Archive for: August, 2010

Trauma and Adaptation

Aug 30 2010 Published by under [Biology&Environment], [Brain&Behavior], [ScienceInSociety]

I owe friend of the blog and fellow neuroblogger (who you should totally be reading, by the way) Scicurious for inspiration on this next series of related posts. I highly recommend that you go check her blog out, because she does a lovely job at explaining many neuroscience topics, especially the WEIRD science. In fact, she's just reposted a series about neuroanatomy that might be helpful background reading!

Let’s start the science in today’s post with a quote of old to set the stage.

'Selection is the very keel on which our mental ship is built. And in the case of memory its utility is obvious. If we remembered everything, we should on most occasions be as ill off as if we remembered nothing.' -William James, 1890

I’ve liked this quote since I first read it, because it reflects the importance of our subconscious mechanisms in maintaining memory. Most of the time we don’t really give a lot of consideration to the processes of learning and memory modification- they just happen as we go about our lives. When something disrupts those processes, and we don’t like the results, the importance of that stuff comes to light.

We need to have a good memory and an ability to modify it. Gaining experiences in the world doesn’t do much for us unless we can remember them! Our brains are very good at collecting associative memories for negative circumstances. Danger, pain, trauma, stress, you name it- the brain will pick up cues associated with aversive circumstances and set off a series of alarms when you encounter them again. This reaction might allow you to avoid what could be a repeat scenario of a bad experience.

But what about when associative memories aren’t so relevant to your everyday existence anymore, but everyday things bring those memories back? Say you were in a really high-stress situation and you heard terrible sounds like gunfire. When you get back to your everyday life, the sound of fireworks, or anything else that sounds like gunfire serves as a vivid reminder of that bad experience. Surely when you’re safe in your home, when that situation ends, you don’t need to have everyday things reminding you of that experience.

These kinds of severe stress reactions are not uncommon. Experiencing something terrible and traumatic is hard on you overall, and that includes your brain! Most of the time we can re-adapt out of that high-stress state after a short while, and get back to our usual baseline. But in some cases, for some people, that re-adaptation process doesn’t work as we would expect. That’s where we get into the realm of stress and anxiety disorders.

There are as many different ways to react to a traumatic experience as there are individuals in this universe. I want to make that clear. But we tend to look at collective symptoms as a disorder when they start to disrupt an individual’s normal daily life. There are a couple of different disorders associated with re-adaptation out of that high-stress state, which are distinct but related:

Acute Stress Disorder (ASD) – as you might guess, this is a short-term series of stress symptoms.

Post-Traumatic Stress Disorder (PTSD) – a more severe and generally more chronic set of stress reactivity symptoms.

Of course, the stress reaction has its origins in various places in the brain, and in the interactions between multiple brain regions. We might not know everything there is to know, and there is much work for science to continue doing, but we have a basic idea of the science going on here. Next up we’ll look at the neuroscience of stress reactions, how adaptations in stress signaling occur during and after heavy stress, and what's available for treatment of stress and anxiety disorders.

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Sleep, New neurons, and Cognition

Aug 23 2010 Published by under [Biology&Environment], [Brain&Behavior]

I've mentioned my general interest in how the brain adapts or responds to variables in the local environment. One thing I think we can all identify with, at some point in our lives, is how slow we can start to feel under some extended less-than-ideal sleep circumstances. That feeling kinda sucks, doesn't it?

It's not just you feeling generally crappy and tired- your brain is actually making some changes in response to the lack of sleep. So with that I'll introduce my first literature blog post, in which I review a paper that I think is cool.
ResearchBlogging.org

Sustained sleep fragmentation results in delayed changes in hippocampal-dependent cognitive function associated with reduced dentate gyrus neurogenesis.

N. Sportiche, N. Suntsova, M. Methippara, T. Bashir, B. Mitrani, R. Szymusiak, and D. McGinty.

Why did I pick this paper?

I really like studies that investigate not only behavior but also associated changes in biochemical goings-on in the brain. And the hippocampus is just cool. How can you not like the hippocampus?

Overall, what did they do in this study?

These researchers looked at the effects of sleep fragmentation on cognitive function by testing sleep-fragmented rats in a maze task, and then looking at how many new neurons they made in the dentate gyrus of the hippocampus during a phase of the sleep fragmentation treatment.

How did they do it?

They implanted electrodes to measure rats' sleep-wake cycles.  Using the sleep-wake data, they started a treadmill to wake up the rats anytime they had been asleep for 30 continuous seconds, for 12 days. Two weeks after the rats finished the sleep fragmentation, they spent 5 days training in the Barnes maze. This is a large circular platform, with eight holes evenly spaced on the outer edge. One of the eight holes is the escape, and the rat should use visual cues around the room to navigate its way to the escape chute. (It's actually identical to and visually indistinguishable from all the other holes in the maze, I just can't resist the phrase "escape chute.") After the 5 days of Barnes maze training, they were given two days on a reversal task in the Barnes maze. The reversal task tests the rat's ability to adapt to changing locations of the escape chute. The rat had to un-learn the original escape position, and learn the new escape position.

Once the researchers observed this learning behavior, they counted new neurons that were born in the dentate gyrus during the fragmented sleep treatment.

What did they find out?

Sleep patterns

Rats in the sleep fragmentation group (black triangles) got shorter lengths of non-REM sleep at a given time, but they also got *more* fragments of sleep. This is looking like some disruption from normal.

Sleep fragmentation changes search strategy in the Barnes maze

First, the authors provide examples of search strategies that rats might have used to find the escape chute in the Barnes maze after they learn where the chute is.

1. Direct- the rat goes directly from the starting point to the correct escape point.

2. Quadrant- the rat goes to the correct quadrant of the maze, and then finds the hole that leads to the escape chute.

3. Error direct- The rat goes directly to the wrong hole- oops! - but then goes immediately to the correct hole next.

4. Serial- the rat checks every hole until it encounters the escape. This score and higher ones involve the rat not using spatial cues to navigate its way to the escape, it's just going on the premise that there is an escape and eventually it will run across it.

5. Serial-Random- the rat tries some serial, and some random wandering around the maze, to eventually run across the escape.

6. Random- the rat just wanders around until it runs across the escape.

Alright. Now while they show these nice pictures in the above figure and label them 1-6 with a decreasing sophistication of search strategy, they turn around and score these in reverse order. That was a touch confusing when I first read it. So when you look at this next graph, think backwards from the above figure. Lower score is worse performance, higher score is better. Lower = random, Higher = Direct.

The black vertical line divides the regular Barnes maze task on days 1-5 and the reversal task on days 6-7. SF rats (black triangles in the left-side graphs) are different in some ways from the control groups. They made significantly more Random-strategy attempts (top left). These scores are averaged on the top right.

The Technique score, based on the Low=Random to High=Direct scale, isn't particularly different on a given day. But when they average the scores from the entire testing session, they see a significant reduction in overall score in the SF rats.

Overall, this means that the SF rats used less sophisticated methods to find their way out of the maze, relying on the fact that they would eventually run into the exit rather than learning how to navigate using the spatial cues to take the direct way out.

Newborn neurons

As a final observation, the authors looked at the number of neurons that were made in the hippocampus on days 4-5 of the sleep fragmentation treatment. This is done using a chemical that integrates into the DNA of new cells, we're going to call it BrdU and leave it at that. BrdU labeling will show up only in cells that were made during BrdU treatment- not before, and not after. And those new labeled cells do have to stay alive between the time they are made and the time they are counted, too!

We're interested in newborn neurons in the hippocampus for many reasons, not the least of which is the vital role the hippocampus plays in cognitive performance in tasks like the Barnes maze. We have some hints that sleep disruptions might reduce neurogenesis, the process of making these new neurons, and that reduced numbers of newborn neurons might reduce our ability to adapt to and learn new things (like un-learning the first Barnes maze escape, and learning a new one in the reversal task).

It's pretty clear from this figure that the counts of newborn neurons are quite a bit lower in the SF rats than in their control groups. They show a couple of very nice example photos, a bit of double-staining to demonstrate that they are staining newborn cells and that those cells are indeed neurons (and not other interesting non-neuron type cells).

Recap

We learned some interesting things in this paper. First, rats seem to compensate for fragmented sleep by getting more fragments. I suspect people are the same, but that's just speculation. Nonetheless, the rats with sleep fragmentation tended to use a less "sophisticated" strategy to get out of the Barnes maze. Rather than using spatial cues around the room to learn which hole they should use to escape directly, they tended to use the serial and random type strategies, just checking every hole and exiting the maze when they ran across the escape. The sleep fragmented rats did have a lower number of newly made neurons in the dentate gyrus of the hippocampus compared to the control groups, as well.

Maybe you've had a few sleep-fragmented weeks- or months, or years.  This doesn't mean your brain is toast, though some days it totally feels like it. In fact, the brain can be really great about bouncing back from such things, and to bring your spirits up I'll see what I can find on that topic next. But, I'm just gonna warn ya here, if you're sleep fragmented, you might reserve showing off your awesome maze escape performance skillz until you've gotten a little more rest.

Sportiche, N., Suntsova, N., Methippara, M., Bashir, T., Mitrani, B., Szymusiak, R., & McGinty, D. (2010). Sustained sleep fragmentation results in delayed changes in hippocampal-dependent cognitive function associated with reduced dentate gyrus neurogenesis Neuroscience, 170 (1), 247-258 DOI: 10.1016/j.neuroscience.2010.06.038

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Cannabinoid agonist JWH-018 (part 2)

Aug 19 2010 Published by under [Biology&Environment], [Brain&Behavior], [Medicine&Pharma]

[second in a two-part repost series for your reading pleasure! -leigh]

Continuing my discussion of the purported “legal marijuana” from my previous post, for this post I’ll move to the topic that’s probably of greater interest: what do these drugs actually do, and what’s different about them?

I already covered that JWH-018 is a synthetic compound that is structurally unrelated to THC, the principal psychotropic component of marijuana. I also mentioned, but not in great detail, that it works via the same receptors as THC does, and that it and some other compounds from its family of structures (the aminoalkylindoles) produce cannabimimetic (cannabis-mimicking) effects.

Cannabimimetic effects encompass several different physiologic changes. In rodent models, a “tetrad” of effects (catalepsy, decreased locomotion, hypothermia, and hypoalgesia) are measured as the benchmark of cannabimimetic effects. Of course, rodents aren’t so good at telling us when they’re experiencing particular psychedelic effects, so we can’t measure that specifically. In humans, perceptual alterations, memory alterations, and euphoria are commonly discussed cannabimimetic effects.

That brings us to the big question:

If these drugs produce similar effects and work via the same mechanism, how can they be different?

Oh, there are many ways.

Let’s consider some of the most basic pharmacological properties of any given drug. The drug has to bind to its target, it has to cause an action at that target- and if it’s psychotropic, it has to get across the blood-brain barrier to do any of this. Only then are the effects of the drug actually set into motion.

Before it can cause an effect, the drug molecule needs to run into and bind to its target. This very first step carries a lot of variability across different drugs, even at the same target. Seemingly small changes in chemical structure of a drug can have a dramatic impact upon how well that drug will bind to its target. In this case, the target is the cannabinoid CB1 receptor, which is expressed widely throughout the brain and mediates the psychotropic effects of THC. Since living systems add a big pile of other variables we won’t get to just yet, pharmacologists typically measure this basic property of drug-target affinity in vitro. If a drug will bind easily to the receptor even at very low drug concentrations (very low doses), that constitutes very good affinity. Potency is a closely related measure, where the dose that causes a physiologic effect in a system is measured.

Figure 1. Drug potency as shown in typical dose-response format. A drug that produces an effect at a lower concentration is considered to be more potent. Lower potency drugs have curves that are shifted to the right, meaning that more drug is required before physiologic effects can be measured.

The few studies that have looked at the pharmacology of JWH-018 at the CB1 receptor have shown that JWH-018 is more potent than THC. It will bind the CB1 receptor at considerably lower concentrations than THC will, and lower doses of JWH-018 are required to produce physiological responses.

Next is the specifics of the drug action on its target. Most drug targets don’t function as all-on or all-off, like a light switch. Instead, consider them more like a dimmer switch. Different drugs (again due to their differences in chemical structure) can cause different levels of activation of the target. This is the efficacy of a given drug at a given target.

Figure 2. Drug efficacy, again in typical dose-response format. Drugs with high efficacy produce a greater maximal effect than low-efficacy drugs. These curves can also vary by effect for drugs that produce multiple measurable effects. There are places in medicine, for example, where full agonists are the preferred tool to use, and places where a partial agonist is better. It all depends on the conditions! More effect is not always better.

A drug that activates the receptor is generally known as an agonist. But since there are varying levels of activation that a given drug can cause at a receptor, we sort the agonists into categories. There are partial agonists, that don’t activate the full capacity of the target, and full agonists, that do. THC is a partial agonist at the CB1 receptor, only partially activating it. On the other hand, JWH-018 is a full agonist. This is a major difference in and of itself- CB1 receptor responses, and immediate and long-term cellular adaptations in response to drug, vary with different agonist efficacy. The particular psychotropic effects of THC are distinctly related to its partial agonist nature. This does not mean that JWH-018 will make users “more high” than THC or is somehow “better” than THC – just that the immediate and long-term effects are distinct and can’t be described as “the same thing but more powerful.” If you take one thing away from this post, let it be that.

Recall that living systems add a whole lot of complexity on top of the already fairly complex drug-target interactions that I’ve discussed so far. Let’s consider how the drug gets to the receptor in the first place. Drugs have varying absorption and distribution kinetics, which can also modify the drug effect. Something that gets into the brain very slowly will give a different effect than something that reaches the brain rapidly. We know essentially nothing about the absorption and distribution kinetics of JWH-018, it’s all up to speculation.

Speaking of kinetics, metabolism/elimination kinetics are also quite variable between different drugs. And on that hand, we’re in the same position as with the absorption and distribution kinetics. No solid understanding. Some clever folks are developing methods to detect metabolites of JWH-018, but that’s where we are.

So to summarize:

1. JWH-018 is more potent than THC. Lower concentrations of drug will produce notable effects with JWH-018 than with THC.

2. JWH-018 is more efficacious than THC. The maximal effect of JWH-018 is greater than that of THC in every physiological measure that’s been captured to date.

3. The points I bring up in 1 and 2 DO NOT mean that JWH-018 is like THC, but “better” or “stronger” or any other comparator. The considerably different pharmacological properties of these two drugs causes them to have (perhaps related but) distinct effect profiles.

4. We have little to no scientific information about how JWH-018 is distributed and eliminated from the body.

5. We have little to no scientific information about JWH-018 beyond what I’ve outlined here.

Alright, we can talk theoretical concepts and isolated measured properties of drugs all day, but the bottom line is that people are trying this stuff out and perhaps using it regularly. How do the limited data we have translate to people? Unfortunately, there’s not a ton of properly-controlled study of the stuff in model organisms, much less humans. So we know very little except what we can speculate from the basic pharmacology that we do know about.

Not surprisingly, there are plenty of people willing to venture out and be their own n=1 case study, but the information we can gain from those people is pretty constrained. Is this a call for more study? Perhaps…

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Cannabinoid agonist JWH-018 (part 1)

Aug 19 2010 Published by under [Biology&Environment], [Brain&Behavior], [Medicine&Pharma]

[another repost in a 2-part series, but this time because the topic is very much in demand lately. -leigh]

I’ve been noticing lots of talk of these “new” synthetic cannabinoids floating around out there lately, now that Spice and K2 have gotten a lot of media coverage. I also found a lot of hearsay and uninformed opinion floating around on the internet in various places, but not so much of the scientific information. Let’s remedy that, shall we? I’ll cover the basics over a couple of posts and more if there are remaining questions.

Spice and K2 are being floated as the new “legal marijuana” – a supposedly marijuana-like high without legal consequences. Abel Pharmboy kicked off the discussion with a Research Blogging post about synthetic cannabinoids that you should definitely check out. DrugMonkey brought up an interesting thought in his post on the topic: does the US Controlled Substance Analogue Enforcement Act of 1986 apply? This act states (I paraphrase here) that a compound that shares a similar chemical structure or pharmacological action and is intended for human consumption is treated as a Schedule I classified drug. According to some interpretations of people who know more about legal stuff than I do, that might be a negative. So let’s explore the chemistry of the cannabinoid agonists** to get started.

**Disclaimer: I am not an organic chemist. Don’t crucify me.

Delta-9 THC, the principal psychotropic ingredient in marijuana, is a terpenoid compound produced by the Cannabis sativa plant. You can examine its structure here:

Figure 1. THC chemical structure (via Pubchem)

THC acts through brain cannabinoid receptors to produce its typical effects. However, those receptors are involved in a whole lot more than just producing the psychotropic effects of cannabis intoxication. The pursuit of understanding the mechanism of action of cannabinoids, as well as further research to better understand the normal and abnormal physiology of the endogenous cannabinoid signaling system, has resulted in many novel synthetic drugs designed to target the cannabinoid receptors in experimental systems. They were devised to be used as tools to elucidate what happens when we probe the system- for instance, what molecular properties are required for a given drug-receptor interaction property (efficacy, affinity, what have you).

There are multiple classes of structurally distinct cannabinoid agonist drugs that emerged from these efforts. Given the topic under discussion here, I will focus on the aminoalkylindoles. They are structurally unrelated to delta-9 THC, as you can gather by the structure.

Figure 2. Aminoalkylindole cannabinoid agonist WIN55,212-2 structure (also via Pubchem)

Here’s where I bring in the so-called “legal marijuana” – one of the compounds that’s causing this stir, named JWH-018, is a derivative of the aminoalkylindole class of drugs. Take a look for yourself, and consider the similarities to the aminoalkylindole above.

Figure 3. JWH-018 structure. Rotated (imperfectly, but you get the idea) to demonstrate structural similarity to figure 2.  Pubchem may be a good start, but how about we get something that lets us rotate around bonds? Get on that, NCBI.

Note again that these are synthetic compounds- they are not analogs of THC and not produced by the Cannabis sativa plant. They are structurally unrelated, but act upon the same receptor as does THC. They have different pharmacological properties: efficacy and potency, which I will discuss in the next post. This does not make them “better” in some or any way compared to the plant-derived cannabinoid compound.

Now the curious thing is that while these synthetic classes of compounds may be structurally distinct from the original cannabinoid compound of interest, they do produce pharmacological effects that are classified as cannabimimetic. And yet, one does not need a DEA license to obtain some of these research chemicals.

Many of these “legal” products are distributed as plant matter soaked in JWH-018 and other compounds, and then marketed as incenses- covered with warnings about how they are not intended for human consumption. This is also curious. How long will this hold off the inevitable? I don’t have a guess.

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A midweek note

Aug 18 2010 Published by under [Etc]

I'm getting some fabulous comments, folks. Suggestions of more things to blog about, notes of congratulations/support for the new blog, things that crack me up, stuff like that. These and more are very much appreciated, do keep it up!

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various tags!

Aug 18 2010 Published by under [Etc]

leigh has been tagged by multiple people in the 10 words of blogging philosophy meme! i noticed the tags, decided to wait until i had the blog here up and running, and promptly lost track. i know that Dr O and Biochem Belle over at Lab Spaces (which you should most definitely check out!) tagged me, and my apologies to others that did and i totally missed it. here is the meme:

1. Sum up your blogging motivation, philosophy and experience in exactly 10 words.

2. Tag 10 other blogs to perpetuate the meme.

i see pharmacology everywhere, and i explain what i see.

or:

no, there are still not enough cannabinoid jokes in pharmacology.

[a small taste of the blog's future, new readers...]

or:

brains, drugs, miscellany. does it get any better than that?

i have completely lost track of who has and has not been tagged or done the meme. if you feel so inclined, consider yourself tagged, go for it, and let me know in the comments.

but friend of the blog, noted architect of rhyme, and fellow Scientopian Scicurious turns this thing up a notch with an additional challenge.

In the first, you must express your TWEETING! philosophy and motivation in ten words AND under 140 characters (this probably isn’t hard). You must then tag ten other tweeters. Extra fun and bragging rights goes to those who RHYME!

holy crap, Sci! i'm nowhere near the wordplay prodigy that you are, but i'll give this a try. whoa!

drugs going to brains, tweets about stuff running through veins.

anyone else up to this challenge? whew!

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Fun with pharmacokinetics (part 2)

Aug 17 2010 Published by under [Biology&Environment], [Medicine&Pharma]

[the pharmacokinetics topic is a big one, so i decided to break it down into drug-gets-in and drug-gets-out sections. -leigh]

Distribution

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 that whole party. Wherever the blood is going, the drug is in there and it’s going too.

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 cytochrome 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, is 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 curtains for that particular drug 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.

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 "real" 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 (or, you can get more of the story at WhizBang!, our local expert blog). Drugs can be excreted through all possible excretion routes the body has to offer.

There you have it. The very long story that boils down to this:

Drug gets in, drug meets target, drug gets broken down, drug gets kicked out. The story of pharmacokinetics.

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Fun with Pharmacokinetics (part 1)

Aug 17 2010 Published by under [Biology&Environment], [Medicine&Pharma]

[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!

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What's pharmacology about?

Aug 13 2010 Published by under [Biology&Environment], [Medicine&Pharma]

In all the writing about science, pharmacology, and pharmacology topics that I've done so far, I can't recall that I have ever sat down and described what pharmacology IS in basic terms. This is probably a way to kick-start the science topics of the blog here, yes? So let's explore.

I know many people who appreciate the phrase, "better living through chemistry" - and they are quite correct, we owe quite a bit to our chemist friends. But for chemical stuff that affects physiological function, we can generally take it one step further and add pharmacology as a co-conspirator in the better living racket.

Pharmacology is, in the broadest sense, the study of drug-body interactions. Using a wide variety of scientific tools, pharmacology can be applied to ask and answer many drug-body questions. What does drug X target inside the body? What effects will drug X cause? How will the body distribute and break down drug X? Is drug X safe (and how do we define "safe" anyway)?  How might we develop something that is more safe and more effective? What other targets can we investigate with our newfound knowledge of where/how drug X works? Pharmacology helps to define drugs as physiological tools- whether that tool is in your morning cup of caffeinated goodness or your asthma rescue inhaler.

When you look at all the questions and angles and approaches involved, one quickly sees that pharmacology is incredibly multidisciplinary. It employs multiple sub-disciplines of chemistry, biology, physiology, behavioral study, genomics, proteomics, and MANY more to find the answers to the important questions. I personally think the wide variety of approaches used in pharmacology make it really exciting! In order to answer a broader question, you can end up learning how to do a bunch of very different scientific techniques, bring all of them together, and create a coherent and comprehensive answer out of your multiple-angled observations.

I am, of course, a little biased. You can probably tell. At least I'm open about it.

Many people think that pharmacology is mainly about drug discovery. That is indeed a major part of the discipline. We can use the multidisciplinary approaches of pharmacology to gain an understanding of how the body works, then work with that information to develop workarounds when things don't function as expected. Many of those workarounds come in the form of therapeutic compounds. But there is much more than drug discovery here. Plenty of natural and synthetic compounds are already in regular use today, that are not as well-understood as they could be. There are chemical entities involved in medicinal properties of plants and fungi that have not been isolated and made more useful to us. The toxic effects of common and uncommon chemicals often need to be more thoroughly described as well. I could go on, but these are just a few examples. Pharmacology is vast.

As we gain a little steam here on the blog front, I'll expand on several these topics individually. There is so much to pharmacology that a single post will either become too massive or too nonspecific, so I'm trying to strike a middle ground by stopping here. Just please, don't ask me if I'm a pharmacist. Don't get me wrong, pharmacists do a crucial job, but pharmacologists are on the research side. And I'll bet we have more fun. ;)

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Welcome!

Aug 12 2010 Published by under [Etc]

Welcome to the Neurodynamics blog! I’m Leigh, and I’ll be your tour guide.

Yes, I’m a bit late to the big launchfest. Some things going on in real life have turned me into that friend who always misses out on the most awesome things because she can’t get out of work on time. But, now I’m here, and I’ve brought another round of drinks and a few more fireworks to keep the party rolling.

First, a bit about the blog:

You’ve probably surmised by the banner that the content here will be mostly neuropharmacology. That sounds like I’ve narrowed the subject matter down some, right? Pharmacology, check. Of the brain, check. [psst, Dr. "the brain confounds everything" Isis, i can just see your comment coming, bite me.] But there are a lot of topics left in that particular box. Because I think it’s cool, and because this is *my* little corner of the interwebs, discussion will focus around how the brain adapts to outside and inside stimuli. Your brain is along for the rollercoaster ride that is your life with you- happiness, stress, varying degrees of intoxication, nervousness- while you change as a person in response to your experiences, your brain changes as well! This blog will generally focus around the science behind those adaptations.

And about your narrator/tour guide:

Leigh is a neuropharmacologist by day, and… well… a neuropharmacologist by evening and night, too. She’s navigating the early-career stages of science, collecting experiences and anecdotal data to help decide what she might end up doing with her life someday.

So grab a seat, make yourself comfy, and enjoy the ride! I'm incredibly excited to be a part of Scientopia and look forward to lots of great science blogging.

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