Dr zunnera Rashid.

Drug distribution
Learning objectives

 Volume of distribution – definition

 Factors affecting distribution
 Lipophilicity of drugs
 Blood flow
 Capillary permeability
 Plasma protein binding
 Clinical significance
Drug distribution

Definition

The process by which a drug reversibly leaves the bloodstream


Enters the extracellular fluid (interstitial fluid) and tissues.

Reversible mechanism
Factors affecting distribution

 Lipophilicity of the drug

 Cardiac output
 Local blood flow
 Capillary permeability
 Tissue volume
 Degree of binding of the drug to plasma proteins
 Degree of binding of drug to tissue proteins,

 Lipohilicity of the drugs
Lipopilic drugs hydrophilic drugs
Not charged charged drugs

lipid soluble water soluble

Non polar polar

unionized ionized

uniform distribution of electrons Non uniform distribution of electrons

Readily pass through most biologic Do not readily penetrate cell membrane
membranes – depends on blood flow
Pass through the slit junctions.
Permeate the entire cell's surface.
Cardiac out put and Blood flow

 Greater is the cardiac output - Greater is the blood flow

More distribution

Areas with High blood High lipid

flow solubility

less distribution
Areas with Areas with Skeletal muscles
Brain Adipose tissues
high blood flow Liver low blood flow Skin
Kidney Viscera
Example of distribution

Q Why I/V injection of Propofol produces short hypnosis ?

Variation in blood flow

Propofol I/V
CNS Skeletal
Rapidly enters CNS High blood muscles
flow Low blood flow
Rapidly produce hypnosis High lipid
solubility
(short duration)

Drugs moves from the region of high blood flow to the region of

low blood flow (passive distribution) rapid redistribution

Capillary permeability

 Determined by two factors

 Capillary structure
 Chemical nature of the drug.

Capillary structure:

fraction of the basement membrane exposed to slit junctions

between endothelial cells.
Capillary permeability
 Brain liver and spleen

Capillary structure Capillary structure

 continuous, large gaps
 no slit junctions large plasma protein and drugs
 drugs not pass easily pass

 Blood brain barrier
 Q. How drugs enter the brain

Lipid-soluble drugs

Dissolve in endothelial cells

readily penetrate into the CNS

Water soluble drugs

Not enter the CNS, no slit junctions

Active transport – some drugs

Specific transporter carry drugs to brain

 Factors affecting drugs bound to plasma protein

 Q. Explain the characteristic of a drug bound to plasma protein ?

 Drugs reversibly binds to albumin

 Albumin act as reservoir of drugs
 Binding of drug to plasma proteins

Albumin is the major drug binding protein

Albumin act as drug reservoir

As the concentration of the free drug decreases in plasma due to

elimination

The bound drug dissociates from the albumin and is free to act

This Maintains
Free-drug concentration
as a constant fraction level
Factors affecting drugs bound to plasma
protein
 The extent of binding to proteins is dependent on the factors

 Factors increasing binding of drug

 Affinity of drug - More affinity more binding

 Number of binding sites – More binding site more binding
 Drug concentrations at the site
 More drug concentration
 more binding
Factors increasing unbound free drug

 Reduced albumin levels

 1- kidney leak of albumin
 2. chronic liver disease (hypoproteinemia)
 3. Malnutrition (hypoproteinemia)
 4. late pregnancy
 5. Drug displaced by other drugs
 6. Therapeutic saturation
 Factors affecting drugs bound to plasma
protein

 Factors increasing unbound free drug

1- Renal impairment (leaking albumin)

2- Chronic liver disease and malnutrition

Low plasma albumin levels (hypoproteinemia)
Factors affecting drugs bound to plasma
protein

Factors increasing unbound - free drug

1- Drugs displaces the drugs from binding sites

Aspirin,
Sodium valproate,
sulfonamides
Factors affecting drugs bound to plasma
protein

2- Late Pregnancy—
Increase in blood volume
counters increased albumin production

3- Saturability of plasma protein-binding sites

within therapeutic range,
Increases free drug concentration
Phenytoin
Factors affecting drugs bound to tissue protein

+ ++
Tissue +
 Many drugs accumulate in tissues +++ ++
++
Higher concentrations in tissues Interstitial
Than in interstitial fluid and blood. fluid ++++
+
Blood +++
In Tissues drug binds to lipids, proteins and nucleic acids.

Active -T
Tissue Nucleic acid Drugs may also undergo active transport
Protein
into tissues Lipids

There is accumulation of drug in tissues

 t

Factors affecting drugs bound to tissue
protein

Tissue act as a reservoirs of drug

 prolong its actions and causes local drug toxicity.
T
D

 Bladder

 Acrolein, the metabolite of cyclophosphamide causes

hemorrhagic cystitis because it accumulates in the bladder.

Binding capacity of albumin.

 Binding capacity of albumin is variable and reversible

 low capacity (one drug molecule per albumin molecule)

high capacity (many drug molecules per albumin)

Affinities of Albumin

Strong affinity for lipophilic drugs

.
low affinity for hydrophilic drugs
.
Competition for binding

When two drugs are given

Each with high affinity for albumin,

they compete for binding sites.

The drugs with high affinity for albumin can be divided into two
classes

 1- dose of drug is greater than binding capacity

 2- dose is less than, the binding capacity of albumin

Drug binding

 Class I drugs:
Dose of drug is less than
 the binding capacity of albumin,

 The dose/capacity ratio is low.

 The binding sites are in excess

The concentration of free drug is low

 Include majority of clinically

 useful agents.
Drug binding

 Class II drugs:

 Drugs concentration greater than

albumin binding sites.

 The dose/capacity ratio is high,

 high proportion of drug exists

 in the free state,

 All binding sites are occupied

 Clinical Importance of drug displacement.

Class I drug, such as warfarin (red)

Class II drug, sulfonamide antibiotic.(green)

Warfarin is highly bound to albumin,

a small fraction is free.

If sulfonamide is administered,

displaces warfarin from albumin

Increase in levels of free warfarin in plasma,

Increased toxic effects


Discussion
 Q1- explain the characteristic of drug bound to plasma protein

 Q2 - Describe the clinical consequences of displacement of a

drug from plasm protein binding

 Q3. define volume of distribution

Discussion

Q1- Explain the characteristic of drug bound to plasma protein

1-greater is the affinity of drug for binding to plasma protein

more is the binding of drug
2- Bound drugs do not produce therapeutic effect and are
inactive
3- Bound drugs have prolonged half life
4. If albumin level low less drug binds and more is in free form
Q1
 Albumin maintains the free drug concentration at a constant
level because it possess which of the following property ?

 A. albumin has increased binding sites

 B. albumin act as reservoir of drugs
 C. albumin has high affinity for drugs
 D. albumin has reversible drug bindings
 E. albumin has low binding capacity
Q2
 A 53 year old patient on warfarin therapy was prescribed
sulfonamide for the treatment of his bacterial infection. what
is the most likely clinical presentation of this patient after I
week ?

 A. bleeding gums due to warfarin toxicity

 B. hepatitis as side effect of sulfonamide
 C. nausea vomiting due to warfarin
 D. head ache , body aches due to sulfonamide
 E. Diarrhea and colitis due to sulfonamide
Q3
 Hydrophilic drugs cannot easily pass through brain
capillaries because brain cell membrane possess which of the
following property ?

 A. large gaps in between endothelial cell

 B. greater blood supply to cell membrane
 C. more lipophilic cell membranes
 D. no slit junctions in cell membrane
 E. No active transport or carrier protein