CHAPTER 2 INTRODUCTION TO HERBAL MEDICINE
Herbal medicine, also known as phytomedicine, can be broadly defined as both the science and the art of using botanical medicines to prevent and treat illness, and the study and investigation of these medicines. The term ‘phytotherapy’ is used to describe the therapeutic application of herbal medicines and was first coined by the French physician Henri Leclerc (1870–1955), who published numerous essays on the use of medicinal plants (Weiss 1988).
Phytotherapy can be considered one of the oldest forms of medicine. Since the dawn of time, plants have been used by people of all races, religions and cultures to sustain life and alter the course of disease. Over this time, the medicinal use of plants has evolved along two parallel paths, with the comparatively recent evolution of modern medicine. One path involves the accumulation of empirical knowledge over centuries. Gathered through careful observation of nature and disease, and from cumulative experiences of informed trial and error, the empirical knowledge base for herbal medicines is very large and diverse. For example, the Rig veda, a text from India, and the Egyptian papyri Antiquarium both date from 3000 BC and contain extensive lists of medicinal plants used to treat illness (Berman et al 1999). In South America, the use of herbal medicine has also been documented, such as in the Badianus manuscript, a text written by the Aztecs (Walcott 1940). Their use of herbs, such as datura and passionflower, has been adopted in modern European and American pharmacopoeias. Native Americans were particularly knowledgeable about the botanical medicines in their environment. It has been estimated that more than 200 medicines that were used by one or more Indian nations have been incorporated into the US Pharmacopoeia or National Formulary (Vogel 1970).
Two of the most prominent historical figures in European herbal medicine are Dioscorides and Galen, who were both physicians in ancient Greece. Dioscorides was a Greek army surgeon in the service of the Roman emperor Nero (54–68 AD). He is best known for his De materia medica, which describes more than 600 herbs and their uses. Today this work is considered to be the first book ever written about medical botany as an applied science. Galen (131–201 AD) not only wrote several dozen books on pharmacy, but also developed an elaborate system of herbal polypharmacy in which herbal combinations were devised to produce more specific results. The modern term ‘galenicals’ is still used to describe herbal simples.
Alongside the ‘empirical knowledge’ approach, a second path developed, which involved a more theoretical and formalised method of diagnosis and treatment. The resulting ‘healthcare’ systems were complex and often used herbal medicines as an important part of a more comprehensive approach to treatment that also included dietary control, lifestyle changes and spiritual practice. This approach reached its peak in the East with traditional Chinese medicine and Ayurvedic medicine in India.
Although contemporary clinical practice of herbal medicine still relies heavily on traditional wisdom, this knowledge is now being re-examined with the aid of modern analytical methods and scientific methodology. The use of science to establish an evidence base in modern healthcare is changing the way herbalism is being practised and who is using herbs. An emphasis on phytochemistry and an assessment of risk are inherent features of contemporary research into herbs. While these are important gains in knowledge about the actions and uses of herbs, there is an accompanying shift in the practice of herbal medicine, with less emphasis on the importance of traditional and empirical knowledge, which in time may lead to a loss of the paradigm of holistic and individualised care (Evans 2008). Whether this improves patient outcomes remains to be seen.
Most pharmaceutical medicines contain a single, highly purified, often artificially produced substance that has a well-known (and occasionally specifically designed) chemical structure that can be patented and owned by the company that developed it. The dosage of these chemicals can also be precisely calculated down to the microgram and can usually be characterised by a very clear pharmacokinetic profile. Additionally, pharmaceutical drugs tend to have a generally agreed upon mechanism of action and series of indications that guide their use within the Western medical model.
As most of these drugs do not exist in nature, they must go through extensive testing to ensure efficacy and safety. New drugs are assessed in test-tube and animal studies for their potential to cause cancer, fetal malformations and other toxic effects, and are ultimately tested on humans to further define the safety profile, pharmacokinetics and drug effectiveness in a targeted disease (Wierenga & Eaton 2003). This process is very costly and requires the application of highly specialised knowledge and infrastructure, as well as many years of concentrated effort. It is estimated that the development of a new drug requires the investment of approximately US$800 million, but it is also extremely lucrative (Di Masi & Grabowski 2003).
In 2001 and 2002, approximately one-quarter of the best-selling drugs worldwide were natural products or derived from natural products. Research on natural products further accounted for approximately 48% of the new chemical entities reported from 1981 to 2002.
Modern drug discovery from medicinal plants has evolved to become a sophisticated process that includes numerous fields of enquiry and various methods of analysis. Typically, the process begins with a botanist, ethnobotanist, ethnopharmacologist or plant ecologist collecting and identifying plants based on the biological activity suggested by their traditional use. Additionally, plants are randomly selected for inclusion in screening programs based on molecular targets identified through the human genome project (Balunas & Kinghorn 2005).
Pharmacognosy is the term used to refer to the study of botanical supplements and herbal remedies, as well as to the search for single-compound drugs from plants. Increasingly, pharmaceutical medicines and preclinical research into herbal medicines are focused on identifying suitable chemical entities that may form the basis for novel treatments (Balunas & Kinghorn 2005).
In contrast to pharmaceutical drugs, which are based on single molecules that may or may not be derived from natural substances, herbal medicines are chemically complex and may contain many hundreds or even thousands of different ‘phytochemicals’, including various macro- and micro-nutrients such as fats, carbohydrates and proteins, enzymes, vitamins and minerals. A group of important secondary metabolites are also present, which are generally chemicals used to defend against herbivores, pathogens, insect attack and microbial decomposition, or which are produced in response to injury or infection, or used for signalling and growth regulation. It is these compounds, such as tannins, isoflavones, saponins, flavonoids, glycosides, coumarins, bitters, phyto-oestrogens etc, that are often responsible for the therapeutic properties of herbal medicines (Mills & Bone 2001).
As the secondary metabolites largely dictate a herb’s pharmacological nature, a knowledge of herbal chemistry is essential to understand a herb’s use and provide valuable insight into its clinical effects. It is sometimes tempting to take the modern reductionist approach and predict the pharmacological activity of a herbal medicine from an understanding of the effects of one key constituent or chemical group; however, this is unlikely to be entirely accurate. In practice, the overall pharmacological activity and safety of each herb is the result of the interaction of numerous constituents, some of which have demonstrated pharmacological effects, rather than the effect of a single active ingredient.
An example of this is the herb Paullinia cupana, commonly known as guarana. As there are limited clinical studies on guarana, it is often reported that the herb owes its pharmacological activity to one key constituent, caffeine, which may be present in concentrations as high as 10%. Studies referring to the isolate caffeine provide some clues about the effects of guarana, but are not entirely accurate, as other important constituents are also present in the remaining 90%. This has been borne out recently in clinical studies of low-caffeine-containing guarana preparations, which still demonstrated significant effects on cognitive function.
Because of the range of phytochemicals present in plants, herbal medicines often include many different active substances with different pharmacokinetics that work at different sites with different mechanisms of action. Herbal medicines therefore potentially have multiple pharmacological actions and many different clinical indications. Furthermore, in addition to the active ingredients, herbs may also contain substances that act to inhibit or promote the active properties, and/or potential unwanted side effects of the active agents. Thus, although specific components may not be active themselves, they may influence the activity of other components by altering their solubility, absorption, distribution or half-life.
For instance, berberine is a constituent of herbs such as goldenseal and barberry and exhibits numerous activities in vitro; however, in vivo, it has poor bioavailability (Pan et al 2002). Berberine has been shown to upregulate the expression and function of the drug transporter P-glycoprotein (P-gp) (Lin et al 1999), thereby reducing the absorption of P-gp substrates. Studies with the P-gp inhibitor cyclosporine have shown that it increases berberine absorption six-fold, as it counteracts the inducing effect of berberine (Pan et al 2002). P-gp inhibitors are also found in nature, such as the virtually ubiquitous quercetin, and when they are present in the same herb competing effects on P-gp expression and function will occur.
The herb St John’s wort provides yet another example. The extraction method used in Germany in the product’s commercial manufacture was modified in the late 1990s, resulting in higher concentrations of hyperforin than previously obtained (Madabushi et al 2006). Since then, numerous reports and studies have identified pharmacokinetic drug interactions with St John’s wort, based on its ability to induce cytochromes and P-gp. It is now well established that hyperforin is the key constituent responsible for these unwanted effects, and St John’s wort preparations manufactured with this newer extraction method, such as LI 160, can put people at risk of interactions. Meanwhile, studies with low-hyperforin preparations, such as Ze117, have found that it fails to induce the same interactions (Madabushi et al 2006). Unfortunately, this distinction between St John’s wort preparations is not well known and many references and texts fail to mention this important point.
As these examples and many others in this book demonstrate, each herb is chemically complex and produces a pharmacological effect based on the total sum of actions produced by a myriad of constituents that may be acting in synergy. This complexity complicates the ability to test herbal medicines as they are most commonly used (that is, in their more natural states) and in combination with other herbal medicines.
The concept of synergistic interactions is another fundamental difference between herbs and drugs and explains how a single herb may have a number of seemingly unrelated mechanisms of actions and be indicated for a variety of conditions. Intra-herbal interactions between active and apparently non-active constituents also mean that tests performed with single, isolated constituents will not accurately represent the actions and safety of the entire herbal medicine. As such, these tests provide limited information. By and large, it is suspected that it is the intra-herbal interactions that give herbs a broad therapeutic range and very good tolerability.
St John’s wort, popularised as a useful treatment for depression, is also an excellent example of intra-herbal interaction. It contains many different constituents, such as hypericin and pseudohypericin, flavonoids such as quercetin and rutin, vitamins C and A, phenolics such as hyperforin, sterols, and an essential oil. Although many of the herb’s pharmacological activities appear to be attributable to hypericin and hyperforin, it is now known that the flavonoid content also contributes to its antidepressant activity. In other words, the antidepressant effects identified for isolated hypericin or hyperforin are greater when the whole herb is used.
In practice, synergistic interactions are used in another important way — herbal polypharmacy. This is the combining of different herbal medicines within the same treatment for a more specific outcome, and is similar to the method Galen described centuries ago. In Chinese medicine the concept of synergistic interactions has reached a great level of sophistication, with Chinese formulas containing as many as 20 different herbs. In that system, the herb possessing the primary action of the formula is considered the ‘emperor herb’, while ‘minister herbs’ support the primary action and ‘assistant herbs’ modify the formula according to the needs of the individual. Finally ‘messenger herbs’ are used to aid absorption or reduce side effects of the formula. The practice is also common in Ayurvedic medicine and, in fact, in all traditional systems of herbal practice. Although it may be common in conventional medicine to give certain drugs specifically to reduce the side effects of other drugs, such as the administration of antiemetics and laxatives together with opiates, generally the giving of multiple drugs in combination is discouraged. In contrast, in herbal medicine this practice is often considered essential to provide both safety and the best effects.