Fun with Pharmacokinetics (part 1)

[note: Leigh was out ridiculously late last night, mayhem was involved, and she's wiped out. since we're on general pharmacology topics, it works out nicely that she can cop out with an updated repost of something she wrote a while back. enjoy!]

This topic always brings me back to the early part of my grad school years. In those days, I much preferred the pharmacodynamics (what the drug DOES when it reaches its site of action) over how the drug got to where it got. But of course, pharmacokinetics is just as important to the cumulative drug effect as pharmacodynamics. And as such, here’s how drugs get to where they’re going.

What is pharmacokinetics?

Pharmacokinetics (which is a long damned word to type, so I’m going to refer to it as PK), is the study of how the drug enters and distributes in the body. Also, how the body inactivates and eliminates the drug. Bottom line, it’s all about the basic mechanics that lead to the drug being able to work at its designated site of action, how long it takes to work, and how long it is effective.

Ok, first things first. How do drugs get into the body?

There are several ways for drugs to enter your system. I’ll go through them individually.

Oral- drugs are very commonly ingested in pill form. This means the pill dissolves in your GI tract and is absorbed through it at some stage from your stomach to your intestines. I’ll get to the complexities of absorption in a minute.

Injection- Injections can be vascular (into the blood directly) or extravascular (not directly into the bloodstream). Several different types of injections are out there. For most small molecule drugs, they can be injected intravenously or intraarterially. This is just into an available vein or artery, where it goes straight into your bloodstream, no membrane-crossing absorption needed. This is important, because there are plenty of drugs out there that won’t absorb through membranes and must be injected. There are also drugs that will be degraded by the low pH in your stomach- think protein-based drugs in an environment that has evolved to break down protein. The other injection routes are into muscle (intramuscular), subcutaneous (under the skin), and finally intraperitoneal (into the abdominal cavity).

Inhalation- You didn’t think I would leave this one out, did you? Inhalation is a very common drug administration route. For asthma, for example, inhaling your fast-acting drug puts the drug directly where you want it. For other than asthma- smoking is a very effective way to rapidly get a highly lipophilic drug into your system, particularly for drugs that are CNS active. The aerosolized drug meets the large surface area in your lungs, if it’s lipophilic it will slip right on through the membrane, and tada! It’s on its way to your brain, which is perfused with freshly oxygenated blood from your lungs.

Intranasal- Yes, this is a word for “snorting” a drug- yet another way to put drug into your body. Again, if the drug crosses membranes easily, it’s suddenly right there in the circulation in your head. Gets rapid action of lipophilic CNS-active drugs.

Percutaneous- Patches of drug are fairly common- ever try to quit smoking with the nicotine patch? Heard of the (now fairly unpopular) birth control patch? Both of these administer drug through your skin. Those of you familiar with pain management have probably heard of the fentanyl patch, same concept.

Those are pretty much the most common things people run across. So, what’s next? For most routes of administration, the drug has to get from its entry point in your body to the bloodstream. (Of course, for vascular routes of administration, we bypass this step.)

Getting into the bloodstream

Primarily, the challenge of getting drug into your bloodstream comes down to the ionization state of the drug. Let me explain. An ionized drug is charged, and charged molecules don’t make it across hydrophobic membranes. Just to stop and clarify, something that is hydrophobic will not mix with water. Hydrophilic is the opposite- it will mix with water easily. And lipophilic is pretty much the same as hydrophobic- will not mix with water, will mix with oily things. Ok, back on track. So charged molecules are happier in water-based solutes and won’t go through membranes. Uncharged molecules stand an infinitely better chance of crossing a membrane like the ones that stand between the drug and your bloodstream.

The charge of your drug depends on its pKa and the pH of the environment. The pKa of your drug is a constant (ie, it differs for each drug) determined by its molecular composition. iI you’d like, we can get into the biochemistry of pKa but for now let’s keep it at the level of the pKa being a constant that’s unique for each drug. The pKa in combination with the Henderson-Hasselbalch equation will tell you the ratio of charged molecules to uncharged molecules at a given environmental pH.

The Henderson-Hasselbalch equation tells us:

pH = pKa + log(charged/uncharged)

So knowing this relationship, if we know the pH of the environment the drug is in (say, the stomach), we can determine how much of the drug is in an uncharged state and therefore will cross the membrane to get into the bloodstream.

Assuming the drug is uncharged, it will cross through membrane layers like the ones in the cells that make up your stomach lining, your alveoli (those are in your lungs), and your blood vessels. And now it’s in your blood and can get distributed throughout your body!

Stay tuned, tomorrow we'll have Part 2, in which the drug is distributed and metabolized! It's a gripping story. Be sure to catch it!