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These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not. So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

I chose to work on this subject for December because I may end up teaching a lecture or two on metabolism in early February to pharmacy students.  Obviously I’ll go more in-depth with them, but that isn’t the purpose of these Primers: they are intended as introductions.

Merriam-Webster defines “metabolism” as such:

Metabolism –noun

a.  …the chemical changes in living cells by which energy is provided for vital processes and activities and new material is assimilated

b. the sum of the processes by which a particular substance is handled in the living body

This definition is all well and good, but we’re talking about a specific form of “metabolism” here, one that really is talking about the breakdown of a chemical compound not necessarily for the purpose of generating energy.

Wikipedia provides us with a separate definition for drug metabolism:

Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems.

So when we’re talking about an individual, such as an athlete, that has a “strong metabolism,” we’re talking about related but separate processes from the ones typically involved in modification and removal of drugs from your system.

In general, drug metabolism consists of two separate processes known as Phases.  In Phase I metabolism, a given compound is broken down and typically inactivated (but not always, as we’ll see shortly).  It usually involves a specialized protein called an enzyme that removes a specific portion of the compound, rendering it pharmacologically inactive.  Phase II metabolism typically involves the addition of another molecule onto the drug in question, something we call a “conjugation reaction.”  This process serves to also increase the polarity of a given drug.  Usually, we think that Phase I reactions precede Phase II reactions, but not always.

When I say “polar,” I mean it in a sense similar to a planet, in that a planet has “poles” (e.g. north and south).  For the sake of simplification, you can also think of a magnet or a battery instead, with a “positive” pole and a “negative” pole.  In this fashion, chemicals also have a positive and negative charge, including chemicals like water:

In this case, the oxygen atom in water (i.e. H2O) is negative while the two hydrogen atoms are positive.  Therefore, water is polar: it has an end that is more positive and an end that is more negative.  Polar compounds are also considered “hydrophilic” (i.e. “water-loving”), mostly because these polar chemicals tend to dissolve readily in water.

There are examples of “hydrophobic” (i.e. water-fearing) chemicals as well, also known as non-polar.  You know how oil and water don’t mix?  That’s because oils like fats or lipids are hydrophobic and non-polar, made up of molecules that look kinda like these.

These are all examples of hydrophobic (non-polar) compounds, those that do not mix well with hydrophilic (polar) molecules like water.

The key to drug metabolism is to realize that most of your cells, and thus organs, are made up of lipids such as these, so if you have a drug that is particularly “lipophilic” (and thus, hydrophobic), then the drug is more likely to hang around in your body.  That is to say, a drug that is non-polar can hang around longer, affecting you for longer than you may otherwise want.  If you use a more polar drug (i.e. hydrophilic), it’s more likely to get passed out of your body much faster.  Much of your body’s ability to expel chemicals and metabolites depends on the ability of your kidney and liver to get those chemicals and metabolites into a form that works well with water, as water is what you typically get rid of (i.e. urine).

When your body recognizes a foreign compound, such as a drug, it wants to make that drug more polar so it can excrete it.  Thus, your liver contains a number of enzymes that do their best to make those foreign compounds more polar so you can get rid of it.

This process, obviously, impacts the ability of a drug to take action, which is why this process is important.  There’s a reason why drugs are introduced to your body orally (i.e. through the stomach/intestines), or intramuscularly, or intravenously.  If you were to take a drug orally, then it is subjected to what is termed as First-Pass Metabolism.  Typically, when you eat something, the nutrients from whatever you ate are taken up through the portal system and hit your liver before they hit your heart, which only then go on to the rest of your body.  Therefore, if you take Tylenol for a headache in a pill form, it some of it will be broken down in the liver before the heart gets it, and then it gets pumped to your brain to help with your headache.

Alternatively, you could take Tylenol intravenously, which bypasses the liver and thus gives you a full dose.  However, Tylenol is toxic in high doses, so you would never want to inject much of it (or any of it…there are better choices if that’s what you’re considering….) for fear that it could kill you.

The final concept to consider, aside from drug modification, polarity and first-pass metabolism, is how we could use this system to our advantage.  There are times when you take a drug, such as a benzodiazepine like valium (diazepam).  Valium, on its own, is very useful as a depressant, used to treat things from mania to seizures, however the act of drug metabolism produces metabolites that are also active (called, not surprisingly, active metabolites).  In the case of valium, it is broken down in the liver to nordiazepam, then temazepam and finally oxazepam.  Each one of these metabolites is active to some extent, which means that a single dose of valium will last for quite awhile as it’s broken down into other compounds that still affect you.

Sometimes, you can administer a non-active drug that then becomes active once it’s modified in your liver.  We call this a prodrug.  Codeine, for example, is modified by Phase I metabolism to its active form, morphine.  You typically administer morphine to someone intravenously, as it’s rapidly metabolized in the liver.  Codeine allows you to take advantage of your liver to give you morphine in a pill form, which you otherwise wouldn’t be able to do (as it would be broken down too far before it even hit your heart).

In short, drug metabolism is an extremely important process to consider when designing a drug.  You need to take ease of use and route of administration into account, you need to consider whether a drug has active metabolites or not, and you need to be aware of how hydrophilic/hydrophobic a drug is if you want it to remain in your body for any reasonable amount of time.

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not. So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

I can’t say I’ve been excited about writing this one, as brain anatomy is, quite possibly, the most boring thing I can think of to write about.  I did a rotation at SLU in a lab that focuses on anatomy and how individual brain structures interact with one another, and that 6 week period was more than enough for me.  As that professor told me, it’s very important work that someone needs to do, even if it may not seem all that interesting.  This kind of work is how researchers have figured out which brain component “talks” to which other one(s), and how intertwined all these connections really are throughout the brain.

For the sake of this posting, I’ll simply point out that brain mapping has been carried out in a variety of ways.  Quite a bit of it has been done over decades when people would hit their heads.  If they would lose their memory, or their sense of smell, clinicians could localize the injury to a specific area of the head, then look at the brain post-mortem and see what happened.  Ultimately, they would find a lesion of dead tissue in that region that lead to the deficiency.  Similarly, the study of stroke victims also provided clues to the function of certain brain locations, as a stroke occurs when blood flow is cut off to an area of the brain, typically leading to damage.  Alternatively, modern science uses a series of stereotactic injections of traceable materials in mice, rats and primates that can be visualized in brain slices, showing that a series of neurons in one area are connected with neurons in a separate region of the brain.

It is through this work that certain pathways were elucidated, including the reward pathway (very important for drug addiction, gambling addiction, etc.); the movement pathway (mostly for Parkinson’s disease, but important for voluntary movement, in general); the sensory systems (how the visual cortex signals, the auditory cortex, etc.); the amygdala (figuring out what this structure did and where it went led to quite a few labotomies back in the day); and memory (signals transfered between the hippocampus, the reward system, and the cortex…very complicated network…).  It is through brain mapping like this that helped determine where everything connects together, and which areas are important.

While the human brain is a difficult nut to crack, it can be divided up into different portions.  For the sake of this little blurb, we’ll focus on the three primary divisions of the brain: the prosencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain).

The prosencephalon, or forebrain, is further divided into the telencephalon and the diencephalon.  The telencephalon consists, primarily, of the cerebrum, which includes the cerebral cortex (voluntary action and sensory systems), the limbic system (emotion) and the basal ganglia (movement).  As you can see from that list, for the most part, the telencephalon is what constitutes what “you” are: your thoughts, your feelings, and your interaction with the world around you.  It’s where a lot of your processing happens.  The telencephalon in humans is quite a bit more developed than in other species, which is really what separates their brain from other, lesser developed species (i.e. the human telencephalon is what really separates them from a chimpanzee).  The diencephalon, on the other hand, consists of the thalamus, hypothalamus and a few other structures.  The thalamus and hypothalamus are very important for various regulatory functions, including interpretation of sensory inputs, regulation of sleep, and release of hormones to control eating, drinking, and body temperature.

The mesencephalon is comprised of the tectum and the cerebral peduncle.  The tectum is important for auditory and visual reflexes and tends to be more important in non-vertebrates, as they don’t have the developed cerebral cortex that humans do (more on that later).  The cerebral peduncle, on the other hand, is a mixed bag of “everything in the midbrain except the tectum.”  It includes the substantia nigra, which ties into the movement system and reward system.  I think it’s fair to say that, aside from these things, the function of the midbrain, overall, has yet to be fully determined.

The rhombencephalon is quite important, even though it’s probably the oldest part of the brain, from an evolutionary standpoint.  It includes the myelencephalon (medulla oblongata) and the metencephalon (pons and cerebellum).  The medulla oblongata is important for autonomic functions like breathing and heart function.  The pons acts primarily as a relay with functions that tie into breathing, heart rate/blood pressure, vomiting, eye movement, taste, bladder control and more.  Finally, the cerebellum is important for a feeling of “equilibrium,” allowing for coordination of movement and action, timing and precision.

As you may have noticed, if you go from back-to-front, you’ll get increasing complexity in brain function.  For example, the hindbrain is important for very basic things like breathing, heart rate, and coordinated movement.  These are functions that are important in nearly all organisms, but especially so all the way down to the smallest worm and insect.  Further up, the mesencephalon starts to work in further control of reward and initiation of voluntary movement, giving the organism voluntary control rather than solely reflexive control.  Then, the diencephalon starts acting like a primitive brain, working in regulatory functions and more complicated reflex action to help maintain the more complex organism that has been assembled.  And finally, the telencephalon yields the ultimate control over the organism, with things like memory, emotion, and greater interpretation of sensory inputs.  As the image above dictates, the hindbrain (to the right-hand side) remains a large portion of the brain in the rat and the cat, but the human forebrain (the top/left-most portion) gets much larger, relative to the hindbrain.  With that size comes greater development of brain structure and function.

So yeah, the brain is kinda complicated.  Actually, it’s really complicated and, for the most part, I do my best to ignore all of the complex wiring networks that occur within.  However, it is important work that needs to be done in order for surgeons to do what they do, and for neuropharmacologists to develop drugs that target some brain areas and not others.  For the most part, I’ll leave this research to more interested people…