General Principles Of Pharmacology/Drug Excretion:Mechanisms of Renal Excretion

From Pharmpedia

< General Principles Of Pharmacology

Previous Page: Renal Extraction Ratio

Fig. 3.3 The maximum efficacy of diuretics in removing salt and water related to the site of action

Maintains the volume and composition of body fluids

Controls acid-base balance

Eliminates end-products of metabolism

Eliminates foreign compounds (e.g., drugs)

Physiology

The two 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. About 20% of this is converted to glomerular ultrafiltrate.

Further absorption and reabsorption takes place at various points along the nephron.

The final product (urine) is only about 1% of the volume of the original glomerular filtrate.

Renal Clearance

Clearance (C) = UV/P

Where:

U = concentration in urine (mg/ml)

V = rate of urine flow (ml/min)

P = plasma concentration (mg/ml)

The units of clearance are ml/min, or to allow us to make comparisons between species, ml/min/kg.

The renal clearance of a substance corresponds to the hypothetical volume of plasma completely cleared of that substance per minute. As with the volume of distribution (Vd) of a drug, the renal clearance rarely corresponds to a physiological rate of flow that actually occurs.

Glomerular Filtration

The pore size of glomerular capillaries is about 40 Å. The glomerular ultrafiltrate will therefore contain soluble drugs and other molecules including small proteins. Albumin (MW 69,000) is not filtered, but smaller proteins are; the rate being dependent on their size. Drugs bund to large plasma proteins (e.g., albumin) will not be filtered and so the filtration rate of a drug will be directly proportional to its free concentration in plasma.

Glomerular Filtration Rate

The glomerular filtration rate (GFR) has a major effect on renal clearance of drugs. It can be determined by measuring the renal clearance of a marker that is freely filtered through the glomerulus, is not protein-bound, is not secreted or reabsorbed by the renal tubule, and does not affect renal function. In this case, the renal clearance is equal to the GFR. Examples of substances used to meaure GFR are inulin (MW 5200) and creatine (MW 131).

GFRs (ml/min/kg) for various species:

Tubular Secretion

In the proximal convoluted tubule, there is an active secretion of ionized drugs into the lumen. This ensures that drugs, which are protein-bound, are excreted. These transport systems are rather nonspecific and are of two types: one transports organic acids and the other transports organic bases. Active tubular secretion can be saturated, and drugs can compete for secretion.

Drugs excreted by a carrier mediated process in the proximal tubule:

Table 5. Drugs excreted by a carrier mediated process

Tubular Reabsorption

Despite glomerular filtration and active secretion, the renal clearance of many drugs is slow because they are substantially reabsorbed from the distal portion of the nephron. This is a passive process and will be affected by the following factors:

Concentration:

About 99% of the water filtered through the glomerulus is reabsorbed in the kidney tubule. This results in a considerable concentrating effect which will lead to passive reabsorption. This can be reduced by increasing the urine flow.

pH:

Urine pH will have significant effects on reabsorption of weak acids and bases. This effect is described by the Henderson Hasselbalch relationship. The excretion of weak acids can be increased significantly by alkalinizing the urine (sodium bicarbonate); excretion of weak bases can be increased by acidifying the uring (ammonium chloride). Weak bases are excreted more efficiently by carnivores (acid urine) and weak acids are excreted more efficiently by herbivores (basic urine).

Lipid solubility

Highly lipid-soluble drugs will be rapidly reabsorbed from the kidney tubule.

Protein binding

Although many protein-bound drugs are actively secreted into the proximal tubule, reabsorption is generally favored with drugs that are largely protein-bound in plasma.

Excretion in the Bile

This is the second most important route by which drugs and their metabolites are excreted. Large polar molecules (MW > 300) are often excreted in bile since they are not reabsorbed in the intestine. These drugs cannot diffuse across membranes and are therefore actively transported into bile. The ability of different species to excrete in the bile polar compounds with molecular weights between 300 and 500 varies:

Good: dog; chicken; rat

Moderate: cat; sheep

Poor: guinea pig ; rabbit ;monkey ; man

Enterohepatic Circulation

Drugs and drug conjugates entering the gut in bile may be reabsorbed and subsequently excreted in urine or returned to the bile. This occurs particularly with small, less polar drugs. Glucuronide conjugates of drugs may also be cleaved by enzymes in the intestinal microflora (e.g., beta-glucuronidase) to liberate the parent lipid-soluble drug, which is then reabsorbed.

Fig. 3.4 Entero hepatic circulation

Saliva and Gut

Secretions from the saliva and gut play a small part in excretion. Bile is the major source of drugs excreted in the feces.

Alveolar

This route is of major importance in the excretion of volatile anesthetics. The large surface area and rich blood supply ensure that equlibration between blood and alveolar air is extremely rapid.

Milk

Excretion in milk is of particular concern in dairy animals.

Sweat and Tears

Excretion in sweat and tears is insignificant.

Previous Page: Renal Extraction Ratio