2 Principles of herbal pharmacology CHAPTER CONTENTS associated with cell wall polymers and can be released under 2 Defi ning our ground . 17 mild extraction. Another interesting exception comes from the clinical use of a leaf concentrate from alfalfa (Medicago Pharmacodynamics of the archetypal plant sativa ) as an effi cacious iron and folate supplement. 3 constituents . 22 The archetypal plant constituents making up the vast Pharmacokinetics in herbal medicine . 58 majority of the pharmacological properties of plants generally come from the class of plant metabolites (phytochemicals) that are known as secondary metabolites. Primary metabolites are fundamental to the life of the plant and include enzymes Defi ning our ground and other proteins, lipids, carbohydrates and chlorophyll. In contrast, secondary metabolites do not appear to be necessary Pharmacology can be defi ned as the study of the interac- 1 to sustain life at a fundamental biochemical level. However, tion of biologically active agents with living systems. The they probably do have more subtle functions that increase the study of pharmacology is further divided into two main areas. survival prospects of the plant in its natural environment. A Pharmacodynamics looks at the effects of an agent at active brief general discussion of the functions of secondary metabo- sites in the body. In contrast, pharmacokinetics is concerned lites (there are still many gaps in this knowledge) is provided with the effects the body has on the medicine, and specifi - below. cally the concentrations that can be achieved at active sites. The phytochemistry of secondary metabolites is com- The approach used in this chapter, and to some extent in the prehensively covered in the relevant texts. Textbooks on therapeutic chapters, is to examine the pharmacology of key pharmacognosy are especially relevant for the student of chemical groups in plants, the ‘archetypal plant constituents’, phytotherapy and two such texts have been drawn on for the as much as individual herbs. (For detailed information on the phytochemistry content of this chapter: pharmacology of selected herbs see Part Three.) ● The chemical nature and classifi cation of these archetypal Bruneton J. Pharmacognosy, Phytochemistry, Medicinal plant constituents are studied within the discipline known as Plants , 2nd ed. Paris: Lavoisier Publishing; 2008. phytochemistry. Hence, any discourse on herbal pharmacol- ● Evans WC. Trease and Evans’ Pharmacognosy , 16th ed. ogy must be founded on a sound knowledge of phytochem- London: Saunders Elsevier; 2009. istry. A misconception about ‘why medicinal plants work’ The fi eld of pharmacognosy (from the Greek pharmacon sometimes occurs in lay and even in professional circles. This for medicine and gnosis for knowledge) is the study of the is that the various nutrients such as vitamins, minerals and so defi nition, description and phytochemistry of natural drugs on are largely responsible for the pharmacological activity of (typically medicinal plants or preparations derived from plants. (It is perhaps supported by the fact that most herbal them). 4 In fact, the term drug is derived from the old French products in the United States are regulated as ‘dietary sup- word drogue , meaning to dry, referring originally to dried plements’.) Almost without exception, this is not the case. herbs. These days the application of pharmacognosy often One notable exception is that certain plants, such as net- extends to knowledge about the pharmacology of medicinal tle leaf ( Urtica species ) and horsetail ( Equisetum species ), plants, and in some circles the term is used to specifi cally are rich sources of the trace element silicon. There is evi- denote the study of herbal pharmacology, although this is dence that part of this silicon in horsetail is found intimately technically incorrect. © 2012 2013 Elsevier Ltd. All rights reserved. DOI: http://dx.doi.org/10.1016/B978-0-443-06992-5.00002-5 PART ONE Background and Strategies There are also some primers in phytochemistry aimed at the By way of elaboration, lipids are essential for the short- herbal reader who does not have a strong background in natural term functioning of the cell and all cells contain a mix of products chemistry. In addition to this chapter, they represent lipids. But there are some individual lipids made by only a few a useful starting point for students of phytotherapy. 5,6 species and, when their synthesis is inhibited, the cell suffers Why should secondary metabolites have biological activity no short-term disadvantage. 9 in animals? One suggestion put forward by Michael Baker is Since there is no consensus yet on this issue, the term ‘sec- that enzymes in animals can share a common ancestry with ondary metabolites’ will still be employed in this chapter. Be enzymes or proteins in plants. 7 This evolutionary kinship, they speculative, supportive or secondary metabolites, their when combined with structural similarities between plant specialised functions include:10 and animal substrates for these enzymes, could explain the ● defence against herbivores (insects, vertebrates) hormone-like or hormone-modulating effects of several arche- ● defence against plant pathogens typal plant constituents in humans. (See the licorice mono- ● defence against other plants graph for one such example.) ● signal compounds to attract pollinating and seed dispersing animals The role of secondary metabolites ● signals for communication between plants and symbiotic Before discussing the pharmacodynamics of the archetypal microorganisms plant constituents, it is worthwhile to consider some exam- ● protection against ultraviolet light, oxidation and other ples of their value to the plant. physical stressors. The immobility of plants in diverse and changing physical Based on their biosynthetic origins, plant secondary metab- environments, along with the possibility of attack by animals olites (the archetypal plant constituents) can be divided into and pathogens, has necessitated the development of numer- three major groups: the terpenoids, the alkaloids, and the ous chemical mechanisms for protection and offence. Over phenylpropanoid and allied phenolic compounds. 8 All terpe- the past few decades, considerable attention has been paid to noids, including the primary metabolites, are derived from the specifi c ecological roles of secondary metabolites, which the fi ve-carbon precursor isopentenyl diphosphate. Alkaloids were often formerly regarded as waste products. are biosynthesised principally from amino acids, and the phe- However, there is still considerable debate on this complex nolic compounds by either the shikimic acid pathway or the issue. Even the line between primary and secondary metabo- malonate/acetate pathway. 8 lites can be arbitrary. They cannot be readily distinguished on According to Efferth and Koch, two large groups of second- the basis of precursor molecules, chemical structures or bio- ary plant metabolites can be distinguished in terms of their synthetic origins. For example, both primary and secondary biological/therapeutic activities: 11 metabolites are found among the diterpenes and triterpenes. ● A smaller group of highly active compounds possessing a In the diterpene series, both kaurenoic acid and abietic acid high selectivity for cellular targets are formed by a similar sequence of related enzymatic reac- ● tions; the former is an essential intermediate in the synthe- A larger group of moderately or weakly acting compounds sis of gibberellins. These are growth hormones found in all that interact with a broad range of cellular targets (hence plants. 8 The latter is a resin component. Similarly, the essen- possessing molecular promiscuity). tial amino acid proline is classifi ed as a primary metabolite, These authors refl ect that medicinal plants with highly whereas the six-carbon ring analogue pipecolic acid is consid- active phytochemicals represent only a minority of those ered an alkaloid and hence a natural product. Even lignin, the commonly used (probably because of potential toxicity). essential structural polymer of wood and second only to cellu- However, plants with highly active phytochemicals are sought lose as the most abundant organic substance in plants, is con- after in natural products research because they represent sidered a natural product (secondary metabolite) rather than a prime candidates for new drug discovery. In contrast, 90% primary metabolite. 8 of all thoroughly described medicinal plants contain broad- It has been suggested that, in the absence of a valid dis- spectrum phytochemicals with weak or moderate bioactiv- tinction based on chemical structure and biochemistry, a ity. Efferth and Koch suggest that plants have learned to cope functional defi nition becomes the logical choice.8 Primary with the problem of resistance development by producing metabolites participate in nutrition and essential metabolic combinations of pleiotropic multi-targeted phytochemical processes inside the plant, whereas secondary metabolites complexes (see also the concept of intelligent mixtures dis- infl uence ecological interactions between the plant and its cussed later). 11 They also note that those medicinal plants environment. synthesising certain classes of highly active compounds might But even here, there is disagreement. Firn and Jones have protect themselves by producing ‘prodrug’ phytochemi- recently argued that the terms primary and secondary metab- cals that are activated only in predators or on damage to