Introduction to Pharmacokinetics
Drug Distribution
Course Name: Basic Pharmacology & Pharmacotherapy of the PNS
Course Code: PHD 122
Date: January 2016
Prepared by: Dr. Maryam Farooqui, Senior Lecturer, Faculty of
Pharmacy, Bertam Campus
Lesson Outcomes
At the end of this lecture, students should be able to:
understand the concept of drug distribution.
understand the various factors that could influence the rate
of drug distribution.
Drug Distribution
A process by which drugs reversibly leaves
the blood stream and enters the interstitium
and/or the cells of the tissues. i.e.
transfer of drug between regions of the body and
its distribution between blood/plasma, tissues,
organ, body fluids etc
The rate of distribution determines by drug
characteristics, tissue properties and blood
flow.
https://www.youtube.com/watch?v=kLvYCOSnPDc
Drugs injected or absorbed into the blood stream is carried
by the blood and tissue fluids to the site of pharmacologic
action, metabolism and excretion.
Most drug molecules enter and leave the blood stream at
the capillary level through gaps between the cells that form
capillary walls.
Drugs are distributed rapidly to organs receiving a large
blood supply such as heart, liver and kidneys, while
distribution to other organs such as muscle, fat and skin is
low.
Drug distribution patterns
Drug that stays in vascular system
Large molecular weight, tightly bound to plasma protein, lipid
insoluble– e.g. plasma substitutes.
Drugs that distributes in body water
Low molecular weight, but hydrophilic in nature can distribute in
interstitial fluid but cannot cross cell membrane.
Drugs that concentrates in specific tissues
Chloroquine in liver
Tetracycline to bone/teeth
Iodine in thyroid glands
Drug that distributes throughout body and tissues
Lipid-soluble drugs with low molecular weight reach all
compartments.
Apparent volume of distribution
The ratio of the amount of a drug in the body to its
concentration in the plasma or blood.
Amount of drug in body (dose)
Vd =
Concentration of drug in plasma (C0)
Volume of Distribution
Vd gives a quantitative estimation of drug
distribution in the body.
A small Vd means that a drug is in the extracellular
fluid or plasma. i.e. Vd is inversely related to plasma
drug concentration.
A large Vd means that a drug is concentrated in
tissues.
Factors Affecting Drug Distribution
The delivery of drug from the plasma to the
interstitium primarily depends on:
Blood flow
Capillary permeability
Plasma protein binding
Size of organ
Solubility
Anatomic barrier
Storage sites
https://www.youtube.com/watch?v=8zYIEiXvSZY
Blood flow
Rate of blood flow to all tissues is not equal
due to unequal distribution of cardiac output.
Drugs are rapidly distributed to highly-
perfused (highly vascular) tissues. E.g.
Brain, heart, liver & kidney
In less-perfused (reduced vascularity) tissue,
drugs are more slowly distributed due to
lower blood flow. E.g. muscle, skin, adipose
tissues.
Capillary permeability
The walls of capillaries are very thin,
consisting of only a single layer of
endothelial cells, making them highly
permeable.
Capillary permeability is determined by
capillary structure and by chemical nature
of drugs.
Capillary structure
The endothelial cells of brain capillaries are much more
firmly joined to one another.
The circumferential tight junctions of the endothelial cells
of the brain capillaries forms the Blood Brain Barrier
(BBB).
The blood brain barrier screens certain classes of drugs to
the brain
Lipid soluble drugs will pass fairly readily into the CNS
whereas lipid insoluble drugs will have little or no effects.
Ionize and polar drugs usually fail to enter CNS.
The blood brain barrier is formed by:
1) tight junctions between capillary
endothelial cells.
2) basement membrane.
3) Astrocyte foot processes.
•BBB effectively prevents many molecules from traversing from the blood to the brain.
•It also prevents harmful substances that may present in the blood from entering the brain.
It can prevent some drugs from crossing into the CNS and causing adverse effects.
Drowsiness due to antihistamine is common and can be prevented by formulating
antihistamine that are not lipophilic enough to cross the BBB. E.G Levodopa-carbidopa for
Parkinson’s
Plasma Protein Binding
Drugs can be reversibly-bound to circulating
plasma proteins or is free in an unbound state.
Albumin, the principle protein of plasma, is the
protein with which the greatest variety of drugs
combine (protein usually stays in the plasma.
Drug that are bound to the plasma protein are
neither free to move to a site of action nor free to
produce biologic effect.
Plasma protein binding acts as a drug reservoir,
slowing onset and prolonging duration of action
(Suramine, for sleeping sickness)
Since the system is in equilibrium as the drug is
eliminated from the body, more (protein bound
drug) can be dissociated from the protein complex
to replace what is lost.
They also can be displaced by another drug which
has higher affinity to the protein. (Phenytoin
displacement from binding site by valproic acid).
For example: Warfarin and aspirin shares same
binding sites
Warfarin and aspirin share similar binding site on plasma
proteins.
But aspirin bounds more strongly than warfarin.
Aspirin can displace warfarin from its binding site.
Warfarin is therapeutically active only when in free state
So when warfarin is given with aspirin there is more than
usual amount of warfarin in the plasma.
This can result in higher “free” drug concentration
which can lead to increased pharmacological effect/adverse
effect.
For example:
-Phenytoin dose adjustment is required in ESRD patients due
to hypoalbuminemia)
-Liver disease, which affects albumin concentration can alter
the drug concentrations.
Disease states which may affect serum albumin concetration
are burns, hepatic cirrohosis, nephrotic syndrome,
pregnancy, cyctic fibrosis
Size of organ
The size of the organ determines the concentration
gradient between blood and the organ.
Larger organs require more drug to reach an
equivalent concentration.
Skeletal muscle (large organ) can take up a large
amount of drug because the concentration in the
muscle tissue remains low (and the blood-tissue
gradient high) even after relatively large amount of
drugs have been transferred.
The brain (smaller organ), distribution of a smaller
amount of drug into it will raise the tissue
concentration.
Solubility
The solubility of a drug in tissue influences the
concentration of the drug in the extracellular fluid
surrounding the blood vessels.
If the drug is very soluble in the cells, the
concentration in the extracellular space will be lower
and diffusion from the vessel into the extravascular
tissue space will be facilitated.
Ionized drug molecules cannot penetrate the cell
membrane i.e. not lipid soluble.
In contrast, non-ionized drug molecules are more
lipid soluble & can easily cross cell membranes
Anatomic Barriers
Capillaries of the CNS differ from those in most parts of
the body.
The endothelial cells of brain capillaries are much more
firmly joined to one another.
The circumferential tight junctions of the endothelial cells
of the brain capillaries forms the BBB.
The BBB screens certain classes of drug to the brain.
Lipid soluble drugs will pass fairly readily into the CNS
whereas lipid insoluble drugs will have no or little effects.
Storage Sites
Fat tissue will act as a storage site for lipid soluble
drugs.
Drugs that have accumulated there, may remain
for some time.
Calcium containing structure such as bone and
teeth can accumulate drugs that are bound to
calcium.
Distribution of a given drug may also vary from person to
person.
For instance, obese people may store large amounts of
fat-soluble drugs, whereas very thin people may store
relatively little.
Older people, even when thin, may store large amounts
of fat-soluble drugs because the proportion of body fat
increases with aging.
During pregnancy most drugs cross the placenta and
may affect the fetus.
During lactation many drugs enters the breast milk and
may affect the nursing infant.
Thank you
