VPT 311: General and Systemic Veterinary Pharmacology (2+1)

RENAL ELIMINATION OF DRUGS

Routes of elimination

• 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 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 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:

Acids	Bases
Penicillin G	Procainamide
Ampicillin	Dopamine
Sulfosoxazole	Neostigmine
Phenylbutazone	N-methylnicotinamide
Furosemide	Trimethoprim
Probenecid
p-aminohippurate
Glucuronic acid conjugates
Ethereal sulphates

• 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. Quarternary drugs are polar at all urine pH. They are eliminated rapidly because they cannot be reabsorbed.