Pharmacokinetics - Drug elimination

The concentration of a drug in the plasma or at its receptor sites may be reduced in three basic ways:

1.     distribution or redistribution into various compartments,

2.     metabolic inactivation and

3.     excretion from the body via one of the several possible routes.

Routes of elimination - Drugs are excreted mainly by the kidneys into the urine and the liver into the bile and subsequently into the feces. Alveolar elimination is of major significance when inhalant anaesthetics are used. The main factors governing elimination by this route are concentration in plasma and alveolar air and the blood/gas partition coefficient. Other less common routes of elimination include saliva, milk, and sweat. The salivary route of excretion is important in ruminants because they secrete such voluminous amounts of alkaline saliva.

Some drugs excreted unchanged but the vast majority of the drugs undergo biotransformation to more water-soluble metabolites which can be excreted via the kidneys. This is the commonest route of drug excretion. The liver may also involved when drugs are excreted into the bile (e.g., ampicillin) and some volatile drugs can be excreted via the lungs. Saliva often contains low concentrations of drugs and, in a sense, this may also be regarded as a mechanism of excretion, except the saliva is to be swallowed and does not contribute significantly to drug clearance. Secretion of drugs into milk may also be of importance in animal husbalndry.

Drug elimination or excretion is greatly affected by dehydration, kidney, liver or heart disease, age and a variety of other physiological and pathological conditions. Failure to compensate for altered drug elimination is a common cause of inadvertent drug toxicity.

Renal elimination of drugs - In the kidneys, circulating drugs are cleared from the blood through filtration and active secretion. The degree of renal perfusion influences the amount of drug entering the glomerular filtrate. Reduced renal blood flow decreases filtration of drugs in the glomerulus, resulting in decreased elimination. This is the reason for reduced dosage of the drug in older animals with reduced renal function and in animals with hypotension. Increased glomerular filtration results in more rapid removal of drug molecules from the systemic circulation. Some drugs are actively secreted into the renal tubules. Secretion of drug molecules into the proximal convoluted tubule requires significant energy. Anything that interferes with cellular energy production reduces the excretion of these drugs from the body. From the proximal convoluted tubule the drug moves to the loop of Henle, where some drugs are reabsorbed from the filtrate into circulation. This occurs by passive diffusion. Drug molecules that are nonionized are reabsorbed while those that are ionized are excreted. But the degree of ionization depends on the pH of urine and alterations in urinary pH can alter the elimination

Hepatic elimination of drugs - Hepatically eliminated drugs usually move by passive diffusion from the blood into the hepatocyte at which point they are secreted into the bile or metabolised first and then secreted into the bile. The bile then conveys this to the duodenum. In acute liver diseases and in chronic degenerative processes like cirrhosis the ability to metabolise and/or eliminate drugs is reduced. Therefore the dose of the eliminated by liver must be reduced in liver disorders in order to prevent drug accumulation in toxic concentrations. Choleretics or a high fat intake promote bile flow and therefore, biliary excretion and enhance the hepatic secretion of drugs. Broad spectrum antibacterial agents are expected to diminish the hydrolytic action of intestinal flora and thus, may prevent effective enterohepatic cycles.

Excretion of drugs in milk - This route of excretion has both therapeutic and public health importance. The principles of excretion through the mammary gland are similar to those acting in the kidneys, namely the diffusion of unionised lipid soluble forms of the drugs diffusing through the epithelial cells of the mammary gland. The pH of plasma and milk are important factors. Since milk is usually more acidic than plasma the basic compounds may be slightly more concentrated and acidic compounds are less concentrated in milk than plasma. Excretion of drugs is altered in cases of mastitis due to changes in the pH of milk.

Prolonging drug action

Action of a drug may be prolonged to

1.  Reduce the frequency of administration

2.  Avoid large fluctuations in plasma concentration

3.  Maintain drug effect overnight without disturbing sleep.

This can be achieved by

1.  Delaying absorption - It is desirable to delay absorption, either to reduce the systemic actions of drugs that are being used to produce a local effect or to prolong systemic action. Addition of epinephrine or norepinephrine to local anaesthetic delays absorption due to vasoconstriction. This prolongs the anaesthetic effect and in addition reduces systemic toxicity. From the subcutaneous or intramuscular administration sites, absorption can be delayed by using a relatively insoluble 'slow-release' form. A poorly soluble salt, ester or complex -  injected either as an aqueous solution or an oily solution will have delayed absorption. Procaine penicillin is a poorly soluble salt of penicillin which when injected is slowly absorbed. Esterification of steroid hormone delays absorption. Physical characteristics of a preparation may also be changes so as to influence the rate of absorption. Examples include insulin zinc suspension. Another method of achieving slow and continuous absorption is by using subcutaneous implants. The rate of absorption is proportional to the surface area of the implant. Sustained release tablets, spansules etc. wherein the drug particles are coated with resins, plastic material or other substances that temporarily disperse the release of the active ingredient in the gastrointestinal tract. Transdermal delivery system in which the drug is impregnated in adhesive patches releases the drug slowly over a prolonged period of time.

2.  By increasing the plasma protein binding - Congeners have been prepared which are highly bound to plasma protein and are slowly released in the free active form to have a prolonged duration of action like sulphamehtoxypyridaiazine.

3.  By reducing the rate of metabolism - Small chemical modifications may markedly affect the rate of metabolism without affecting the biological action. Inhibition of specific enzymes by one drug can prolong the action of the other drug. For example physostigmine prolongs the action of acetylcholine by preventing its metabolism.

4.  By reducing renal excretion -Tubular secretion of drug being an active process, it can be suppressed by a competing substance. Example - Probenicid prolongs the duration of action of penicillin and ampicillin.