Hello everyone!
In celebration of the release of the Korean edition of ‘Drunk Flies and Stoned Dolphins’, here for your reading pleasure, is an excerpt from chapter 2 of the book, pages 45-53; notes at the end of the excerpt😊.
Enjoy!
Hugs,
Oné
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THE PHILOSOPHY OF PHARMACOLOGY*
It is unusual to see these two academic terms in the same sentence, as pharmacology and philosophy do not seem to be related to one another. However, each scientific discipline in fact has its own set of guiding philosophical principles, and pharmacology is no exception. The first order of business is to define what exactly we mean when talking about a “drug.”
As with many important concepts in life, this term is subjective, meaning that its precise meaning will depend on whom you ask. Nonetheless, we can say for sure that at the fundamental level, a drug is a chemical, and a common definition of a drug is “a chemical used to treat a disease.” This being said, there are many compounds that are not medicines, but which we still classify as drugs. Take the example of nicotine, which is probably the most addictive substance known. This drug is extensively abused by humans, yet I know of no bona fide, medically approved use for nicotine so far.**
Perhaps a better way to define “drug” would be to differentiate it from food, as few of us drink martinis for their nutritional value; however, just as defining drugs as “medicine” isn’t quite right, defining them as “not food” has its own problems, which we’ll delve into more later. For our working definition, then, perhaps the best we can do is something like “a non-nutritional substance or chemical that affects the function of your body.” At any rate, we call the branch of science that studies drugs—whether medicinal or recreational—pharmacology. Like most modern scientific subjects, pharmacology is interdisciplinary in nature; it has to be, because in its modern inception, this science deals with the effects of drugs on humans and animals, from biochemistry to behavior.
Almost without exception, pharmacologists (including yours truly) rely on four core principles that guide our work and help organize our thoughts and ideas. These apply whether the context is one of experimentation or of established drugs used in clinical practice, and keeping them in mind will help us understand what is going on as we continue to explore the world of animals on drugs, and drugs more generally.
1. Cause and Effect = Dose and Response
Depending on the context, we can call this principle the dose-response concept or the concentration-response concept.*** This means exactly what it sounds like: for any given drug, the induced effect is proportional to the amount given (but please see principle #2 below!). In other words, the higher the drug dose, the larger the effect and vice versa. Of course, this is true whether we are talking about a drug’s desired effect or other, less desired consequences of its consumption. Too much of a good thing oftentimes becomes a bad thing, which brings us to our second principle.
2. There Is a Fine Line Between a Drug and a Poison
About five hundred years ago, the Swiss scientist Paracelsus gave us these wise words: “Sola dosis facit venenum.” For those of you whose Latin is a bit rusty, this roughly translates to “The dose makes the poison.” You’ve probably heard this phrase before; it is oft-quoted precisely because it is so important. This principle tells us that no substance is 100 percent safe, meaning that if you take any substance—and I mean any substance, even water—in excessive amounts, said substance is likely to become harmful. We usually refer to this harm as toxicity.****
The concept of toxicity was the origin of pharmacology’s evil twin: toxicology. This discipline essentially studies the pharmacology of a drug’s harmful effects or, as I call it in my silliest moments, when pharmacology attacks. † It is critical to understand that in the medical sciences the decision to administer a medicine is largely a matter of determining the cost/benefit ratio. In other words, doctors give a medicine when the small probability of harm is more than offset by the likely benefits (or by the certainty of harm if nothing is done to prevent or treat a given disease).††
Of course, while this cost/benefit ratio applies on a population level to drugs we decide are safe enough (at a particular dose) to be used as medicines, it is applied by doctors on an individual level, too: a particular drug might not work equally well for everyone, while on the other hand not all substances are equally toxic to everyone (not everyone is allergic to penicillin, for instance). After accounting for factors such as age, general health state, and so on, the varying effects that the same compound might induce in different individuals are largely a matter of genetics, which brings us to our third principle.
3. We Are All Different
Populations are almost never made up of clones; in nature, a clonal population is generally not a very good idea because variation is one of the main prerequisites for evolutionary change and adaptation.††† As for how this relates to drug effects, the main idea is this: in any normal population of a particular species, all individuals will have a basic genome that defines their particular species. For example, all seven billion or so of us humans on this planet right now share the same basic set of genetic material (what we call the human genome). However, with the exception of identical twins, triplets, and so on, there exist many individual differences going “beyond” that basic genome. This is self-evident; just think about all the physical differences in any group of people—aside from the aforementioned exceptions, everybody looks a bit different, while still having the general arrangement of anatomical features that are the hallmark of what we know as “human.”
Applying this reasoning to our genes, there is a series of genes that define us as being human; there is little wiggle room in these (for example, no normal humans—except for moms—have eyes on the back of their heads).
Other genes, like those that control the color and texture of hair (red/brown/black/blond hair or—in my case—no hair at all), can “come” in several variations. The genes that may affect our responses to drugs fall into this latter category. Let’s explore this concept a little further. Take three people who, sadly, are each suffering from a headache (and to make things simpler, let’s imagine their headaches are all the same). Perhaps the first person only needs one regular aspirin to get rid of the pain, while the second one needs two of those, and aspirin does not even work for person number three, but another drug does the trick. This possibility of variation applies to virtually every medicine at our disposal, and it’s the same with poisonous substances. Prolonging our hypothetical headache (it’ll be over soon, pharmacologist’s promise!), suppose that we have a large group of sufferers and a supply of standard 325 mg aspirin tablets. Many of the individuals in this population will be able to rid themselves of their headache with only one tablet. But a certain percentage of the population will need much less than 325 mg to feel better, while another fraction of the population will require more. There might even be a fraction that is either completely insensitive to aspirin or even poisoned by the smallest amount of it. Animal populations are no different.
Please keep this idea in the back of your mind as we continue our conversation!
For some reason, we humans have a tendency to assume that all animals of a certain type are pretty much the same—we are less likely to do this with familiar creatures we are used to thinking of as individuals, like dogs, but when we think about, say, koalas, we often imagine them as a bloc. However, just as we discussed for human populations above, animal populations also display a high degree of genetic variability. Thus, if we talk about a certain animal species’ sensitivity to a particular drug, it will almost never mean that 100 percent of the individuals of such a species will be identically affected.
For example, later on we will talk about the active chemical in catnip and its effect on, well, cats. As we will see, only about 70 percent of individual cats seem to react to catnip (please see my book excerpt from chapter 6 – Catnip!). This fact does not only apply to house cats, mind you, but bigger cats as well (think tigers and lions). We may not have this kind of detailed information for every animal species that we encounter in this book, but if I have found it and it is relevant to our conversation, I will mention it. The bottom line is that, for all creatures great and small, some individual variability in response to a drug is not surprising and even expected.
4. Everything Begins with Binding
Until now, I have not said too much about how drugs are able to affect biological systems. To illustrate the mechanism behind this process, let’s think about how we hear music. We cannot capture the music carried by electromagnetic waves traveling through space at the speed of light without an appropriate device such as a radio. ††††
Similarly, for an organism to react to a particular drug, it needs a means of detecting the presence of the chemical. No chemical is capable of inducing a specific biological effect without physically interacting with a specific molecular “antenna,” usually located at the surface of certain cells. We call these antennae receptors, and the interaction between a drug and its receptor is called binding.¥
In essence, a receptor’s job is to react to the presence of a chemical when said chemical comes in contact with it (here we’d say that the chemical binds to the receptor). As a result of this reaction, something happens (muscle contraction, hormonal signaling, and so forth). In general, receptors are proteins that control biological responses; their specific nature depends on what they do in the organism. The formal pharmacological definition of a receptor implies a protein to which a chemical binds, making something happen. However, there are many variations on the theme—for example, transporters (which do exactly what it sounds like they do), enzymes (essentially the molecular entities that perform the actual work in a cell, like controlling chemical reactions), as well as quite a few other classes of receptor-like molecules.
So when your dentist gives you a local anesthetic, the anesthetic molecules bind to a population of specific proteins on the surface of your nerves, inactivating them (hence, no pain). In this case, the protein receives the substance, but instead of activating the protein and making it do something, this binding turns it off. The point is that any drug that enters the body interacts with a target protein (or more likely proteins) in exactly the same way than a natural neurotransmitter or hormone will, by binding.
In some cases, the drug will mimic the action of a natural substance (in this case we call it an “agonist”); in some other cases, it will prevent such action (we call these “antagonists”); still other times, we might be talking about “modulators.”
What are modulators?
I’m so glad you asked!
Imagine a light switch. Ordinarily, we might turn it “on” (as when an agonist activates). We can also turn it off (as when an antagonist inactivates). Or we might have a dimmer, which we can manipulate to make the light bulb brighter or fainter. That’s a modulator.
(Can you tell that I am an actual pharmacologist? 😊 I could talk about these things until the proverbial cows come home, but let’s get back to the point, shall we?)
From now on, unless I tell you otherwise, whenever we talk about a particular substance you may assume that said substance interacts with a specific receptor—more often than not, with a family of such receptors. There are receptors for virtually every substance we will talk about, including hallucinogens, nicotine, morphine, neurotransmitters, hormones, and so on. And in the special case of a drug that interacts with a transporter or an enzyme, I will note it and provide any additional information relevant to our conversation.
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NOTES
* Please note that this is not an “official” integration of these disciplines. I have to confess that for a nanosecond I considered titling this section “Pagán’s Rules of Thumb,” but I thought that was a bit much, perhaps. At any rate, the point is that, while this formulation is my own, these concepts are not merely my invention; they are widely used in biomedicine.
** However, there are some interesting pieces of evidence suggesting that nicotine can act as a neuroprotective agent in animals, as well as a possible pharmacotherapy against Parkinson’s disease (also done only in animals so far). For representative publications, please see Ferrea and Winterer (2009), Thiriez and collaborators (2011), and Quik and collaborators (2008).
***In general, “dose-response” refers to the administration of drugs to humans or animals, while “concentration-response” refers to the testing of drugs in tissue, cells, or biochemical preparations. Please see Tsatsakis and collaborators (2018).
****For an excellent exploration of the dose-response concept within the context of toxicology, please see Calabrese (2016).
†Of course, toxicity also deals with substances that we do not generally associate with consumption for either medicinal or recreational effects, like certain heavy metals or cyanide, for example.
††One example of this idea is the use of certain steroids to treat asthma. Several of these steroids’ side effects include elevated blood sugar, which can be a concern in many people. However, during an asthma attack, the most pressing concern is restoring the ability to breathe, not a transient elevation of blood sugar.
†††Please see my book Strange Survivors: How Organisms Attack and Defend in the Game of Life, Pagán (2018), for a more detailed exposition of evolutionary processes.
††††If you hear music in your head—that you are not thinking about—without the help of a radio or any other kind of electronic device, please see a licensed health professional.
¥ In other words, everything begins with binding. This is my free translation of the famous (among pharmacologists) maxim of the father of receptor theory, Paul Ehrlich: “Corpora non agunt nixi fixata,” which pretty much means that “chemical entities cannot interact with each other unless they are in physical contact.” For example, a local anesthetic must bind to certain parts of the nerve cell in order to prevent pain.
I have no idea what the cover at right is saying… Really!
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