2. Objectives
• Define drug distribution and understand the
processes involved.
• Understand volume of distribution and its
interpretation
• Understand factors affecting drug distribution
3. Introduction
• After absorption into the bloodstream, drugs
are distributed to receptors at its site of
action, to silent or inactive receptors in other
tissue and to sites of metabolism and
excretion.
• Via blood flow and diffusion and/or filtration
across the capillary membranes of various
tissues.
4. • Drug Distribution is the delivery of drug from
the systemic circulation to tissues
• It also means the reversible transfer of drug
from one location to another within the body
• Therefore, it is the reversible movement of
drug from the systemic circulation to tissues.
5.
6.
7. • Initial distribution is determined by cardiac
output and regional blood flow.
–▴ Drugs are initially distributed to tissues
with the highest blood flow (e.g., brain,
lungs, kidney, and liver).
–▴ Tissues with lower blood flow (e.g., fat)
receive drugs later.
8. • Distribution to some tissue compartments is
restricted by barriers.
– ▴ The blood-brain barrier restricts distribution of
hydrophilic drugs into the brain.
9. Drug Redistribution
• After the initial distribution to high-blood flow
tissues, drugs redistribute to those tissues for
which they have affinity.
• Drugs may sequester in tissues for which they
have affinity.
10. • These tissues may then act as a sink for the
drug and increase its apparent volume of
distribution (see later).
• In addition, as plasma concentrations of drug
fall, the tissue releases drug back into the
circulation, thus prolonging the duration of
action of the drug.
11. Drug distribution patterns
1. The drug may remain largely within the
vascular system.
• Plasma substitutes such as dextran are an
example of this type, but drugs which are
strongly bound to plasma protein may also
approach this pattern.
12. 2. Some low molecular weight water soluble
compounds such as ethanol and a few
sulfonamides become uniformly distributed
throughout the body water.
13. 3. A few drugs are concentrated specifically in
one or more tissues that may or may not be
the site of action.
• Iodine is concentrated by the thyroid gland.
• The antimalarial drug chloroquine may be
present in the liver at concentrations 1000 times
those present in plasma.
14. • Tetracycline is almost irreversibly bound to
bone and developing teeth.
• Another type of specific concentration may
occur with highly lipid soluble compounds
which distribute into fat tissue.
15. 4. Most drugs exhibit a non-uniform distribution
in the body with variations that are largely
determined by the ability to pass through
membranes and their lipid/water solubility.
19. • The volume of distribution represents the
theoretical volume in liters into which a drug
is dissolved to produce the plasma
concentration observed at steady state.
• Also called apparent volume of distribution.
• Denoted as Vd .
• Volume of distribution is calculated as the
quotient of the amount of drug administered
and the steady state plasma concentration
22. • Vd will be affected by drug binding to different
physiologic compartments.
• Vd can be used to infer some characteristics of
drug distribution.
• Vd is largely determined by the chemical
characteristic of the drug and its ability to
interact with various tissue compartments.
– ▴ Vd in excess of total body water (approximately
42 L) indicates that drug is being sequestered in a
tissue compartment.
• Lipophilic drugs (e.g., thiopental) tend to sequester in fat.
• Some drugs bind with high affinity to certain tissues.
Digoxin tends to bind to protein in skeletal muscle.
23. • Water-soluble drugs have a Vd that
approximates the total extracellular water
(approximately 14 L).
• Drugs that bind extensively to plasma proteins
generally have a relatively small volume of
distribution (e.g., 7 to 8 L) because these drugs
will be highly restricted to the plasma.
• Changes in Vd influence drug plasma
concentrations and may necessitate changes in
dosage or result in toxicity.
24. • For example, loss of skeletal muscle mass with
aging or disease (heart failure) requires a
reduction in the dose of digoxin, a drug that is
highly bound to skeletal muscle protein.
• The dose of digoxin is often adjusted to lean
body mass.
25. • Apparent volume of distribution ( Vd) is a
useful indicator of the type of pattern that
characterizes a particular drug.
• A value of Vd in the region of 3-5 liter (in
an adult) would be compatible with
pattern 1. This is approximately the
volume of plasma.
• Pattern two would be expected to
produce a Vd value of 30 to 50 liter,
corresponding to total body water.
26. • Agents or drugs exhibiting pattern 3 would
exhibit very large values of Vd. Chloroquine
has a Vd value of approximately 115 L/ kg .
• Drugs following pattern 4 may have a Vd value
within a wide range of values.
27. Factors affecting drug distribution:
• Once a drug has entered the blood
compartment, the rate at and the extent to
which it penetrates tissues and other body
fluids depends on several factors
28. Factors Affecting Distribution
A- Rate of distribution B- Extent of Distribution
1. Membrane permeability
2. Blood perfusion
1. Lipid Solubility
2. pH – pKa
3. Plasma protein binding
4. Tissue drug binding
29. Rate of distribution
1. Membrane permeability:
• Capillary walls are quite permeable.
• Lipid soluble drugs pass through very rapidly.
• Water soluble compounds penetrate more slowly
at a rate more dependent on their size.
• Low molecular weight drugs pass through by
simple diffusion. For compounds with molecular
diameter above 100 Å transfer is slow.
• For 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.
30. 2. Blood perfusion rate:
• The rate at which blood perfuses to different
organs varies widely.
• Occurs when tissue membranes present no
barrier to distribution.
• Expressed in units of milliliters of blood per
minute per volume of tissue.
• If all factors remaining equal, well perfused
tissues take up a drug much more rapidly than do
poorly perfused tissues.
31. • The rate at which a drug reaches different
organs and tissues will depend on the blood
flow to those regions.
• Equilibration is rapidly achieved with heart,
lungs, liver, kidneys and brain where blood
flow is high.
• Skin, bone, and depot fat equilibrate much
more slowly.
32.
33. Extent of Distribution
1.Lipid Solubility:
• Lipid solubility will affect the ability of the
drug to bind to plasma proteins and to cross
lipid membrane barriers.
• Very high lipid solubility can result in a drug
partitioning into highly vascular lipid-rich
areas.
• Subsequently these drugs slowly redistribute
into body fat where they may remain for long
periods of time.
34. 2. Effects of pH:
• The rate of movement of a drug out of
circulation will depend on its degree of
ionization and therefore its pKa.
• Changes in pH occurring in disease may also
affect drug distribution. For example, blood
becomes more acidic if respiration is
inadequate.
35. 3.Plasma protein binding:
• The interaction between a protein and drug is
reversible ,it obeys the law of mass action.
36.
37. • And is determined by
- the concentration of drug
- the affinity of the protein for the drug and
- the number of binding sites available.
38. • Plasma proteins, such as albumin, α-
glycoprotein, and steroid hormone binding
globulins, exhibit affinity for a number of
drugs.
• While many acidic drugs bind principally to
albumin,
• Basic drugs frequently bind to other plasma
proteins, such as lipoproteins and α1-acid
glycoprotein (α 1-AGP)
39. • Plasma protein binding greatly reduces the
amount of drug free in the plasma.
40. Clinical importance of Protein binding
• For highly protein-bound drugs, a small
change in plasma protein binding can lead to
a large change in the proportion of free drug
in the plasma and may lead to toxicity.
• For a drug that is 99% bound to plasma
protein, only 1% is free in the plasma.
Reduction of plasma protein binding to 98%
results in a doubling of free drug and drug
effect.
41. CONT….
Changes in plasma protein binding can occur as
a result of:
– Disease (malnutrition, liver and renal )
–Saturation of binding sites
– Competition between drugs for the same
binding site
42. CONT..
• One drug may displace another from the same
binding site e. g. coumarin anticoagulants, are
able to displace less tightly bound compounds
from their binding sites.
• One drug bound may alter binding of another
43. • Interactions can occur when one drug
displaces another
• Competition lead to increased free drug
concentration
• Protein binding limit/contain the drug in the
plasma.
44. 4. Tissue Drug Binding
• In addition to plasma protein binding, drugs
may bind to intracellular molecules.
• The affinity of a tissue for a drug may be due
to: binding to tissue proteins or to nucleic
acids, or in the case of adipose tissue,
dissolution in the lipid material.
45. • Binding to tissues results in sequestration of
drug in the tissue.
• Tissue bindings sites:
• Increase the apparent volume of
distribution.
• Represent potential sites for drug
interactions.
• Result in sequestration of drug in the tissue.
• May release the drug back into the
circulation as the plasma concentration
falls. Thus tissue binding may represent a
reservoir of drug that can extend the
duration of action of the drug.
46. SPECIAL BODY COMPARTMENTS
AND SPECIAL BARRIERS:
• For tissues with a lipid membrane between
plasma and the site of drug action and a large
blood flow ( e.g. brain, placenta ) drug
permeability across the membrane is usually
the limiting factor(BBB,BPB)
47. THE BRAIN
• The brain is inaccessible to many drugs
• However in some parts of the brain like the
chemoreceptor trigger zone (CTZ) the BBB is
leaky and allows some drugs to enter like
domperidone a dopamine receptor agonist
• Domperidone is useful in preventing nausea
and vomiting induced by dopamine receptor
agonists like apomorphine
• Fat insoluble drugs generally do not penetrate
the BB
48. • Highly polar, water-soluble drugs ( e.g.
Gentamicin ) penetrates slowly, if at all in the
brain
• Non-polar, lipid-soluble drugs ( e.g.
Thiopentone ) penetrates rapidly, and drugs
with intermediate solubility ( e.g. Tetracycline
) penetrate at intermediate rate.
49.
50. -Essential nutrients ( amino acids, glucose,
purines, pyrimidines) are actively transported
into the CSF and brain.
-Levodopa ( which is a naturally occurring amino
acid ) and its analogue methyldopa also enter
by this means.
51. • Inflammation does disrupt the integrity of the
BBB allowing some water soluble drugs to
enter the brain
• Drugs like penicillin readily enter the brain
during meningitis
52. PLACENTA
• Lipid-soluble drugs cross the placenta readily
• Hence general anaesthetic agents can
interfere with respiration in the newborn child
after administration to mother during delivery
• Morphine and related analgesic agents cause
the same problem
• All drugs penetrate into the foetal circulation
at some rate.
• Even highly polar water-soluble drugs [ e.g.
gentamicin ] penetrate to the foetus slowly.
53. BREAST:
• The breast is an example of a pharmacokinetic
deep compartment with a moderate blood
supply.
• Most drugs enter breast milk by passive
diffusion through lipid membranes.
• Compounds with a MW less than 100 Da
(Ethanol ) enter by passive diffusion through
water filled pores in the membrane.
• Iodine is actively transported and, therefore,
administration of radio-active iodide to
mother is an absolute contraindication to
breast feeding.
54. • For most drugs concentrations in milk are
similar to those in plasma at equilibrium.
• However, as the amount of drug in plasma is
usually small in relation to the total amount
in the body, so the total amount of drug
delivered to infant during breast feeding is
small in relation to doses recommended for
therapeutic purposes in infants.
55. • Hence feeding can be, continued when the
mother is taking digoxin, tricyclic anti-
depressant drugs paracetamol, phenytoin,
diuretic agents and even warfarin.
• Breast feeding should be discourage where
the mother is taking drugs for prolonged
periods and where the drugs could have
serious adverse effects on the infant ( radio-
active iodide, cytotoxic drugs, carbimazole,
theophylline, sulphonylurea oral
hypoglycaemic drugs ).
56. ABSCESS CAVITIES:
• Acute abscesses are thin walled and have an
increased local blood flow.
• Consequently antibiotics penetrate readily.
• Chronic abscesses have thick avascular walls
and drugs do not penetrate.
• Similarly penetration into sputum is slow.
• In acute ( but not chronic ) otitis media (
infection of middle ear ) the organisms are
accessible.
57. SKIN AND NAILS
• These are avascular and thus penetration of
drugs from the systemic circulation is very
slow.
• Griseofulvin, an anti-fungal agent, has a large
affinity for keratin and so achieves selectively
large concentrations in skin and nails.
58. BONES AND TEETH:
• Drug access is proportional to local blood flow.
• The growth region of bone is moderately well
perfused.
• Blood flow becomes very small when growth
ceases.
• Certain drugs and ions form complexes with
bone salt, especially in growing bone ( e.g.
Lead, Fluoride, Tetracyclines ).
59. SEROUS CAVITIES:
• In general, all drugs enter and leave serous
cavities ( pleural, pericardial, peritoneal sacs,
joint spaces ) slowly.
• Water-soluble drugs penetrate slowly and lipid-
soluble drugs more rapidly.
• Acute inflammation facilitates the penetration
of drugs, as the movement of water through the
capillary epithelium increases during
inflammation.
• Chronic inflammation, however, leads to fibrosis
and this impedes penetration.
