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What Is a Drug?

September 13, 2011

A considerable number of the recent series of posts have been concerned with molecules that can be referred to as drugs. It seems useful here to take a look at this from a semantic point of view.

Drugs at Different Levels

Most people carry around in their minds more than one specific meaning ascribed to the small word ‘drug’. If you hear “He’s a drug dealer” or, “She’s on drugs”, the references are not likely to be to antibiotics or blood-pressure medication. Conversely, the sentence, “My doctor prescribed a drug for me” is most unlikely to refer to crystal meth. As a result, the great majority of people realize (even if only intuitively) that the illegal band of drugs are but a subset of a much larger group, that includes substances both universally approved and potentially truly life-saving. It would then be reasonable to assume the definition of a ‘drug’ in this larger sense should be fairly straightforward.

Some standard dictionary references are along the lines of: “A substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication” or, “a chemical substance that affects the processes of the mind or body”. The US Food & Drug Administration (FDA) defines drugs with wording introduced by the Food, Drug, & Cosmetic Act of 1938, as “articles (other than food) intended to affect the structure or any function of the body of man or other animals” [Sec. 201(g)(1)]. These definitions are quite broad, especially the latter. But speak of ‘drugs’ with a pharmacologist, and small molecules are most likely to be the topic of conversation, and not just any small molecules. Indeed, the term ‘drug-like’ is frequently used in the general field of drug discovery to encapsulate (so to speak) the special features which a successful medicinal drug should embody. Obviously, a drug must have definable function(s), which means that it must be directed to a specific molecular target or a limited set of targets (very often, but by no means exclusively, proteins). But a number of additional properties are very important if the drug is to successfully survive in an active form long enough to be useful, and to find its way to the desired target when administered to a patient. For example, a simple set of guidelines for evaluating a candidate compound formulated by Lipinski has been termed the ‘rule of five’, owing to the recurrence of five (or multiples of it) in the definition of the useful range of properties to look for. Getting a drug to where it needs to go is the preoccupation of the burgeoning field of drug delivery, which now intersects in many cases with advances in nanotechnology.

These rules were designed expressly with reference to small molecules, since increasing molecular size is often associated with diminishing returns in terms of delivery, and sometimes physical properties such as solubility. But that is certainly not to say that large molecules cannot be useful pharmacological and therapeutic agents. In the previous post, it was noted that it has only been in very recent times (historically speaking) that large proteins (especially antibodies) could be garnered from the biosphere for useful human applications. In fact, (as also noted), antibodies have become a billion-dollar industry, especially where monoclonal or specifically engineered antibody variants are concerned. And these antibodies are often referred to as drugs, especially in lay usage. Though obviously moving beyond a tight pharmaceutical definition of ‘drug-likeness’, this is perfectly consistent with the above broad definitions, including that from the FDA. But there are some gray areas…..

Drugs and Category Overlap

It is quite clear that some classes of substances or preparations may have members which have dual drug and nondrug characteristics. One such case noted by the FDA is the field of cosmetics, where even more narrow types of products differ in this kind of duality. For example, shampoos may be seen as primarily hair cleansing, or cosmetic, preparations, and indeed many are simply that and no more. But certainly some have additional functions, such as treating fungal (dandruff) or louse infestations. In this case, specific compounds are added for the indicated medicinal specifications. Although it is obviously of practical significance for product safety and efficacy requirements that some preparations should be regulated and licensed as both drugs and cosmetics, here the relevant products are mixtures, and specific molecules are not doing functional double-duty. For example, an anti-dandruff shampoo may have many different components, but the most significant are the detergent (usually sodium lauryl sulfate, for the cosmetic washing function) and the dandruff inhibitor (specific compounds such as zinc pyrithione). In other words, we cannot speak of either of these individual compounds as having an overlapping drug / cosmetic function; it is only as mixtures (along with various other materials) that the product as a whole acquires this status.

Yet there are certainly well-defined cases where specific molecules share categorization as a drug in combination with other properties. A prime case in point is a contender for the title of oldest drug used by humans: ethyl alcohol, or ethanol. Its psychoactive and other physical effects clearly indicate its drug status, but ethanol can also be metabolized to yield specific calorific value. As such, it is then a food as well as a drug. This is straightforward, but some other areas of ‘foods’ are less so. One definition of a ‘food’ might focus on the ability of a substance to be digestible, or act as source of energy, but clearly this is not sufficient for a healthy diet. There are numerous nutritional ‘cofactors’ which are essential for human health, included among which are a number of inorganic elements (principally metals, but also some other trace elements), and a group of vitamins.

Where do vitamins stand with respect to drug classification schemes? As small molecules which act as organic enzymatic cofactors for catalysis (coenzymes), the defined vitamins are an essential human dietary requirement, owing to our inability to synthesize them. But since they are not directly digestible themselves, they are classified by the FDA as ‘dietary supplements’, which are encompassed within the broader area of foods, and not drugs. Vitamins, then, fall into the this category and therefore would escape labeling as drug materials, unless they were chemically altered from the natural forms. Most dictionary definitions of ‘food’ also include vitamins. Even so, in other quarters vitamins have been clearly depicted as drugs. One basis for doing so is that vitamins can clearly cure diseases – but since the relevant diseases are deficiencies of the vitamins themselves, this would seem to be a special case. As we have seen with alcohol, assignment of a specific compound as a food does not mean it cannot also be a drug. But clearly there is a difference here: vitamins are essential for life, while alcohol (whatever some people might say) is not.

The figure below depicts two separate classifications where the vitamins are considered either as drugs (A) or not (B):


Two depictions of drug categorization and its overlapping areas. These are not to scale in terms of the relative sizes of the respective groups, and are schematic only. ‘Food / nutrients’: This refers to subtances which directly provide energy, structural building blocks, or essential assistance with normal metabolic functioning.  ‘Dietary cofactors’ in general include both vitamins and inorganic substances (such as essential metals). ‘Proteins / macromolecules’: Not all macromolecular therapeutic agents are proteins, as for example nucleic acid aptamers. A, Vitamins considered as drugs. Some cosmetic preparations contain vitamins, so vitamins are shown to intersect with the ‘drug-overlap’ region of all cosmetics. B, Vitamins excluded from classification as drugs.


Does this cover everything? Well, there is an additional broad grouping of substances termed ‘nutraceuticals’, a hybrid term from ‘nutrient’ and ‘pharmaceuticals’. A nutraceutical in principle can be any food source component with biological properties outside of direct nutrition, but many of the best-known examples are antioxidants. Included among these are phytoestrogen compounds, considered in an earlier post. Resveratrol in particular (see the relevant Figure from this same post ) has generated enormous interest for its observed anti-ageing effects.

Where do these compounds reside in the above figure? Although they are by definition associated with some kinds of foodstuffs, they are neither directly digested (as for proteins, and digestible carbohydrates and fats), nor required for essential metabolism (as for vitamins). Therefore, it is logical that they be considered a subset of the large drug category, outside of the macromolecular subregion, as shown above. These compounds can be identified, purified, synthesized,  and administered independently of their original sources. In this respect, they are no different from any other small molecule natural products derived from the biosphere.

Drugs as Foreign?

Can drugs be thought of as molecules which are ‘foreign’ to the body to which they are administered? (In other words, compounds which are not synthesized by the human or animal which receives them). In a strict sense, this would include vitamins which are dietary essentials through the lack of synthetic machinery for their production by a host animal or person. But there are problems with this proposal, and vitamins themselves are a case in point. For example, although Vitamin C is essential for human health (scurvy resulting in its absence), rats, mice and numerous other species have no problem making their own. Is Vitamin C then a drug for humans (capable of curing scurvy) but not for rats?

And numerous human proteins can be administered under circumstances where they can be considered drugs. Antibodies are an interesting case in  point. Originally, monoclonal antibodies were of murine origin owing to the technological requirements of their production. The xenogeneic (foreign) nature of these proteins resulted in the induction of immune responses against the monoclonal antibodies themselves, when they were given to patients. In more recent times, fully human monoclonal antibodies have been developed, in order to circumvent this very significant problem. Yet an antibody of this type is still not literally and totally ‘self’, since its specific combining site is generated by recombinational and mutational mechanisms such that its exact sequence is not directly encoded in the human germline.

But non-variable molecules both large and small also come into this picture. Think of human growth hormone, of value for treating some forms of dwarfism – and sometimes abused for the purposes of body-building. Numerous other proteins and small molecule hormones can also be cited – so the notion of ‘foreign-ness’ for drugs in general becomes untenable.

Drugs, Poisons, and Doses

Drugs have been termed ‘poisons that save lives’, which carries the implicit message of the importance of dosage. But stating that ‘all drugs are poisons’ may be technically correct at a broad enough level, yet not particularly useful, given the vast differences in dosage ranges for efficacy vs. safety seen with different therapeutic compounds. Here a balance or ‘window’ must be found between the two poles of beneficial drug activity and unacceptable toxicity. The old saying ‘the treatment was successful, but the patient died’ provides an ironic testament to this inherent dilemma of drug pharmacology.

As an example of the great range of drug therapeutic windows which can exist, consider the treatment of syphilis. The pioneer of chemotherapy, Paul Ehrlich, found an arsenical compound (Salvarsan) which became an effective treatment for syphilis through its activity against the bacterial causative agent Treponema pallidum. But its toxicity at therapeutic doses was a major problem encountered in a high percentage of patients, so it was clearly not ideal. When penicillin became available in the 1940s, it was not only highly effective but also associated with very low toxic side effects. Indeed, the rising problem of bacterial resistance was initially countered by simply increasing the dosage of penicillin (or its many derivatives) without problems – but of course this soon becomes ineffectual as resistance increases. (Penicillins can actually induce serious problems through allergies in a minority of people, but this is quite distinct from direct toxicity).

There is also a piece of folk-wisdom along the lines of ‘too much of anything can hurt you’, which is certainly true for some natural nutritional requirements as well as drugs. In a general sense, too much food is clearly bad through the development of obesity, but the ‘dosage’ effects of nutrients can be observed in a much more specific manner. We can look within the set of vitamins once more for useful comparisons, which also demonstrate similar variation in the ‘safety’ windows of dosage as seen within artificial drugs. Vitamin C has exceedingly low (if any) toxicity, for example, and some people have routinely taken very high doses of it for long periods as part of ‘megavitamin’ therapy. On the other hand, the fat-soluble Vitamins A and D are unquestionably highly toxic when taken in excess of recommended daily requirements.

The dosage effect can also be related to the above observation that drugs need not be alien to the biochemistry and physiology of the patient (or animal) undergoing treatment. A pathology caused by a deficiency in a specific molecule can be corrected through artificial intervention. Conversely, certain pathological states may benefit from the provision of ‘unnatural’ administration of normal bodily proteins, such that the circulating amounts of the factor of interest are maintained for therapeutic purposes at higher levels than would normally be the case.

After this short foray into some issues surrounding the meaning of drugs, I’ll conclude with references to ‘nutraceuticals’ once more, by means of a biopoly(verse) note.

By analyses really quite shrewd

On mixtures both complex and crude

Smart chemists have shown

(And now it is known)

Natural drugs exist in some food.

References & Details

(In order of citation, giving some key references where appropriate, but not an exhaustive coverage of the literature).

‘….. (FDA) defines drugs….’    For FDA definitions of both drugs and cosmetics, see the relevant page of the FDA site.

‘….set of guidelines for evaluating a candidate compound formulated by Lipinski…’    For a discussion of the basis of the Rule-of-five and moving beyond it, see Zhang & Wilkinson 2007.

‘…..field of drug delivery, which now overlaps with advances in nanotechnology.’   For a recent review of this topic in the cancer field, see Chidambaram et al. 2011.

‘….sodium lauryl sulfate….’   Also known as sodium dodecyl sulfate, this detergent also has wide application in laboratories as well as cosmetics.

‘…..a contender for the title of the oldest drug used by humans….’     Often alcohol is definitively cited as the oldest drug. I call it ‘a contender’ here since (as noted in an earlier post), the use of botanical medicines is also very old, and can even be linked with primate behavior (see a previous post on zoopharmacognosy). On the other hand, the use of alcohol (or abuse, depending on one’s views) is possible simply from natural cases of fruit fermentation, also seen with animals. So the origins of alcohol sampling by humans need not require any technology, and is undoubtedly of great antiquity.

‘……ethanol can also be metabolized……’    For an example of the differing influences of food vs. drug effects in an animal system, see Dole et al. 1985.

‘…..classified by the FDA as ‘dietary supplements’….’    For the FDA definitions of dietary supplements, see the relevant page of the FDA site.

‘…..vitamins can clearly cure diseases…..’    This was noted by Tulp et al. 2006, and that vitamins were thus ‘drugs by any definition’. Taken literally, this is clearly incorrect (one can simply exclude vitamins from a drug definition as dietary supplements, as for the FDA).

‘…..nucleic acid aptamers….’ (Figure footnotes).   See a previous post for a brief consideration of RNA aptamers. From large libraries of variants, RNA molecules can be selected to bind desired ligands, and this can be used therapeutically. The first therapeutic aptamer (‘pegaptanib’) was directed against a specific form of vascular endothelial growth factor, for the treatment of ocular vascular diseases. See Ng & Adamis 2006.

‘……an additional broad grouping of substances termed ‘nutraceuticals’……’   For example, see Tulp et al. 2006.

‘……Resveratrol in particular …… has generated enormous interest for its observed anti-aging effects……’    See Pezzuto 2011.

‘……Vitamin C is essential for human health (scurvy resulting in its absence), rats, mice and numerous other species have no problem making their own.’    See Martí et al. 2009 for more information. The production of Vitamin C from glucose requires the enzyme L-gulonolactone oxidase, which humans, primates, and guinea pigs lack. Lachapelle & Drouin 2011 look at when this occurred in evolutionary time.

‘…..its exact sequence is not directly encoded in the human germline.’   Antibodies are composed of constant and variable regions, where the variation of the latter accounts for the vast range of different antibody binding specificities which can be induced by immunization. Particular variable region sequences allowing antigen recognition are specific to that immunoglobulin molecule, and are termed an ‘idiotype’. See Searching for Molecular Solutions Chapter 7 for a more detailed discussion of this.

Numerous other proteins and small molecule hormones can also be noted…..’   Proteins such as interferons were noted in the previous post. Small molecules include adrenalin, thyroid hormones, and natural steroids. In all such cases, though, there is the potential (realized in many cases) for rendering such molecules ‘non-natural’ by various forms of artificial tinkering to improve their performances as drugs.

‘….pioneer of chemotherapy, Paul Ehrlich…’     See Thorburn 1983 for some biographical and other relevant information.

‘……certain pathological states may benefit from the provision of ‘unnatural’ administration of normal bodily proteins…..’    Again, see the reference to the example of interferons in the previous post.

Vitamin C ….. ‘megavitamin’ therapy.’    The Nobel Prize-winning chemist Linus Pauling was a notable proponent for the efficacy of large Vitamin C (ascorbate) doses for conditions ranging from viral infections to cancer. (For example, see Pauling & Moertel 1986).  However, no experimental evidence has validated these claims.

‘…..fat-soluble Vitamins A and D are unquestionably highly toxic….’    It is notable that the livers of certain polar animals (including bears and seals) are very rich in Vitamin A, and the eating of such livers by polar explorers has resulted in Vitamin A poisoning (hypervitaminosis A). See Rodahl & Moore 1943.

Next Post: Two Weeks from now.

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