Posted by: leigh | March 6, 2009

fun with pharmacokinetics

i hated pk when i was learning it my first couple of years in grad school. see, we learned from a hardcore dude at mega u and he was tough! i much preferred the pharmacodynamics over how the drug got to where it got. but of course, pk is as important to drug effects as pd. 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 the proper 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. pain patients 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. if 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.

so. 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!


that’s right, when you take a drug, it goes everywhere. it gets into your bloodstream and it goes everywhere your blood goes. now it’s just along for the ride among your red blood cells and clotting factors and immune cells and whatnot. (“and whatnot”- i should be ashamed of myself!) wherever the blood is going, the drug is in there and it’s going too.

so you can see now that the administration route has an effect here. from your lungs, it’s hitching the express train to the brain. from the stomach, not only is that going to take longer, but it goes to your liver first. the liver is your body’s drug deconstruction factory, where your metabolic enzymes (the P450s) live. vascular injections are immediately effective.

also, there are lots of things your drug can bind to or equilibrate with as it travels along through your bloodstream. there are proteins in the blood that drugs bind to. fat-soluble drugs will inevitably get into the fat depots that we all have. in the end the drug distributes to wherever it can possibly get. and that likely includes the site of action where you want it to work. but you see that a lot of things can affect how available the drug is by the time it reaches the site of action!

but the drug gets there, or we wouldn’t even bother with any of this, would we?

extra barriers

there are a couple of areas of your body that have extra protection from the blood circulating in your body. first, of course, the brain. the brain isolates itself with the blood-brain barrier. this is basically a specialized membrane coating of all the blood vessels that run through your brain. it still gets the nutrients it needs from the blood, but much fewer things are able to cross that extra barrier. so for a drug to be cns active, it has to be particularly lipophilic, meaning it is ideally a small molecule that is not charged at blood pH. (ideally.) another barrier that exists in some of us some of the time is the placental barrier. like the blood-brain barrier, the placental barrier protects the growing fetus from a number of things hanging out in mom’s bloodstream. this includes quite a few drugs. but again, there are things that get through it quite easily with the right properties. so while it’s helpfully protective, it’s not the intense shield we would like it to be (or some of the vital things wouldn’t make it across either!)

and the drug gets metabolized too

now we have this drug that’s circulating all through your body. but waiting in your liver, as i mentioned earlier, are enzymes that are ready and waiting to modify any drug that they come across that fits their active site. that means as soon as the drug runs into that enzyme, it’s over for that particular molecule. (though some drugs have active metabolites, or are administered in the inactive form and then metabolized to become active.) but there are only so many enzymes available, so if there’s a ton of drug and less than a ton of enzyme, some drug will make it through the liver intact for another run through the body. and then maybe another.

so what this comes down to is that the drug concentration in your blood gets reduced on a per-time basis. we call this the half life (or alternately, the half time or t1/2). the half life, as you might guess, is the amount of time it takes the body to get rid of half the concentration of drug in your bloodstream. depending on what mechanism is responsible for getting rid of the drug, you will have different half lives. for alcohol, interestingly, there isn’t a half life but a maximal amount that your body is capable of breaking down per hour. this is called zero-order kinetics.

i think we’re going to stay away from enzyme kinetics for this post, as much as i love the biochemistry behind it.

of course, your body is always excreting things from your bloodstream too. your kidneys are a big player in drug excretion. they filter stuff out of your blood and you probably know the rest of the story. drugs can be excreted through all possible excretion routes the body has to offer.

so there you have it. drug gets in, drug meets target, drug gets broken down, drug gets kicked out. the story of pharmacokinetics. it’s a little late, so i might just have to go back and do some editing/clarification tomorrow.

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  1. AWESOME, Leigh!!! I will be linking to this…

  2. lol… i knew you’d totally love this one, fellow pharm nerd! i had one too many search hits that indicated a screaming need for this post.

  3. [...] for a little pharmacokinetics action. leigh is not necessarily an avid pk lover, but she’ll engage it as needed. after all, it’s an important part of pharmacology. and practical knowledge to [...]

  4. [...] It really takes very little time for the drug effects to kick in when you smoke marijuana. Eating it is another story. If you’d like to catch up on your pharmacokinetics to understand why this is, check out an older post. [...]

  5. [...] It really takes very little time for the drug effects to kick in when you smoke marijuana. Eating it is another story. If you’d like to catch up on your pharmacokinetics to understand why this is, check out an older post. [...]

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