:
1. Liquids are better absorbed than solid
2. Crystalline “ “ than colloids
3. Amorphorous “ “ than crystalloid
2. Lipid solubility:
1. Highly lipid soluble unionized drugs are absorbed more rapidly
than those drugs which lipid solubility is low
2. Examples : fat soluble Vit A, D, E, K are better absorbed
3. Formulation:
1. Substance like sucrose, lactose, starch & calcium phosphate are
used as inert diluents in formulating tablets. These agents may
interfere with active drugs & affect its absorption
2. Sustained release dosage- delay absorption

5. 6. pH & Ionization
 pH of the gastrointestinal fluid & blood may interfere
with the absorption of drugs
 Acidic drugs are better absorbed in stomach
 e.g aspirin ( weak acid) remain unionized form in acidic
medium of stomach, it favour their absorption
 Basic drugs ( morphine ) better absorbed in intestine
7. Gastrointestinal emptying time (GET)
 The presence of food, volume & tonicity of the stomach
or gastric contents can influence drug absorption by
altering the GET
 Rapid absorption occurs if the drug is given before meals
 E.g : atropine -- increase GET--- impair absorption
8. Area of the absorbing surface
 Larger the surface area, faster absorption will be. So
orally administered drugs are usually absorbed from
small intestine rather than stomach becoz of large
surface area.

6. 9. Blood flow:
 Drugs are absorbed most rapidly from sites where
blood flow is high
10. Metabolism of drugs
 Rapid degradation of a drugs by liver during first pass
metabolism affect absorption & bioavailability
11. Disease states
 Absorption can be affected in condition like
thyrotoxicosis, achlorhydria & liver cirrhosis

7. Drug has to cross membranes inorder to reach
the target sites
Three ways to cross membrane:
1. Passage through channels or pores
2.Passage with the help of transport system
3. Direct penetration of the membrane

8. 1. Channels or pores:
1. Very few drugs cross membrane by channels or
pores. The channels in membranes are
extremely small ( 4 angstroms), Only small
compound ( mol wt < 200) can use these routes
2. Example : sodium, potassium
2. Transport systems:
1. Passive transport
2. Active transport
3. Vesicular transport

9. 1. Passive transport:
1. Drug molecule pass cross the membrane in direction
of its conc gradient i.e from region of higher conc to
lower conc.
2. Most of the lipid soluble drugs are transferred by
passive diffusion
2. Active transport:
1. Needs specific carries protein
2. Moves against conc gradient
Example : steroids, cephalosporin, large molecular size

10. 3.. Vesicular transport:
1. It is process by which the substance is engulfed
by the cell membrane & carried into cell.
2. Example : iron , vit B12
4. Direct penetration of the membrane
Large molecules with lack of transport system
follow this pathways
So for direct penetration drug must be lipid
soluble.

11. Absorption & Ionization
Non-ionised drug
More lipid soluble drug
Diffuse across cell
membranes more easily

12. HOW CHANGE IN ABSORPTION PATTERNABSORPTION PATTERN MODIFY THE
THERAPEUTIC EFFECT…….
12
Think of all the
EXTREME
possibilities in
relation to
absorption and
try to imagine
the
consequences..

13. Pharmacokinetic parameter governed by
absorption is …..BIOAVAILABILITY….
BIOAVAILABILITY ---It measures the fraction
(F) of administered dose of a drug that reaches
the systemic circulation in unchanged form.
If BA is 100 %  I.V parenteral dose
BA is calculated by AUC (Area Under Curve)
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14. PLASMA CONCENTRATION TIME
CURVE
14
Concentration
Time1 2 3 4 5 6
Drug A
Drug B
7 8 9
NOW WE WILL STUDY
FRIGHTENING TERMINOLOGIES!!!
1.Cmax  Peak(maximum) plasma
concentration
2.Tmax  time at which maximum
concentration is obtained
3.AUC (Area Under
Curve)
Minimum
Effective
Concentration
Maximum safe
concentration

15. 15
Bioavailability =
AUC after oral dose
AUC after IV dose
X 100
Cmax & Tmax measures the rate of absorption,
AUC measures the extent of absorption.

16. Drug Distribution
It is defined as the movement of drugs throughout
the body
Drug distribution is the process by which a drug
reversibly leaves the blood stream and enter the
interstitial and cell of the tissues.
Rate and extent being dependent on
Capillary permeability
Lipid solubility
Ionization at physiological pH
Extent of binding to plasma and tissue protein
Blood flow 16

17. Distribution
The movement of drug from the blood
to and from the tissues

18. Drug is administered
HOW CHANGE IN DISTRIBUTION PATTERNDISTRIBUTION PATTERN MODIFY THE
THERAPEUTIC EFFECT…….
18

19. 1.Blood flow:
Blood flow to the brain, liver and kidney is greater than
that to the skeletal muscles, whereas adipose tissue has
a lower rate of blood flow.
2.Capillary permeability
Capillary permeability is determined by capillary
structure and by the chemical nature of the drug.
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20. a. Capillary structure:
Capillary structure varies widely in terms of the fraction
of the basement membrane that is exposed by slit
junctions between endothelial cells.
In the brain, the capillary structure is continuous, and
there are no slit junctions. This contrasts
with the liver and spleen, where a large part of the
basement membrane is exposed due to large,
discontinuous capillaries through which large plasma
proteins can pass.
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21. b.
Blood-brain barrier:
To enter the brain, drugs must pass through the
endothelial cells of the capillaries of the CNS or be
actively transported.
Lipid-soluble drugs readily penetrate into the CNS
because they can dissolve in the membrane of the
endothelial cells.
Ionized or polar drugs generally fail to enter the
CNS because they are unable to pass through the
endothelial cells of the CNS, which have no slit
junctions.
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22. Blood brain barrier
The capillary boundary that is present between the
blood and brain is called BBB
In the brain capillaries, the endothelial cells are
joined by tight junctions.
Only the lipid soluble and unionized form of drugs
can pass through BBB and reach the brain, e.g.
barbiturates, diazepam, volatile anaestthetics etc.
Lipid insoluble and ionized particles do not cross the
BBB e.g. dopamine, aminoglycosides

23. Pathological states like meningitis,
encephalitis increase the permeability of the
BBB and allow the normally impermeable
substance to enter the brain
For example penicillin in normal condition has
poor penetration through BBB but its
penetration increase during meningitis.

24. c. Drug structure:
The chemical nature of a drug strongly influences its
ability to cross cell membranes.
Hydrophobic drugs, which have a uniform distribution
of electrons and no net charge, readily move across
most biologic membranes.
 These drugs can dissolve in the lipid membranes and,
therefore, permeate the entire cell's surface.
Hydrophilic drugs, which have either a nonuniform
distribution of electrons or a positive or negative
charge, do not readily penetrate cell membranes, and
therefore, must go through the slit junctions.
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25. 3.Binding of drugs to plasma proteins
Reversible binding to plasma proteins sequesters
drugs in a nondiffusible form and slows their transfer
out of the vascular compartment.
Plasma albumin is the major drug-binding protein
and may act as a drug reservoir;
--- As the concentration of the free drug decreases
due to elimination by metabolism or excretion, the
bound drug dissociates from the protein.
This maintains the free-drug concentration as a
constant fraction of the total drug in the plasma.
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26. Plasma protein binding
Many drugs bind to plasma proteins like albumin,
α1 acid glycoprotein etc
Clinical importance of PPB:
1. Plasma protein binding favour drug absorption
2.Drugs that are highly bound to plasma protein
have a low volume of distribution
3. Plasma protein binding delay the metabolism of
drugs

27. 4. Highly protein bound drugs have longer duration of
action e.g. sulphadoxine is highly plasma protein
bound and has duration of 1 week
5. In case of poisoning, highly PPB drugs are difficult
to be removed
6. Disease states like anemia, renal failure, chronic
liver disease have low plasma albumin level so there
will be increase in the free form of the drug which
can lead to drug toxiciy
7. Plasma protein binding can cause displacement
interactions.

28. Placenta barrier
The lipid membrane between the mother and foetus
is called placenta barrier.
Unionized and lipid soluble drugs can freely pass the
placenta barrier e.g anaesthetic, alcohol, morphine
etc
Certain drugs when given during pregnancy may
cross the placenta and cause various dangerous effects
in the foetus. This is called teratogenesis
E.g ---thalidomide -- phocomelia
Tetracycline-- yellowish teeth

29. Administration during first trimester cause abortion
and affect organogenesis and produce structural
abnormalities
Second and third trimester can affect growth and
development of foetus
Hence administration during pregnancy shoud be
retricted

31. Apparent Volume of
Distribution
The Apparent volume of distribution ( Vd )is a hypothetical volume
of fluid into which a drug is distributed.
V = dose administered i.v
plasma concentration
A. Water compartments in the body
1.Plasma compartment:
If a drug has a very large molecular weight or binds extensively to
plasma proteins, it is too large to move out through the endothelial
slit junctions of the capillaries and, thus, is effectively trapped
within the plasma (vascular) compartment.
Plasma --- 5%
In a 70-kg individual, about 4 L of body fluid.
Heparin shows this type of distribution.
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32. 2.Extracellular fluid:
If a drug has a low molecular weight but is hydrophilic,
move through the endothelial slit junctions
------------------- interstitial fluid.
Hydrophilic drugs cannot move across the lipid
membranes of cells to enter the water phase inside the
cell.
Extracellular fluids ( 20%)---- plasma (5%) and the
interstitial fluid 15%
About 14 L in a 70-kg individual.
Aminoglycoside antibiotics show this type of
distribution.
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33. 3.Total body water:
If a drug has a low molecular weight & hydrophobic,
not -- move into the interstitium through the slit
junctions & the intracellular fluid.
About 42 L in a 70-kg individual.
Ethanol exhibits this apparent volume of
distribution
4. Other sites: In pregnancy, the fetus may take up
drugs and thus increase the volume of distribution.
Drugs that are extremely lipid-soluble, such as
thiopental may also have unusually high volumes of
distribution.
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34. Apparent volume of distribution
Determination of Vd
a. Distribution of drug in the absence of elimination:
The apparent volume into which a drug distributes, Vd, is determined
by injection of a standard dose of drug, which is initially contained
entirely in the vascular system.
The agent may then move from the plasma into the interstitium and
into cells, causing the plasma concentration to decrease with time.
Assume for simplicity that the drug is not eliminated from the body;
the drug then achieves a uniform concentration that is sustained with
time . The concentration within the vascular compartment is the total
amount of drug administered, divided by the volume into which it
distributes, Vd:
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35. Assume for simplicity that the drug is not eliminated from the body;
the drug then achieves a uniform concentration that is sustained with
time.
The concentration within the vascular compartment is the total
amount of drug administered, divided by the volume into which it
distributes, Vd:
C=D/Vd
Or Vd= D/C
C = plasma concentration of drugs
D = total amount of drug in the body
For example, if 25 mg of a drug (D = 25 mg) are administered and the plasma
concentration is 1 mg/L, then Vd = 25 mg/1 mg/L = 25 L.
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36. b.Distribution of drug when elimination is present:
The initial decrease in plasma concentration is due to a rapid
distribution phase in which the drug is transferred from the plasma
into the interstitium and the intracellular water.
This is followed by a slower elimination phase during which the drug
leaves the plasma compartment and is lost from the body
 The rate at which the drug is eliminated is usually proportional to the
concentration of drug, C; that is, the rate for most drugs is first-order
and shows a linear relationship with time
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37. c. Calculation of drug concentration if distribution
is instantaneous:
Assume that the elimination process began at the time of
injection and continued throughout the distribution
phase. Then, the concentration of drug in the plasma, C,
can be extrapolated back to time zero (the time of
injection) to determine C0, which is the concentration of
drug that would have been achieved if the distribution
phase had occurred instantly.
 For example, if 10 mg of drug are injected into a patient
and the plasma concentration is extrapolated to time zero,
the concentration is C0 = 1 mg/L , and then Vd = 10 mg/1
mg/L = 10 L.
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38. 2. Effect of a large Vd on the half-life of a drug
Delivery of drug to the organs of elimination depends not
only on blood flow, but also on the fraction of the drug in
the plasma.
If the Vd for a drug is large, most of the drug is in the
extraplasmic space and is unavailable to the excretory
organs.
Therefore, any factor that increases the volume of
distribution can lead to an increase in the half-life and
extend the duration of action of the drug.
[Note: An exceptionally large Vd indicates considerable
sequestration of the drug in some organ or compartment.]
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39. Redistribution
Highly lipid soluble drugs given i.v or by inhalation, initially get
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 the drug is
withdrawn from these sites.
If the site of action of drug was in one of the highly perfused
organs, redistribution results in termination of drug action.
Anaesthetic action of thiopentone is terminated in few minutes
due to redistribution. How ever, when the same drug is given
repeatedly or continously over long periods, the low perfusion
high capacity sites get progressively filled and the drug become
long acting.

40. Questions :
1. What is absorption and bioavailability? Explain
the factors affecting absorption with suitable e.g.
2.Describe different mechanism by which drug
cross various biological membrane
3. Write brifely on:
1. First pass effect
2. Volume of distribution and its clinical
significance
3. Redistribution
4. BBB
5. Placenta barrier
6. Clinical importance of plasma protein binding
4.Define drug distribution. Mention the factor that
affect drug distribution in detail.