The pharm + tox lecture series: #3 - Distribution, putting the D in ADME

To recap: Pharmacologists use a cute little acronym, ADME, to describe the path that a drug takes through the body: Absorption into the bloodstream, Distribution to the tissues, Metabolism in some of those tissues to produce metabolites, and finally Elimination in body wastes like urine and poop.

Heh. I said poop.

Today is distribution day. Well, make that more like absorption and distribution day. Allow me to explain.

Most routes of administration involve the delivery of a drug into the body at a site removed from the bloodstream. Hence the drug must pass across cell membranes (including those of the cells that make up the walls of blood vessels) to reach the systemic circulation (i.e. the bloodstream). Once it gets there, it must again pass through cell membranes to exit the blood and enter tissues (and organs, which are a specialized collection of tissues), this being the process of distribution.

All of the fluid in the body (referred to as the total body water), in which a drug can be dissolved, can be roughly divided into three compartments: intravascular (blood plasma found within blood vessels), interstitial/tissue (fluid surrounding cells), and intracellular (fluid within cells, i.e. cytosol). The distribution of a drug into these compartments is dictated by it's physical and chemical properties. I'm gonna discuss a couple of these.

Relative solubility is the solubility of a drug in lipid, which is the primary component of cell membranes, relative to it's solubility in water, the primary component of body fluids. This can be measured by mixing a known amount of drug with equal parts oil and water, and then determining the ratio of the drug concentration in the oil to that in the water (this can be accomplished easily using a radiolabeled drug). This ratio is called the partition coefficient (Po/w) and can be used to determine where a drug likes to go in the body. Any drug with a Po/w greater than 1 is generally going to be capable of rapidly passing (diffusing) through cell membranes with relative ease, and so will likely be found throughout all three fluid compartments. Drugs with low Po/w values (meaning that they are fairly water-soluble) are often unable to appreciably enter the intracellular fluid compartment and require more time to distribute throughout the rest of the body.

The size of a drug also dictates where it can go in the body. Most drugs have molecular weights between 250 and 450 Da. Antibodies and other recombinant proteins and peptides like ADH or insulin range into the thousands of daltons (insulin is about 6000 Da). Tiny drugs (150-200 Da) with low Po/w values (meaning that they are quite soluble in water) like caffeine, furosemide, and ephedrine are able to passively diffuse through cell membranes via water channels called aquaporins. Drugs over 200 Da with low Po/w values cannot passively cross membranes and so require specialized protein-based transmembrane transport systems. Their distribution throughout the compartments of the body tends to be slower. Drugs under a thousand daltons with high Po/w values are able to simply diffuse between the lipid molecules that make up membranes, while anything larger requires specialized transport.

The pharm + tox lecture series: #3 - Absorption, putting the A in ADME

When it comes to describing the journey that a drug takes through the body, pharmacologists like to employ a cute little acronym: ADME. It stands for Absorption, Distribution, Metabolism, and Elimination. I'll be covering the D, M, and E parts in future posts, but for now let's focus on the A.

Absorption, in the pharmacological sense, refers to the passage of a drug from the external environment into your body, usually into systemic circulation (i.e. your bloodstream). In essence, how a drug gets inside you. There are all sorts of interesting ways by which this can be accomplished, so I'll give you the rundown.

Topical administration consists of applying a drug directly to the part of the body where you want it do stuff. The drug does not get into your systemic circulation, either because it is given in such a small amount or it specially formatted so that it won't pass into your blood in appreciable amounts. Examples include skin ointments and creams, eye drops, nose sprays, ear drops, vaginal suppositories, as well as drugs injected into joints (e.g. corticosteroids to treat arthritis), the epidural space (e.g. an epidural), or the cerebrospinal fluid (intrathecal administration, e.g. to treat a brain infection with antibiotics).

Percutaneous or transdermal administration consists of applying a lipid soluble drug to your skin with the intent that it will dissolve through your dermis into your systemic circulation. Nicotine (hooray for quitting tobacco!), scopolamine (to prevent you from puking in moving vehicles) and birth control patches (which apparently make you fat) are primo examples. A similar route is via inhalation, with the drug passing through the lung epithelium instead of the skin. This tends to occur very rapidly. Things like inhalational general anaesthetics (e.g. desflurane or sweet, sweet xenon), medicinal marijuana (wink!), and asthma drugs (e.g. puffers) can be administered this way.

Enteral administration refers to giving a drug in such a manner that it enters your body at some point along your gastrointestinal (alimentary) tract. Sites include your oral mucosa (e.g. buccal or sublingual nitroglycerine drops), your stomach/intestines (referred to as the oral or p.o. route, any drug that you have to swallow), or your rectal mucosa (mmm, mmm, suppositories!).

Parenteral administration means giving a drug 'beside the gut'. In other words, injecting it somewhere with a needle so that it bypasses your gut to get into your bloodstream. The types of injections are fairly self-explanatory. Subcutaneous (s.c.) means under your skin, intramuscular (i.m.) means into a muscle, intravenous (i.v.) means into a vein (the medical world's usual target of choice), and intra-arterial (i.a.) means into an artery (used to direct anticancer drugs at high concentrations into tumours). Another variety of injection that is generally limited to lab animals due to the relatively high risk of infection or injury is intraperitoneal (i.p.) injection. This involves the delivery of a drug into the peritoneum, which has a large surface area and so allows rapid entry into the bloodstream. It's worth noting that some drugs, such as vancomycin or heparin, can only be given parenterally because their chemical structures are such that they are either broken down in the gut or else are not appreciably absorbed through gut walls into the bloodstream.

The pharm + tox lecture series: #2 - Drugs, medications, and poisons (Oh my!)

The name of this site is a misnomer. Sad but true. You see, technically, poisons ARE drugs, so it's pretty silly to make a distinction between them ('Drugs and Poisons'). It's a shame, but at least I wasn't writing a textbook or something.

The definition of a drug is shrouded in caliginous gloom. Actually, it's not that bad (I just wanted to use the word caliginous), but it certainly isn't clear-cut. The key feature of a drug is that it alters in some way the function(s) of an organism when introduced into an organism's body. In a broad sense, food can be considered a drug.

It can get tricky. Estrogen naturally produced in people's gonads is not a drug, but it becomes one once it is packaged into birth control pills.

Anyway, way back in the sixteenth century, this Swiss fellow named Paracelsus (oh for the days of one-word names) introduced an intriguing concept: All drugs are poisons. Any drug, regardless of how benign it may seem, when given in a sufficiently high enough dose, will cause harm to a person. Poisons refer to drugs that are recognized for their ability to cause disease, while medications are drugs that usually treat disease.

In conclusion, I should have named this site 'Medications and Poisons', but 'Drugs and Poisons' sounded too cool to pass up. The end.

The pharm + tox lecture series: #1 - Pharmacy vs. pharmacology (plus toxicology!)

After much thought and careful inaction, I've decided to broaden the content of this site. On an approximately once-a-week basis, I'm going to drone incessantly on about pharmacology and toxicology, the scientific disciplines concerned with, quite appropriately, drugs and poisons.

First off, I need to stress to you a distinction of the utmost concern: pharmacology IS NOT pharmacy. Pharmacologists are not responsible for dispensing drugs at your local Walgreens or Shoppers Drug Mart. Although I've only recently finished up my pharmacology degree, I've already become intimately acquainted with the pain and suffering associated with trying to explain to just about everybody who asks what I've gone to school for that I do not, in fact, plan on opening up my own pharmacy any time soon.

Now that I've got that out of my system, let me break it down for you:

Pharmacology is the science concerned with (a) the fate of drugs in the body after you take/are given them and (b) the actions of drugs on the body. The branch of pharmacology concerned with (a) is called pharmacokinetics, while that concerned with (b) is called pharmacodynamics. Other branches include pharmacovigilance, pharmacoepidemiology, pharmacogenomics, pharmacoeconomics, clinical pharmacology, and agricultural pharmacology.

Pharmacy is a health profession concerned with the preparation and proper use of drugs. A pharmacist attempts to optimize the use of drugs to help make people better, while a pharmacologist attempts to understand how drugs actually work.

Toxicology is the science concerned with the adverse effects that chemicals have on living things, particularly people. It includes the detection and treatment of poisonings.