Pharmacokinetics

Pharmacokinetics is the effect that the body has on drugs.

All aspects of pharmacokinetics can be covered by the acronym ADME, which stands for:

Absorption

Distribution

Metabolism

Excretion

These underpin how a clinician chooses to use a drug and a good knowledge of a drug's pharmacokinetics will help one predict when therapeutic failure may occur and to enable one to safely use unliscensed products or multiple drugs on one patient. It must also be remembered that the the follwing factors also have an effect on a drug's pharmacokinetics:

• renal, hepatic and gastrointestinal disease
• multiple drug therapy
• species treated
• age
• drug formulation

Absorption

Drugs are most usually small molecules (<1000 molecular weight) and thus can pass through cell membranes through passive diffusion and facilitated transport. For further information on these processes please look here. To cross vascular endothelium drugs usually are able to squeeze through the gaps between the cells. The size of these gaps varies between different locations in the bosy; in the liver the gaps ate large but in the central nervous system these gaps are tight junctions.

The ability of a drug to cross the phospholipid bilayer not only infuences the rate and extent of its absorption but also the rate and extent of it's distribution, metabolism and elimination.

Below are the main factors affecting absorption:

Properties of the Drug

• Lipid solubility - the more lipid soluble a drug the easier it is absorbed across the bilayer
• Chemical nature - ie. Is it basic or acidic? Is it ionised or not?
• Molecular weight
• Stability in the gastro-intestinal tract - only applies to orally administered drugs

Physiological Variables

• pH at site of absorption

Many drugs are either a weak base or a weak acid and so will exist in both an unionised and ionised form in the same solution. The ratio of the two forms is dependent upon the pH of the location of the drug. It must be remembered that ionised molecules don't pass easily through lipid membranes. Unionised molecules will diffuse easily as long as they are lipid soluble.

The ionisation reaction of a weak acid is

AH =Ka A- + H+

and its dissociation constant pK_a is given by the Henderson-Hasselbach equation:

pKa = pH + log10 ([AH]/[A-])

The ionisation reaction of a weak base is

BH+ =Ka B + H+

and its dissociation constant pK_a is given by the Henderson-Hasselbach equation:

pKa = pH + log10 ([BH+]/[B])

The dissociaton constant allows one to measure the strength of an acid or base and to determine the charge on a molecule in any givem pH.

Thus the extent of ionisation of a drug and so it's extent of absorbtion, depneds upon its pK_a and the pH within the body compartment.

Due to the above drugs can become ion trapped in certain body compartments. If it is assumed that the ionised fraction is unable to cross cell membranes and the unionised fraction is; then a weak acid will become greatly concentrated in an environment with a high pH. This is because it will donate it's spare protons to the basic elements in the high pH environment and then will be unable to cross out of the environment as the drug is now ionised; it has been trapped.

Insert Diagram Here

In summary a weakly acidic drug will become ion trapped in an environment with a high pH and a weakly basic drug will become ion trapped in an environment with a low pH.

• The Area of the absorbing surface

The larger the surface area for absorption the greater the absorption.

• Local Blood Flow

The greater the blood flow the greater the rate of absorption.