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.

Route of Adminstration

Drugs can be given via a variety of routes. A choice of a specific route is determined by the following factors:

• the properties of the drug
• the therapeutic objective (eg speed on onset, length of duration)
• administration or restriction to a local site

Some of the route options are: oral, rectal, intravenous, intramuscular, sub-cutaneous, intra-articular, inhalation, transdermal patches, topical (eye, ear and nose drops), intramammary, intravaginal, epidural and sub-conjunctival.

Intravenous injections have the highest peak plasma concentrations after administration.

Formulation

For a drug to be absorbed it must be in an aqueous solution. Thus the rate of absorbtion of an injectable formulation is influenced by it's aqueous solubility. As the solubility decreases the rate of absorbtion and thus its plasma concentration is lower.

When considering formulations of drugs it is important to look at their Cmax and Tmax values.

Cmax = The maximum concentration that the drug will reach in that formulation in the body system.

Tmax = The time it takes to recah the Cmax.

Oral Formulations

Usually 75% of a drug is absorbed in 2-3 hours when given orally. The following factors affect their absorption:

• Tablet structure and size - this can be altered to change Tmax and Cmax
• Stomach enzymes - can breakdown the drug
• Stomach acidity - some drugs are unstable in such an acidic environment, others will be ion trapped
• Gastric motility - with increased motility there is less time for the drug to absorbed
• Damage to the epithelial barrier - either due to drugs or disease will result in reduced absorbtion
• Stability of the drug in the gastrointestinal tract
• Presence of food - it can delay drug absorption without changing the amount absorbed, it can delay the absorption and decrease the amount absorbed or it can increase the rate and amount absorbed.
• First Pass Metabolism - a drug can be extensively metabolised before reaching the systemic circulation. This can occur in the gastro-intestinal tract wall, in the portal circulation and in the liver.

Bioavailability

This is the fraction of the administered drug that actually reaches the systemic circulation in its active form. It is expressed as a percentage of the total amount administered and is calculated using plasma drug concentrations.

To calculate bioavailability a curve of time against plasma concentration of a drug must be drawn in both it's intravenous form and then whichever form is underinvestigation, say intramuscular. Then use the following equation to calcute it:

Bioavailability = (Area Under Curve IM/Area under curve IV) x 100%

Products containing the same drug can be said to be bioequivalent if the rate and extent of absorption are the same; ie the AUC, Tmax and Cmax aren't significantly different.

Distribution

Once absorbed drugs can distribute to one of the major body compartments, these are:

• Plasma (5% of body weight)
• Interstitial Fluid (16%)
• Intracellular Fluid (35%)
• Transcellular Fluid (2%)
• Fat (20%)

Many drugs are bound to proteins with acidic drugs binding to albumin and basic drugs binding to globulin. The extent of the binding is dynamic and the bound drug and free drug exist in equilibrium. Normally only the free drug has the capability of crossing the vascular endothelium. Though if damage occurs protein-bound drugs can enter the circulations.

The Volume of Distribution (V_d) is a measure of the volume of fluid needed tocontain the total amount of drug at its plasma concentration.

V_d depends upon the ability of a drug to enter plamsa and interstitial fluid and to cross cell membranes and gives a good indication of the extent of drug distribution.

• Very low (0.005-0.1l/kg) - drug confined to plasma compartment
• Low (02l/kg) - drug confined to plasma and interstitial space
• Intermediate (0.6l/kg) - drug enters total body water
• Very High (>1l/kg) - concentrated in a body fluid other than plasma and there may be bound residues eg i fat

Lipid-soluble drugs reach all compartments and can accumulate in fat. Whilst lipi-insoluble drugs are mainly contained in plasma and interstitial fluids; they are usually incapable of crossing the blood-brain barrier.