1. PHARMACOKINETICS
DISTRIBUTION

2. DISTRIBUTION
Definition:
“Process where by an absorbed chemical moves
away from the site of absorption to other areas
of the body”.
•Following absorption (skin, lung, or
gastrointestinal tract) or systemic
administration (IV, IP, IM) into the bloodstream,
a drug distributes into interstitial and
intracellular fluids.

3. •Interstitial fluid represents about 15% of the
total body weight.
•Intracellular fluid (fluid inside cells) - 40% of
the total body weight.
•Blood plasma - 8% of the body weight.

4. •The rate of delivery and potential amount of
drug distributed into tissues depends on;
• Cardiac output, Regional blood flow, Capillary
permeability and tissue volume.
•Well-perfused organs (liver, kidney, brain)
initially receive most of the drug
•Lesser perfused pnes: delivery to muscle, most
viscera, skin, and fat is slower.

5. Distribution
• determines the transport of
drugs to their site of action, to other sites, and
to the organs of metabolism and excretion.
•Not uniform;
 Difference in perfusion rates.
 Penetrate - capillary endothelium.
 Diffuse across the cell membrane.

6. DISTRIBUTION
• Distribution is the dispersion of the drug among the various organs or
compartments within the body.
• The apparent volume of distribution (Vd), has been devised to describe the
distribution of the drug.
• Apparent volume of distribution is the theoretical volume that would
have to be available for drug to disperse in if the concentration
everywhere in the body were the same as that in the plasma or serum, the
place where drug concentration sampling generally occurs.
• Vd is the volume (Litre/kg) into which the drug appears to
distribute and it is calculated from the dosage (kg) and the
concentration of drug in the blood (kg/L) and body weight
(kgs)
Vd = D/(Cp x k)
• Example: Assume that 100 g of alcohol are ingested by a man who weighs 70 kg and the
blood level is found to equal 2.38 g/L. Vd = D/(Cp x k)
Vd = 0.100 kg/(0.00238 kg/L x 70 kg)
Vd = 0.60 L/kg or 42 L for this man

7. Volume of Distribution (Vd )
• values range from about 5% of body volume to as high as 400 L.
• The latter figure is much higher than anyone’s total volume, so Vd is an
artificial concept.
• Importance - it will predict whether the drug will reside in the blood or in the
tissue.
• Water soluble drugs will reside in the blood, and fat soluble drugs will reside
in cell membranes, adipose tissue and other fat-rich areas.
• Volume of Distribution also relates to whether a drug is Free / protein bound
• Drugs that are charged tend to bind to serum proteins.
• Protein bound drugs form macromolecular complexes that cannot cross
biological membranes and remain confined to the bloodstream.
• Pathological states may also change Vd.
• Because Vd mathematically relates blood concentration to dosage it may be
employed in interpretation of laboratory results.
• Useful for providing an estimate of dosage, it follows that it can help estimate
the amount of antidote to be given.
• Indicate whether there is any value in trying to enhance elimination as, for
example, by dialysis.

8. Volume of Distribution
• Vd is helpful in the context of drug monitoring.
• Predicts whether the practice of drug
measurement in blood will have any clinical
value.
• Psychotropic drugs such as tranquilizers,
antidepressants, antipsychotics, mood-altering agents, etc.,
create their effects by binding at sites within
the central nervous system.

10. Volume of Distribution
• An abstract concept
• Gives information on HOW the drug is
distributed in the body
• Used to calculate a loading dose

12. Clearance (CL)
• Ability of organs of elimination (e.g. kidney, liver) to “clear” drug from the
bloodstream.
• Volume of fluid which is completely cleared of drug per unit time.
• Units are in L/hr or L/hr/kg
• Pharmacokinetic term used in determination of maintenance doses.
• VD is a theoretical Volume and determines the loading dose.
• Clearance is a constant and determines the maintenance dose.
• Rate of elimination = kel D,
– Remembering that C = D/Vd
– And therefore D= C Vd
– Rate of elimination = kel C Vd
• Rate of elimination for whole body = CLT C
Combining the two, CLT C = kel C Vd and simplifying gives:
CLT = kel Vd
• CL and VD are independent variables.
• k is a dependent variable.

13. Clearance
• Volume of blood in a defined region of the
body that is cleared of a drug in a unit time.
• Clearance is a more useful concept in reality
than t 1/2 or kel since it takes into account blood
flow rate.
• Clearance varies with body weight.
• Also varies with degree of protein binding.

14. The factors determinining
Distribution/ tissue permeability of a drug:
The physico-chemical properties of the drug,
Binding to plasma and tissue proteins,
Blood flow
Special compartments and barriers,
Disease states, etc.

15. I. Physicochemical Properties of the Drug:
 Drugs molecular weight (< 500 to 600 Da)
easily cross the capillary membrane to
penetrate into the extracellular fluids (except
in CNS) because junctions between the
capillary endothelial cells are not tight.
 Passage of drugs from the ECF into the cells;
 molecular size
 degree of ionization and
 lipophilicity

16. •Water-soluble molecules and ions of size
below 50 daltons enter the cell through aqueous
filled channels, whereas those of larger size are
restricted unless a specialized transport system
exists for them.
•According to the pH-partition hypothesis,
basic drugs present in blood (pH 7.4) readily
enter into acidic tissues and fluids, including the
intracellular fluids (pH 7.0) and concentrate
there.

17. •Conversely, acidic drugs attain high
concentrations in the relatively more alkaline
body fluids.
•Example:
Weak organic bases administered
paranterally diffuse passively from blood (pH
7.4) into rumen fluid (pH 5.5 -6.5) of cattle and
sheep, where they become trapped by
ionization.
Similarly, weak bases tend to be accumulate
in milk since the pH of milk is slightly acidic (pH
6.5 to 6.8) to the blood.

18. Transportation of Drugs:
•Drugs are transported in the circulating blood
in two forms: free form and bound form
(plasma proteins).
•Free form of drugs is usually dissolved in
plasma and is pharmacologically active,
diffusible, and available for metabolism and
excretion.

19. II. Binding to a) Plasma Proteins:
Significance of plasma-protein binding;
Affects distribution,
Pharmacologically inactive,
Non-diffusible,
Not available for metabolism or excretion
(As they cannot pass through capillaries and cell
membranes because of their larger size).

20. •The plasma protein binding of drugs is usually
reversible (weak chemical bonds); covalent
binding of reactive drugs such as alkylating
agents occurs occasionally.
•The binding of individual drugs ranges from very
little (e.g., Theophylline) to very high (e.g.,
warfarin).
•In circulating blood, there is a constant ratio
between the bound and free fractions of the
drug.

21. •When the concentration of the free drug falls
due to redistribution, metabolism or excretion,
the free: bound ratio is maintained by
dissociation of the bound form of the drug.
•Thus plasma protein binding mainly serve as a
reservoir, which supplies free drug whenever
required.
Free drug Protein bound drug

22. Plasma Tissue
Protein- bound
Protein- bound
drug
drug
Free drug Free drug
The free drug concentration gradient drives transport across the membrane.

23. •A large variety of drugs ranging from weak
acids, neutral compounds, and weak bases bind
to plasma proteins.
•Acidic drugs generally bind to plasma albumin
and basic drugs to alfa1 acid glycoproteins;
binding to other plasma proteins
(e.g., lipoproteins and globulins) occurs to a
much smaller extent.

24. Different drugs binding to different proteins

Binding sites for acidic agents Albumins
Ex- Bilirubin, Bile acids, Fatty acids, Vitamin C,
Salicylates, Sulfonamides, Barbiturates,Probenecid,
Phenylbutazone ,Penicilins, Tetracyclines etc
 Binding sites for basic drugs Globulins
Ex- Adenosine, Quinacrine, Quinine, Streptomycin,
Chloramphenicol, Digitoxin, Ouabain, Coumarin

26. • For the majority of drugs, binding to plasma
albumin (Mol. Wt. 65,000), which comprises
>50% of the total proteins, is quantitatively
more important.
•The binding of drugs to albumin may show
low capacity (one drug molecule per albumin
molecule) or high capacity (two or more drug
molecules per albumin molecule).

27. •The albumin can bind several compounds
having varied structures, some substances even
to a single site. Groups of drugs that bind to the
same site compete with each other for binding.
•Some drugs may bind to blood components
other than plasma proteins (e.g., phenytoin and
pentobarbitone bind to haemoglobin)

29. II. Binding to b) Tissue Proteins:
•Many drugs accumulate in tissues at higher
concentrations than those in the extracellular
fluids and blood called localization.
•Tissue binding of drugs (cellular constituents);
Proteins, phospholipids, or nuclear proteins
and generally is reversible or some case
irreversible (covalent chemical bonding).

30. •Important in distribution from two viewpoints:
Firstly, it increases the apparent volume of
distribution (in contrast to plasma protein binding
which decreases it)
Secondly it results in localisation of a drug at a
specific site in the body produce local toxicity.
Examples:
 Aminoglycoside antibiotic gentamicin Nephro
and vestibular toxicity.

31. Paracetamol and chloroform metabolites
bind hepatotoxicity.
Tetracyclines, fluoride (infants or children)
during odontogenesis results in permanent
brown-yellow discoloration of teeth.
Chlorpromazine, chloroquine leads
retinopathy (Hounds breeds).

33. Drug displacement interactions:
•Drug displacement interactions occur
between two or more drugs that bind to same
plasma protein site.
•If one drug is binding to such a site, then
administration of second drug having higher
affinity for the same site results in
- Displacement of first drug from its binding
site.

34. • Generally, In many cases, the impact of
interactions is minimal
•In some instances a slight displacement of a
drug will result in marked increase in its
biological activity.
Ex: Administration of phenylbutazone to a
patient on warfarin therapy results in
displacement of warfarin from its binding site.

35. •Warfarin has high plasma protein binding of
about 99% (free drug concentration -1%), shows
a small volume of distribution (remains confined
to blood compartments) and has a narrow
therapeutic index.
• If just 1% of warfarin is displaced by the
phenylbutazone, the concentration of free
warfarin will be doubled (2%).
•The enhanced concentration of free warfarin
may cause severe haemorrhagic episodes,
which may result in lethality.

36. Fat As a Reservoir:
•Many lipid-soluble drugs are stored by physical
solution in the neutral fat.
•In obese persons, the fat content of the body
may be as high as 50%, and even in lean
individuals it constitutes 10% of body weight;
hence fat may serve as a reservoir for lipid-soluble
drugs.
Ex: The highly lipid-soluble barbiturate thiopental

37. Bone:
•The tetracycline antibiotics (and other divalent
metal-ion chelating agents) and heavy metals
(Cadmium, Fluoride, lead or radium) may
accumulate in bone and become a reservoir by
adsorption onto the bone crystal surface and
eventual incorporation into the crystal lattice
causes toxicity.
•Adsorption process for some drugs shows
therapeutic advantages for the treatment of
osteoporosis.

38. Blood Flow and Organ Size:
•The rate of blood flow to tissue capillaries
varies widely as a result of unequal distribution
of cardiac output to various organs.
•The drug distribution to a particular organ or
tissue depends on the size of the tissue (tissue
volume) and tissue perfusion rate (volume of
blood that flows per unit time per unit volume
of the tissue).

39. •Highly perfuse tissues such as lungs, kidneys,
liver, heart, adrenals, and brain are rapidly
equilibrated with lipid soluble drugs.
•Muscle and skin are moderately perfuse, so they
equilibrate slowly with the drug present in blood.
•Adipose tissues, bones and teeth being poorly
perfuse, take longer time to get distributed with
the same drug.

40. IV. Specialized Compartment and Barriers:
BLOOD BRAIN BARRIER and BLOOD CSF BARRIER
 Central Nervous System and
Cerebrospinal Fluid:
• The capillary endothelial cells in
brain have tight junctions and lack
pores or gaps.
• Surrounding the tight and overlapping
endothelial layer is a continuous
basement membrane.
• These basement membranes in turn
are enveloped by “perivascular foot
processes” formed by astrocyte cells
that encircle about 85% of the surface
areas of brain capillaries.
• Together these layers add up to a
formidable non-polar barrier called
the blood-brain barrier (BBB).

41. •At the choroid plexus, a similar blood-CSF barrier is
present except that it is epithelial cells that are joined by
tight junctions rather than endothelial cells.
•The lipid solubility of the nonionized and unbound
species of a drug -an important determinant of its
uptake by the brain
•More lipophilic a drug is, the more likely it is to cross
the blood-brain barrier.
•Often is used in drug design to alter drug distribution to
the brain
•e.g: second-generation antihistamines, -loratidine,
achieve far lower brain concentrations than do agents
such as diphenhydramine and thus are non sedating.

42. •Another important factor in the functional blood-brain
barrier involves membrane transporters that are efflux
carriers present in the brain capillary endothelial cell
and capable of removing a large number of chemically
diverse drugs from the cell.
Example:
P-glycoprotein (P-gp, encoded by the MDR1 gene) and
the organic anion-transporting polypeptide (OATP) are
exporters are to dramatically limit access of the drug to
the tissue expressing.

43. Placental barrier:
•The maternal and foetal blood vessels are separated by a layer
of trophoblastic cells that together constitute the placental
barrier.
•The characteristics generally the same as BBB.
• However, restricted amounts of lipid insoluble drugs, especially
when present in high concentration or for long periods in
maternal blood gain access to the foetus by non-carrier
mediated processes.
• Thus, the placental barrier is not as effective as the blood-brain
barrier and impermeability of the placental barrier to polar
compounds is relative rather than absolute.
•So care must be taken while administration of all types of drugs
during pregnancy because of the uncertainty of their harmful
effects on developing foetus.
• Risk Category of Drugs Classification

44. Other barriers:
• The prostrate, testicles, and globe of eyes
• contain barriers that prevent drug penetration
to tissues.
• Lipid soluble drugs can penetrate and reach
these structures freely, whereas water-soluble
drugs entry is restricted.

45. V.Disease States:
Distribution characteristics of several drugs are
altered in disease states.
Examples:
In meningitis and encephalitis, the blood-
brain barrier becomes more permeable and the
polar antibiotics like penicillin-G, which do not
normally cross it, gain access to the brain.

46. In hypoalbuminaemia, plasma protein binding of
drugs may be reduced and high concentration of
free drugs may be attained.
In congestive heart failure or shock the perfusion
rate to the entire body decreases, which affect
distribution of drugs.


48. Redistribution:
•Termination of drug effect after withdrawal of a
drug usually is by metabolism and excretion
•But also may result from redistribution of the
drug from its site of action into other tissues or
sites.
•Redistribution is a factor in terminating drug
effect primarily when a highly lipid-soluble drug
that acts on the brain or cardiovascular system is
administered rapidly by intravenous injection or
by inhalation.

49. Example:
Use of the IV anesthetic thiopental, a highly
lipid-soluble drug. Because blood flow to the
brain is so high, the drug reaches its maximal
concentration in brain within a minute of its
intravenous injection.
After injection is concluded, the plasma
concentration falls as thiopental diffuses into
other tissues, such as muscle.

50. THANK YOU