Drug Excretion

Back to studying Pharmacology!

So far, we've covered Absorption, Distribution and Metabolism- the first 3 letters of that ADME acronym that I've shown you before. Now I'm going to cover the final letter- Excretion!

1) Name and define the physiological processes that permanently rid the body of drugs and foreign chemicals.

Okay so I think this is just the definitions bit. There's a few important definitions that you have to know:

Excretion is the irreversible removal of the parent drug from the body. I *think* metabolism counts in this process, as the parent drug is being transformed into something that is... well, not the parent drug any more.

Elimination is the irreversible removal of the parent drug PLUS METABOLITES.

Clearance is the rate at which excretion occurs. (I think it's excretion rather than elimination anyway, as I'm fairly sure that the liver processing stuff is known as "hepatic clearance.") It is the volume of blood which is totally cleared of the drug per unit time and is thus measured in volume per time, such as litres per hour or millilitres per minute.

(Actually, I might need to double check some of these definitions. I'm currently asking a question on the PHAR2210 forums. I'll update this when I receive an answer- if I remember, anyway.)

One important acronym is f_e: fraction excreted unchanged. It is the fraction of the drug that you pee out again in its original, unmetabolised form. (Sorry, I just put this here because I didn't know where else to put it.)

2) Identify organs and tissues playing the greatest role in removing drugs from the body.

The two main organs for removing drugs from the body are the liver and kidney. Other organs, such as the skin, lungs, hair and breasts (in lactating women) also play roles. I'll be covering all of these in greater detail throughout this post.

3) Identify three processes that control the excretion of drugs by the kidney.

The kidneys are a very important organ for removing drugs and their metabolites. Their functional units are called nephrons. Each nephron contains a glomerular capsule, which is where filtration takes place; proximal tubules, in which active secretion takes place; and the loop of Henle and distal tubules, where most reabsorption takes place.

The first process that occurs is filtration. The glomerular capsule, or Bowman's capsule, located at one "end" of the nephron, consists of a ball of fenestrated capillaries (i.e. capillaries which have larger-than-normal pores between the cells) surrounded by a capsular space. Substances can filter out through the pores in the capillaries; however, they have to be small enough. Hence, generally only unbound drug (i.e. drug not bound to a protein) can fit through- bound drugs tend to remain in the plasma. The glomerular filtration rate in an adult is 120mL/min, or 180L/day. The renal clearance by glomerular filtration can be calculated by multiplying this glomerular filtration rate by the fraction of the drug that is unbound in the plasma.

By the way, there's an acronym for the fraction of the unbound drug in plasma. It's f_u. As our lecturer said, "Not meaning to be rude, but f u." (Oh, and for those of you who are also studying engineering or physics: my dad's a lecturer of electronic engineering, and he once told me that voltage across a diode is denoted by Vd. He finds himself often asking students to find the size of v D. You might have to read that one out loud to get the pun.)

The second process that occurs is active transport, which occurs in the proximal tubules of nephrons. Active transport, as I've mentioned before, involves the use of ATP-powered pumps to transport substances through a membrane. Actually, there are two membranes involved here, because the walls of the tubules are made of cells, and substances have to pass through the two opposite sides of the cell (the basolateral and apical sides) to get inside the nephron on the other side. As there are only a finite number of pumps, saturation can occur when all of the pumps are busy pumping stuff. Once saturation is reached, exaggerated pharmacological effects may be seen due to the extra drug remaining in the blood. This is what happens when people get drunk: their pumps get saturated.

There are two main types of pumps. One type includes the ABC Transporters, or ATP binding cassette. (I'm not sure what these do, to be honest.) The other type includes the SLC transporters, or solute carriers. These include OATs (organic anion transporters) and OCTs (organic cation transporters). These transporters can be blocked by certain drugs. Cimetidine blocks the cation transporters (they both start with c) and probenecid blocks OATs.

The third and final important process is diffusion, which occurs as substances are reabsorbed further down the tubules of the nephrons. Reabsorption is kinda important, because if the 120ml/min that was filtered through the glomerulus all reached our bladders, then we'd spend our lives tied to a toilet. Instead, only 1-2 ml/min of urine forms.

Reabsorption occurs because an increased concentration of substances in the nephron tubules may cause them to diffuse back into the blood down the concentration gradient. This occurs mainly for lipophilic and non-ionised drugs as they can cross the plasma membranes of the cells lining the tubules. The idea that non-ionised drugs reabsorb more easily is important in that this means that pH can affect the rate of reabsorption. You see, pH can affect whether ionisable groups are protonated or not, which in turn the charge on the molecule (see one of my earlier posts on this topic). If the pH is such that the molecule is charged, then it will have a very low rate of reabsorption.

Now to bring it all together! The "baseline" renal clearance is generally taken to be the clearance at the glomerulus, i.e. that old GFR (glomerular filtration rate) x f_u (fraction unbound in plasma) that I alluded to earlier. However, if overall renal clearance is greater than this, this suggests that, overall, more drug must've entered the nephron past the glomerulus by means of active secretion. (Of course, some reabsorption may have occurred, but less was reabsorbed than secreted.) The opposite is true if overall renal clearance is smaller than GFR x f_u: this indicates that more drug was reabsorbed than secreted.

4) Understand biliary excretion of drugs via the liver and the phenomenon of entero-hepatic recycling.

The liver is an important organ for excretion, partly because it's pretty much the first place a drug goes after being absorbed by the GI tract and partly because the liver's pretty awesome and has shitloads of functions, drug excretion being one of them. Liver cells have a lot of transporters and so forth which can move drugs and other substances into the bile duct. The bile duct leads to the duodenum (the very first part of the small intestines), and from there the drug eventually gets pooped out. Generally, drugs that are too large to be removed directly by the kidneys are eliminated via this mechanism.

It's not always as simple as the drug simply being crapped out, though. Some drugs undergo further metabolism in the GI tract. If these metabolites are lipophilic, they can be reabsorbed by the GI tract again and shipped back to the liver. This is a phenomenon known as enterohepatic recirculation. This lengthens the time that the drug stays in the body, and thus increases the time that the patient is exposed to the effects of the drug and/or the metabolite. This can be a problem if the metabolite is toxic.

5) Identify four tissues that play a minor role in drug excretion: skin, lungs, hair and breast milk.

The skin is a pretty minor route of excretion. Most of it happens through sweat, tears, saliva or desquamation (i.e. shedding of old skin cells). This is mainly an issue for miners and other people who have to do hard work with metals, as in these conditions more lead, cadmium, nickel and so forth may be sweated out than excreted via urine. High levels of sweat containing these metals can lead to dermatitis in sweaty areas such as the armpits and groin.

The lungs are somewhat important in secreting volatile substances, or compounds that have gaseous metabolites such as CO₂. Secretion here occurs much the same as normal respiration- by gases in the blood diffusing into the alveoli and then exhaled.

Hair is a somewhat unintuitive one, as we don't often think of hair as a medium for excretion. However, many chemicals do deposit in the hair, and analysing hair segments can give an idea of the length of exposure to the chemical. This is useful for testing for illicit drug use.

Finally, breast milk is a minor route of excretion that can be concerning due to the risk of affecting the baby. Lipophilic and basic drugs can potentially pass into the fatty, acidic breast milk. In some cases, the nursing infant ends up getting a higher exposure to the drug (mg/kg) as compared to the mother.