Transcript Distribution of Drug

DISTRIBUTION
OF DRUG
Dr. Muslim Suardi
Faculty of Pharmacy
University of Andalas
2009
Distribution of Drug
After absorption
or
Injected intravenously
Heart
Bloodstream
Introduction
Once a drug has gained excess to the
blood stream, it is subjected to a number
of processes called as Disposition
Processes that tend to lower the Cp.
1. Distribution: Reversible transfer of a drug
between compartments.
2. Elimination: Irreversible loss of drug from
the body. It comprises of biotransformation & excretion.
Distribution of Drug
Involves reversible transfer of a drug
between compartments.
Drug molecules are distributed is throughout
the body by systemic circulation
Drug Distribution
“Reversible transfer of drug from one site to
another within the body”
Drug Distribution
Reversible Transfer of a Drug between:
Blood
Extra Vascular Fluids
Tissues of the body
(Fat, muscle, & brain tissue)
Distribution Process
• Distribution is a Passive Process
• Driving force is the concentration
gradient between the blood &
extravascular tissues
Drug in Systemic Circulation
Unbound
Bound
Diffusion of Drug
Diffusion of unbound drug until
equilibrium is established.
Distribution of Drug
By blood to:
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2.
3.
4.
5.
6.
7.
Receptor
Non receptor, caused side effects
Eliminating organs: liver & kidneys
Tissues: brain, skin & muscle
Placenta, breast milk
Bound to proteins in the plasma & tissues
Fat
Distribution in Tissue
Distribution of a drug is not uniform
throughout the body because different
tissues receive the drug from plasma at
different rates & to different extents.
Factors Affecting Drug
Distribution
Rate of distribution
• Membrane permeability
• Blood perfusion
Extent of Distribution
• Lipid Solubility
• pH - pKa
• Plasma protein binding
• Intracellular binding
Circulatory System
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Artery: which carry blood to tissues
Veins: which return blood back to the heart
BW 70 kg, 5L of blood, 3 L plasma
50% of the blood is in large veins or
venous sinuses
• Mixing of drug in the blood occurs rapidly
Circulatory System
• Drug molecules rapidly diffuse through fine
capillaries to the tissues filled with
interstitial fluid
• Interstitial fluid + plasma water is termed
the extracellular water
Drug Molecules Across Cell
Membrane
Depend upon:
• Physicochemical nature of both the drug &
the cell membrane
• Cell membrane: Protein & bi-layer of
phospholipid
• Lipid-soluble drug more easily
• Drug-protein complex: too large
Drugs Transverse Process
Passive diffusion (mainly)
Hydrostatic pressure
Passive Diffusion
Drug molecules move from high to low
Fick’s Law of Diffusion
Distribution is a Passive Process
Driving force is the conc. gradient between
the blood & extravascular tissues
Diffusion
Diffusion of unbound drug until equilibrium is
established.
Fick’s Law of Diffusion
Rate of drug diffusion
dQ/dt = -DKA/h (Cp-Ct)
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D = the diffusion constant
K = the lipid-water partition coefficient
A = the surface area of the membrane
h = the thickness of the membrane
Hydrostatic pressure
Figure !
Role of Distribution
Pharmacological action of a drug depends
upon its concentration at the site of action
So that,
Distribution plays a significant role in the:
Onset,
Intensity, &
Duration of action.
Uniformity of Drug
Distribution
Distribution of a drug is not Uniform
throughout the body because different
tissues receive the drug from plasma at
different rates & to different extents.
Patterns of Drug Distribution
1.The drug may remain largely within the
vascular system.
Ex: Plasma substitutes such as dextran &
drugs which are strongly bound to plasma
protein
Patterns of Drug Distribution
2.Some are uniformly distributed
throughout the body water.
Ex: low MW water soluble compounds
(EtOH) & a few sulfonamides
Patterns of Drug Distribution
3.A few drugs are concentrated
specifically in one or more tissues that
may or may not be the site of action.
Ex: Iodine (in the thyroid gland),
chloroquine (in the liver even at conc 1000
times those present in plasma),
tetracycline (irreversibly bound to bone &
developing teeth) & highly lipid soluble
compounds (distribute into fat tissue)
Patterns of Drug Distribution
4.Most drugs exhibit a non-uniform
distribution in the body (largely
determined by the ability to pass through
membranes & their lipid/water solubility).
The highest concentrations are often
present in the kidneys, liver, & intestine.
Volume of Distribution
Apparent Vd: to quantify the distribution
of a drug between plasma & the rest of the
body after oral or parenteral dosing.
Called as Apparent Volume because all
parts of the body equilibrated with the drug
do not have equal conc.
The drug would be uniformly distributed to
produce the observed blood conc.
Factors Related with the Differences of
Drug Distribution
1. Tissue Permeability of the Drug
a. Physiochemical Properties of the drug
eg. MW, pKa & o/w Partition coefficient.
b. Physiological Barriers to Diffusion of
Drugs.
2. Organ/Tissue Size & Perfusion Rate
Factors Related with the Differences of
Drug Distribution
3. Binding of Drugs to Tissue Component
(Blood components & Extravascular
Tissue Proteins)
4. Miscellaneous Factors
Age, Pregnancy, Obesity, Diet, Disease
states, & DI.
Tissue Permeability of the
Drugs
Depends Upon:
1. Rate of Tissue Permeability
2. Rate of Blood Perfusion.
The Rate of Tissue
Permeability
Depends upon:
1. Physicochemical nature of the drug
2. Physiological barriers that restrict the
diffusion of drug into tissues.
Physiochemical Properties that
Influence Drug Distribution
MW
pKa
o/w Partition coefficient.
Diffusion of Drug Molecule
• Drugs having MW <400D easily cross the
capillary membrane to diffuse into the
extracellular interstitial fluids.
• Penetration of drug from the Extracellular
Fluid (ECF) is a function of
MW &
ionization
Diffusion Related with MW &
Ionization
* Molecular Size:
Small ions of size <50D enter the cell through
aqueous filled channels where as larger size ions are
restricted unless a specialized transport system exists
for them.
* Ionisation
A drug that remains unionized at pH values of blood &
ECF can permeate the cells more rapidly.
Blood & ECF pH normally remains constant at 7.4,
unless altered in conditions like systemic
alkalosis/acidosis
Lipophilicity
Only unionized drugs that are lipophilic rapidly
crosses the cell membrane
e.g. Thiopental, a lipophilic drug, largely
unionized at blood & ECF pH readily diffuses
the brain where as Penicillins which are polar
& ionized at plasma pH do not cross BBB.
PENETRATION OF DRUGS
THROUGH BBB
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A stealth of endothelial cells lining the capillaries.
It has tight junctions & lack large intra cellular pores.
Further, neural tissue covers the capillaries.
Together, they constitute the BBB
Astrocytes: Special cells/elements of supporting tissue
are found at the base of endothelial membrane.
• The BBB is a separation of circulating blood & CSF
maintained by the choroid plexus in the CNS.
BBB
• BBB is a lipoidal barrier
• It allows only the drugs having high o/w
partition coefficient to diffuse passively
where as moderately lipid soluble &
partially ionized molecules penetrate at a
slow rate.
BBB
• Endothelial cells restrict the diffusion of
microscopic objects (e.g. bacteria ) & large
or hydrophillic molecules into the CSF,
while allowing the diffusion of small
hydrophobic molecules (O2, CO2,
hormones).
Cells of the barrier actively transport
metabolic products such as glucose
across the barrier with specific proteins.
Various Approaches to
Promote Crossing BBB
• Use of permeation enhancers: DMSO.
• Osmotic disruption of the BBB by infusing
internal carotid artery with mannitol.
• Use of Dihydropyridine Redox system as
drug carriers to the brain (the lipid soluble
dihydropyridine is linked as a carrier to
the polar drug to form a prodrug that
rapidly crosses the BBB )
PENETRATION OF DRUGS THROUGH
PLACENTAL BARRIER
• Placenta is the membrane separating fetal
blood from the maternal blood.
• It is made up of fetal trophoblast basement
membrane the endothelium.
• Mean thickness in early pregnancy is (25
µm) which reduces to (2µm) at full term.
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 &
Cp falls & drug is withdrawn from these
sites.
Redistribution
If the site of action of the drug was in
one of the highly perfused organs,
redistribution results in termination of the
drug action
Greater the lipid solubility of the drug,
faster is its redistribution.
Redistribution
If the site of action of the drug was in
one of the highly perfused organs,
redistribution results in termination of the
drug action.
Greater the lipid solubility of the drug,
faster is its redistribution.
Drug Distribution & t1/2el
• Drug elimination is mainly governed by
renal & other metabolic processes
• Extensive drug distribution has the effect
of diluting in a large volume, harder for the
kidney to filter by GF
• t1/2 el is prolonged if Cl is constant & Vd is
increased
• t1/2 el = 0.693 Vd/Cl
Clinical Examples
Large Vd & long t1/2el
• Dirithromycin is extensively distributed in
the tissues resulting in a large SS Vd of ±
800L. t1/2el in human ± 44h, large total
body Cl 226-1040 mL/min, & given s.i.d.
Small Cl generally leads to a longer t1/2el.
In this case, Cl is large but t1/2el is longer
because of the large Vd.
Clinical Examples
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Small Vd & a long t1/2el
Tenoxicam, is a NSAID
99% bound to plasma protein, t1/2el of 67h
Low lipophilicity & highly ionized
Very polar, drug penetrates membranes slowly
Synofial fluid peak level only 1/3 plasma, occurs
20h later than plasma
Drug poorly distributed to body tissues, Vd 9.6L
In this case: t1/2el is long because the plasma
tenoxicam cl is so small that dominates
Drug Accumulation
Depend upon:
Blood flow
Affinity of the drug for the tissue
Processes of Drug Accumulation
• Affinity of the drug for the tissue
• Concentrated drug in the adipose tissue
• Binding of drug to proteins or other
macromolecules in tissue
• Drug is irreversible bound into a particular
tissue
Affinity of The Drug for
The Tissue
• Uptake of the drug into the tissue is
generally controlled by the difussional
barrier of the capillary membrane & other
cell membrane
• Brain is well perfused with blood, but many
drugs with good aqueous solubility have
high kidney, liver, & lung concentration, &
yet little brain drug concentration.
Concentrated Drug in The
Adipose Tissue
• Drug uptake into a tissue is generally
reversible
• Drugs with a high lipid/water partition
coefficient are very fat soluble & tend to
accumulate in adipose tissue.
• Because of the extraction of drug out of
the tissue is so slow.
• Drug may remain for days
Concentrated Drug in The
Adipose Tissue
• Adipose tissue is poorly perfused with
blood, accumulation is slow
• Once the drug is concentrated in fat
tissue, removal from fat may also be slow
• DDT is highly lipid soluble & remains in fat
tissue for years!
Binding of Drug to Proteins or
Other Macromolecules
• Digoxin is highly bound to proteins in
cardiac tissues, large Vd 440L & long t1/2el
40h
• Some drugs may complex with melanin in
the skin & eye (long term phenotiazine)
• Tetra forms an insoluble chelate with Ca
• Amphetamine is actively transported into
adrenergic tissue
Drug is Irreversible Bound Into a
Particular Tissue
• Drug/reactive intermediate metabolite
become covalently bound to a
macromolecule within the cell
• Many purine & pyrimidine used in cancer
therapy are incorporated into nucleic
acids, causing destruction of the cell
Distribution & Pharmacodynamic
• Onset of drug action depends upon the rate of
unbound drug that reaches the receptor at a
MEC to produce a PD response
• Onset time is often dependent upon the rate of
drug uptake & distribution to the receptor site
• The intensity of a drug action depends upon the
total drug concentration of the receptor site & the
number of receptor occupied by drug
Effect of Binding on Vd
• Extend of protein binding in plasma or
tissue will affect Vd
• Drugs highly bound to plasma proteins will
have a low fraction of free drug in plasma
water, harder to diffuse, & less extensively
distributed to tissues
• Drugs with low plasma protein binding
have greater unbound fraction, easier
diffusion & greater Vd
Protein Binding
Protein Binding
Many drugs interact with:
• Plasma Proteins
• Tissue Proteins
• Macromolecules: melanin, DNA
To form a macromolecule complex
Drug-Protein Binding
Process:
Reversible
Irreversible
Reversible
Weaker chemical bonds:
Hydrogen bond
van der Waals forces
Irreversible
Strongly by covalent chemical bonding
• Toxicity for a long time period (chemical
carcinogenic) or
• Short time period (reactive chemical
intermediates)
• Ex: PCT, reactive metabolite intermediate
interact with liver proteins
Plasma Proteins
Albumin
Acid glycoprotein
Lipoproteins
Studying Protein Binding
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Equilibrium dialysis
Dynamic dialysis
Diafiltration
Ultrafiltration
Gel chromatography
Spectrophotometry
Electrophoresis
Optical rotary dispersion & circulatory dichroism
Important Factors in Binding
1. The drug
2. The protein
3. The affinity between drug & protein
4. Drug interaction
5. The pathophysiologic condition of the
patient
1. The drug
• Physicochemical properties of the drug
• Total concentration of the drug in the body
2. The protein
1. Quantity of protein available for drugprotein binding
2. Quality of physicochemical nature of the
protein synthesized
3. Affinity Between Drug &
Protein
Includes the magnitude of the association
constant
4. Drug Interaction
• Competition for the drug by other
substances at a protein-binding site
• Alteration of the protein by a substance
that modifies the affinity of the drug for the
protein.
• Ex: aspirin acetylates lysine residues of
albumin
5. Pathophysiologic Condition
Example:
Drug-protein binding may be reduced in
uremic patients & in patients with hepatic
disease
REFERENCES
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Shargel, Wu-Pong & Yu, 2004.
Rani & Hiremath, 2000.
Brahmankar & Jaiswal, 2008.
Gibaldi, 1982.