Distribution of Drug in simplest way Pharmacology

DRUG DISTRIBUTION

• Drug distribution is the process by which the drug reversibly leaves the blood stream and enters the extracellular fluid and tissues.

- For drugs administered IV, absorption is not a factor and the initial phase immediately following administration represents distribution phase.

- The distribution of the drug from plasma to interstitium depends upon :

(i) cardiac output & local blood flow

(ii) capillary permeability

(iii) degree of binding of drug to plasma & tissue protein

(iv) lipophilicity of drug

(v) Volume of distribution

(1) Blood flow :

• The rate of blood flow to the tissue capillaries varies widely. For instance, blood flow to vessel rich organs (like : brain, liver & kidney) is greater than skeletal muscles, adipose tissues, skin which have lower rates of blood flow.

-For example: High blood flow together with high lipophilicity of propofol, permits rapid distribution into the CNS and produce anesthesia.

(2) Capillary permeability :

• It is determined by capillary structure and chemical nature of the drug.

For example : • In Brain, capillary endothelial cells are continous & have no slit junction so only lipid soluble drugs can cross.

• In liver and spleen, large part of basement membrane has discontinuations so large drugs mollecule can easily cross.

- lipid soluble deugs can easily cross b/c they dissolve in endothelial cells. By contrast water soluble drugs generally fails to penetrates b/c they donot dissolve in endothelial cells.

(3) Binding of the drugs to plasma and tissues protein :

(i) Binding to plasma protein :

• Drugs bind reversibly with plasma protein in a nondisffusible form which cause slow transfer of drug out of vascular compartment.

- Albumin is the major drug binding protein, it may act as drug reservior. As the concentration of the free drug decrease due to elimination, the bound drug dissociates from albumin. This maintains the free drug concentration as constant fraction of total drug in plasma.

(i) Binding to tissue proteins :

• Many drugs accumulate in tissues, leading to higher concentration in tissues than interstitial fluids and blood.

- drug may accumulate b/c of binding with proteins, lipids and nucleic acids.

- Tissue reservior may serve as major source of drug and prolongs its action or cause local drug toxicity.

- for example : acrolein can cause hemorrhagic cystitis because it accumulates in the bladder.

(4) Lipophilicity :

• The chemical nature of the drug strongly influences it’s ability to cross cell membranes.

- These drugs dissolve in the lipid membranes and penetrated the entire cell surface.

- The major factor influencing the distribution of lipophilic drugs is Blood Flow to that area.

- By contrast hydrophilic drugs donot readily penetrates the cell membrane and must pass through slit junctions.

(5) Volume of Distribution (Vd) :

• also known as apparent volume of distribution. And it is defined as Fluid volume that is required to contain the entire drug in the body at the same concentration measured in plasma.

• Apparent volume of distribution is kinetic parameter of drug which correlates dose with plasma level at zero time.

( Vd = Dose / C’ ) i.e C’ is plasma at Zero level.

- Although Vd has no ohysiologic or physical basis, it can be useful to campare the distribution of the drug with the volume of water compartments in the body.

(A) Distribution into the water compartments in the body:

• once a drug enters the body, it has potential to distribute into any one of the three functionally distinct compartment of the body.

(a) Plasma compartment :

• If a drug have high mollecular weight or is extensively protein bound, it is too large to pass through large slit junction of the capillariesand thus is trapped in plasma (vascular) compartment. As a result it has low Vd that approximates the plasma volume.

- It is about 4L in 70 Kg individual.

- Heparin shows this type of distribution.

(b) Extracellular compartments :

• If a drug has low mollecular weight but is hydrophilic, it can pass through endothelial slit junctions at the capillaries in to interstitial fluid.

- however, hydrophilic drugs cannot move across lipid membrane of the cells to enter the intracellular fluids.

- Therefore these drugs distributes into the volume that is sum of plasma volume and interstitial fluid, which together constitutes extracellular fluid (about 20% of body weight means 14L in 70 Kg individual).

- Aminoglycoside antibiotics show this type of distribution.

• If a drug has low mollecular weight and has enough lipophilicity, it can move into interstitium through slit junction and pass through cell membranes in to intracellular fluids.

- These drugs distributes into the vomume of about 60% of the body weight or about 42L in 70 Kg individual.

- Ethanol show this type of distribution.

=>• Large Vd indicates greater distribution into tissues, a smaller Vd suggests confinement to plasma or extracellular fluid.

=>• Any factor that increases Vd can increase the half life of and extend the duration of action of the drug.

Comments

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