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MIHS 1
By
Dr. Faraza Javaid
MIHS 2
Disposition
Disposition
Once a drug has gained access to the blood
stream, the drug is subjected to a number of
processes called as Disposition Processes
that tend to lower the plasma concentration.
1. Distribution which involves reversible
transfer of a drug between compartments.
2. Elimination which involves irreversible loss of
drug from the body. It comprises of
metabolism and excretion.
MIHS 3
Drug Distribution refers to the
Reversible Transfer of a Drug between the
Blood and the Extra Vascular Fluids and
Tissues of the body
(for example, fat, muscle, and brain tissue).
MIHS 4
•The Process
occurs by the
Diffusion of
Free Drug
until
equilibrium is
established.
Distribution is a
Passive Process,
for which the
driving force is the
Conc. Gradient
between the blood
and Extravascular
Tissues
MIHS 5
MIHS 6
MIHS 7
Distribution of a drug is not Uniform
throughout the body because different
tissues receive the drug from plasma at
different rates and to different extents.
……..
FACTORS AFFECTING
DISTRIBUTION OF
DRUGS
MIHS 8
Following factors affect distribution of drugs.
1. Regional blood flow
2. Capillary permeability
3. The degree of binding of drug to plasma and
tissue proteins.
MIHS 9
A. BLOOD FLOW
 Depends upon cardiac output
 Varies widely due to unequal distribution of cardiac
output to various organs.
 Blood flow to brain, liver and kidney is greater
>then skeletal muscle>then adipose tissue, skin
and viscera.
MIHS 10
B.CAPILLARY PERMEABILITY
CAPILLARY PERMEABILITY DEPENDS UPON:
1.CAPILLARY STRUCTURE
2.CHEMICAL NATURE OF THE DRUG
Capillary structure
 The basement membrane of the capillary wall is
fractioned by slit junctions between endothelial
cells.
 Greater the slit junctions, greater the passage of
drug molecules.
 liver and spleen have more slit junctions
 In brain capillaries ,there are no slit junctions so to
enter the brain the drug must pass through the
endothelial cells of the capillaries or be actively
transported.
MIHS 11
Chemical nature of the drug
 Ionized or polar drugs fail to enter the CNS because
they are unable to pass through endothelial cells.
 Hydrophilic drugs by contrast do not readily
penetrate cell membranes and must pass through
the slit junctions.
 The lipid soluble drugs readily penetrate the CNS
because they can penetrate the endothelial cells of
capillaries.
 Hydrophobic drugs readily cross the biological
membranes and dissolve in the lipid membranes so
the major factor influencing the hydrophobic drug
distribution is the blood flow to the area.
MIHS 12
MIHS 13
C.BINDING OF DRUG TO PROTEINS
THIS INCLUDE:
1) BINDING TO PLASMA PROTEINS
2) BINDIND TO TISSUE PROTEINS
MIHS 14
1)BINDING TO PLASMA PROTEINS
 Reversible binding to plasma proteins sequesters
drugs in a non diffusible form and slows their
transfer out of the vascular compartments.
 Major proteins are albumin and globulin.
 Plasma proteins also act as drug reservoirs that is
when the concentration of free drug decreases
due to metabolism or excretion then the bound
drug dissociates from the protein.
MIHS 15
2)BINDING TO TISSUE PROTEINS
 Drugs may accumulate as a result of binding to
lipids, proteins and nucleic acids.
 Act as tissue reservoirs
 Some times cause local drug toxicity e.g.
ACROLEIN the metabolite of
CYCLOPHOSPHAMIDE is toxic to kidney as it
accumulates in the renal cells.
MIHS 16
D. VOLUME OF DISTRIBUTION
 The Volume of distribution (VD), also known as Apparent
volume of distribution, is used to quantify the distribution of a
drug between plasma and the rest of the body after oral or
parenteral dosing.
 It is called as Apparent Volume because all parts of the body
equilibrated with the drug do not have equal concentration.
 It is calculated by dividing the dose that ultimately gets into the
systemic circulation by the plasma concentration at time zero
(C0).
MIHS 17
Redistribution
 Highly lipid soluble drugs when given by 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 and plasma concentration falls
and drug is withdrawn from these sites Which have
more drug concentration like heart, brain, kidney etc.
 Greater the lipid solubility of the drug, faster is its
redistribution.
MIHS 18
DRUG
RESERVOIRS
MIHS 19
DRUG RESERVOIRS
 Drug reservoirs are the water compartments in the
body as well as the other storage sites .
 Water compartments
1. PLASMA VOLUME
2. EXTRACELLULAR FLUID
3. TOTAL BODY WATER
 Storage sites
1. Adipose
2. Bone
3. Muscle
4. Organs
MIHS 20
Water compartments
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 (4L).
 Heparin shows this type of distribution.
MIHS 21
Water compartments
Extracellular fluid:
 If a drug has a low molecular weight but is
hydrophilic, it can move through the endothelial slit
junctions of the capillaries into the interstitial fluid.
 However, these hydrophilic drugs cannot move
across the lipid membranes of cells to enter the
water phase inside the cell.
 Therefore, these drugs distribute into a volume that
is the sum of the plasma water and the interstitial
fluid, which together constitute the extracellular fluid
(14L).
 Aminoglycoside antibiotic is an example.
22
Water compartments
Total body water:
 If a drug has a low molecular weight and is
hydrophobic, not only can it move into the
interstitium through the slit junctions, but it can
also move through the cell membranes into the
intracellular fluid (42L).
 Ethanol exhibits this type of volume of
distribution.
MIHS 23
Storage sites
ADIPOSE
 For lipid soluble drugs, fat deposits throughout the
body serve as a considerable reservoir .
 Drugs stored in adipose tissue remain there for long
periods because of low metabolic rate and poor blood
perfusion of fat tissues.
 Example ;- barbiturate anaesthetic like THIOPENTAL
Inhalational anesthetics like HALOTHANE.
BONE
 Storage site for several toxic agents especially heavy
metals like lead.
 Example ; TETRACYCLINE 24
Storage sites
Muscle
 long term storage
 Example; antimalarial drug QUININE.
ORGANS
 like Liver and kidneys
 Example; Antimicrobial aminoglycoside agents such
as GENTAMICIN and STREPTOMYCIN that is stored
in renal proximal tubular cells.
MIHS 25
26

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Drug Distribution.ppt

  • 3. Disposition Once a drug has gained access to the blood stream, the drug is subjected to a number of processes called as Disposition Processes that tend to lower the plasma concentration. 1. Distribution which involves reversible transfer of a drug between compartments. 2. Elimination which involves irreversible loss of drug from the body. It comprises of metabolism and excretion. MIHS 3
  • 4. Drug Distribution refers to the Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (for example, fat, muscle, and brain tissue). MIHS 4
  • 5. •The Process occurs by the Diffusion of Free Drug until equilibrium is established. Distribution is a Passive Process, for which the driving force is the Conc. Gradient between the blood and Extravascular Tissues MIHS 5
  • 7. MIHS 7 Distribution of a drug is not Uniform throughout the body because different tissues receive the drug from plasma at different rates and to different extents.
  • 9. Following factors affect distribution of drugs. 1. Regional blood flow 2. Capillary permeability 3. The degree of binding of drug to plasma and tissue proteins. MIHS 9
  • 10. A. BLOOD FLOW  Depends upon cardiac output  Varies widely due to unequal distribution of cardiac output to various organs.  Blood flow to brain, liver and kidney is greater >then skeletal muscle>then adipose tissue, skin and viscera. MIHS 10
  • 11. B.CAPILLARY PERMEABILITY CAPILLARY PERMEABILITY DEPENDS UPON: 1.CAPILLARY STRUCTURE 2.CHEMICAL NATURE OF THE DRUG Capillary structure  The basement membrane of the capillary wall is fractioned by slit junctions between endothelial cells.  Greater the slit junctions, greater the passage of drug molecules.  liver and spleen have more slit junctions  In brain capillaries ,there are no slit junctions so to enter the brain the drug must pass through the endothelial cells of the capillaries or be actively transported. MIHS 11
  • 12. Chemical nature of the drug  Ionized or polar drugs fail to enter the CNS because they are unable to pass through endothelial cells.  Hydrophilic drugs by contrast do not readily penetrate cell membranes and must pass through the slit junctions.  The lipid soluble drugs readily penetrate the CNS because they can penetrate the endothelial cells of capillaries.  Hydrophobic drugs readily cross the biological membranes and dissolve in the lipid membranes so the major factor influencing the hydrophobic drug distribution is the blood flow to the area. MIHS 12
  • 14. C.BINDING OF DRUG TO PROTEINS THIS INCLUDE: 1) BINDING TO PLASMA PROTEINS 2) BINDIND TO TISSUE PROTEINS MIHS 14
  • 15. 1)BINDING TO PLASMA PROTEINS  Reversible binding to plasma proteins sequesters drugs in a non diffusible form and slows their transfer out of the vascular compartments.  Major proteins are albumin and globulin.  Plasma proteins also act as drug reservoirs that is when the concentration of free drug decreases due to metabolism or excretion then the bound drug dissociates from the protein. MIHS 15
  • 16. 2)BINDING TO TISSUE PROTEINS  Drugs may accumulate as a result of binding to lipids, proteins and nucleic acids.  Act as tissue reservoirs  Some times cause local drug toxicity e.g. ACROLEIN the metabolite of CYCLOPHOSPHAMIDE is toxic to kidney as it accumulates in the renal cells. MIHS 16
  • 17. D. VOLUME OF DISTRIBUTION  The Volume of distribution (VD), also known as Apparent volume of distribution, is used to quantify the distribution of a drug between plasma and the rest of the body after oral or parenteral dosing.  It is called as Apparent Volume because all parts of the body equilibrated with the drug do not have equal concentration.  It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0). MIHS 17
  • 18. Redistribution  Highly lipid soluble drugs when given by 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 and plasma concentration falls and drug is withdrawn from these sites Which have more drug concentration like heart, brain, kidney etc.  Greater the lipid solubility of the drug, faster is its redistribution. MIHS 18
  • 20. DRUG RESERVOIRS  Drug reservoirs are the water compartments in the body as well as the other storage sites .  Water compartments 1. PLASMA VOLUME 2. EXTRACELLULAR FLUID 3. TOTAL BODY WATER  Storage sites 1. Adipose 2. Bone 3. Muscle 4. Organs MIHS 20
  • 21. Water compartments 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 (4L).  Heparin shows this type of distribution. MIHS 21
  • 22. Water compartments Extracellular fluid:  If a drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid.  However, these hydrophilic drugs cannot move across the lipid membranes of cells to enter the water phase inside the cell.  Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid, which together constitute the extracellular fluid (14L).  Aminoglycoside antibiotic is an example. 22
  • 23. Water compartments Total body water:  If a drug has a low molecular weight and is hydrophobic, not only can it move into the interstitium through the slit junctions, but it can also move through the cell membranes into the intracellular fluid (42L).  Ethanol exhibits this type of volume of distribution. MIHS 23
  • 24. Storage sites ADIPOSE  For lipid soluble drugs, fat deposits throughout the body serve as a considerable reservoir .  Drugs stored in adipose tissue remain there for long periods because of low metabolic rate and poor blood perfusion of fat tissues.  Example ;- barbiturate anaesthetic like THIOPENTAL Inhalational anesthetics like HALOTHANE. BONE  Storage site for several toxic agents especially heavy metals like lead.  Example ; TETRACYCLINE 24
  • 25. Storage sites Muscle  long term storage  Example; antimalarial drug QUININE. ORGANS  like Liver and kidneys  Example; Antimicrobial aminoglycoside agents such as GENTAMICIN and STREPTOMYCIN that is stored in renal proximal tubular cells. MIHS 25
  • 26. 26