Excretion of drugs

Drugs are excreted mainly by the kidneys into the urine and by the liver into the bile and subsequently into the feces. Alveolar elimination is of major significance when inhalant anesthetics 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 milk, saliva, tears and sweat. The salivary route of excretion is important in ruminants because they secrete such voluminous amounts of alkaline saliva and mammary excretion is important in lactating animals.

Renal elimination of drugs

The basic functions of the kidneys are to maintain the volume and composition of body fluids, control acid-base balance, eliminate end products of metabolism and eliminate foreign compounds like drugs.

The kidneys constitute less than 1% of the total body weight, but receive about 25% of the cardiac output. Afferent arterioles from the renal artery supply blood to the glomerulus at arterial pressure and about 20% of this is converted to glomerular ultrafiltrate.

Further absorption and reabsorption takes place at various points along the nephron. The final product is only ablut 1% of the volume of the original glomerular filtrate.

In the kidneys, circulating drugs are cleared from the blood through filtration and active secretion.

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.

The pore size of the glomerular capillaries is about 40 A^o. The glomerular ultrafiltrate will therefore contain soluble drugs and other molecules including small proteins. Albumin is not filtered and hence drugs that are bound to plasma proteins are also not filtered. The glomerular filtration rate has a major effect on renal clearance of drugs.

Increased glomerular filtration results in more rapid removal of drug molecules from the systemic circulation.

In the proximal convoluted tubules, there is active secretion of ionized drugs into the lumen. This ensures that drugs, which are protein-bound are excreted. The transport systems are non-specific and are of two types. One transport system transports organic acids and the other transports organic bases. Secretion of drug molecules requires significant energy. Anything that interferes with cellular energy production reduces the excretion of these drugs from the body. Tubular secretion being an active process, it can be suppressed by competing substances. Drugs excreted by a carrier-mediated process in the proximal tubule include:

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 of drugs.

Highly lipid soluble drugs will be rapidly reabsorbed from the kidney tubule. For this reason excretion of lipid soluble drugs often occur after conversion to more polar metabolite. Even though, many protein bound drugs are actively secreted into the proximal tubule, reabsorption may be favoured especially with drugs that are largely protein bound in plasma.

In canine the urinary pH range from 5.0-7.0 and in herbivores the urinary pH may range from 7.0-8.0. Excretion can be enhanced for drugs excreted by the kidneys by altering the pH of the urine. For practical purposes this principle can be applied only to weak acidic or weak basic drugs with pH 5.0-8.0. Quaternary drugs are polar at all urine pH. They are eliminated rapidly because they cannot be reabsorbed.

Hepatic routes of elimination

Hepatically eliminated drugs usually move by passive diffusion from the blood into the hepatocyte from where 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 liver’s ability to metabolise and/or eliminate drugs is reduced. Therefore the dose of the drugs 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.

Large polar molecules (molecular weight >300) are often excreted and are not reabsorbed in the intestine.

The ability to excrete polar compounds in bile with molecular weights between 300 and 500 is good in dog, chicken and rat, moderate in cat and sheep and poor in guinea pig, rabbit, monkey and man.

Excretion of drugs in milk

Milk 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.