PHARMACOKINETICS-FUNDAMENTALS-PART-2

PHARMACOKINETIC PRINCIPES-2

DISTRIBUTION

In part-1 for this subject in the last post we dealt with the beginning point of the pharmacokinetics-Absorption.

In this part-2 we will see the next aspect after absorption, the Distribution.

The process of Distribution is defined as the process in which the drug leaves the bloodstream into the tissue cells.

There are three biochemical mechanisms by which the process of absorption and distribution proceeds.

Passive Diffusion:-

Passive diffusion is governed by a concentration gradient formed across the area of absorption and distribution, which is a cell membrane of tissue. The concentration gradient pushes the drug from the area of high concentration to the area of low concentration. Many lipophilic non polar ions are absorbed and distributed by passive diffusion and it is the most common mode of drug distribution.

Active Transport

In this way some drugs move against the concentration gradient. For this a special energy is required which is derived from the conversion of Adenosine Tri Phosphate(ATP) to Adenosine Di Phosphate(ADP) by the enzyme ATP-ase. The best example is the movement of [H+]ion across the membrane of the parietal cell of the stomach by the ATP-ase pump to let out.

Transport by Special Carrier

There are some special proteins that help to distribute the drug by bounding up with them.

Factors Affecting Distribution

1.Blood Flow.

Distribution is directly proportional to blood flow similar to absorption.

2.Capillary Permeability.

Capillaries are having various thickness and permeability in its structure at various organs. For example in the brain the cells are arranged very tightly with the capillaries with very veery narrow junctions and distribution is slow as only smaller molecules are permeable through the junction between the cells. Conversely in liver and spleen the cells are not so tightened in arrangements embedding the capillaries and they joined with wider junctions so that large molecules can pass through the capillaries and distribution is high across these organs.

3.Binding with Plasma Proteins

Albumin is the common plasma protein that binds with the drugs and limits their distribution as albumins are large protein molecules difficult to cross the capillaries.

4.Drug Structure

In the drug molecular structure if they are non-polar lipophilic then they are smaller and are more rapidly distributed than the large ionized polar molecules.

 

 

PHARMACOKINETICS-FUNDAMENTALS-PART-1

PRINCIPLES OF PHARMACOKINETICS

Pharmacokinetics is better defined as the action of the body on the drug from its entry point to its exit point.

The actions of the body can be better classified as Absorption, Distribution, Biotransformation(Metabolism)

and Excretion.

Absorption

Absorption can be better explained as the rate at which the drug is moved from its site of administration into the body.

Factors Affecting Absorption

The rate and efficacy of absorption can be affected by the following factors.

1.Route of Administration:-

At the following sequences, the routes affect the absorption

Sublingual<Buccal<Oral<Dermal<Intradermal<Subcutaneous<Intramuscular and other parenteral <Intravenous.

From the above sequences we come to know that the most effective absorption happened at the intravenous route. The drug is 100% absorbed directly into the system by that route.

2.Blood Flow:-

In a highly vascularized area with heavy blood flow such as in small intestine the absorption is more.

3. Surface Area Available:-

The drug absorption is high at higher surface area available.

4.The solubility of a Drug:-

The ratio of the lipophilic to hydrophilic (Partition Coefficient) will decide whether the drug can permeate into a cell membrane. In short a drug that has higher lipophilic moiety will easily pass into the cell membrane to be absorbed.

5.Drug-Drug Interactions:-

When given in combination they may interact which can determine whether to inhibit or enhance the absorption

6.Hydrogen Ion Concentration:

H-ion concentration is usually measured by the negative logarithmic values in the pH scale. The pH of the drug which is acidic or alkaline may affect the absorption.

Many drugs are either weak acids or weak bases and their ionization is partial. Acidic drugs are uncharged when protonated as follows,

                [H+] + [A-] < > [HA] (uncharged)

Basic drugs are charged when protonated as follows

                [B]  + [H+] < > [BH+] (charged)

Generally the uncharged ions are non-polar and lipophilic and can easily pass through the lipid content of the cell membrane. 

Therefore the amount of drugs absorbed depends upon its ratio of charged to uncharged particles which in turn is determined by the ambient pH at the site of absorption and the pKa value which is the negative logarithm of the dissociation constant of the drug.

The fraction of the administered drug available for its biological effect after absorption is known as bioavailability.

The intravenously injected drug has 100% bioavailability as it is completely absorbed into the system.

The first pass hepatic metabolism and all other factors described earlier that affect absorption are also the factors that affect bioavailability.

Routes Of Drug Administration

1.Alimentary canal

2.Parenteral(Injections,infusions etc.etc.)

3.Inhalation

4.Topical (Skin)

5.Transdermal

Types of Alimentary Routes:-

1.Oral

2.Buccal

3.Sublingual

4.Rectal

Types Of Parenteral Routes:-

1.Intravenous

2.Intramuscular

3.Subcutaneous

4.Intradermal

5.Intrathecal

Many pulmonary agents are preferred for administration through inhalation.

Many drugs to be used for local skin applications are preferred by topical routes.

Many sustained-release drugs are used through the trans dermal route.