The gastrointestinal and biliary system

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Chapter 14 The gastrointestinal and biliary system

Gastrointestinal (GI) and liver disorders account for minor, everyday complaints as well as major health problems. Dietary measures can improve symptoms that are caused, for example, by poor eating habits, but, if these are not successful, phytomedicines are also useful. In fact, natural products are still the most commonly used remedies in cases of constipation, diarrhoea and flatulence. Plants and their derivatives also offer useful treatment alternatives for other problems such as irritable bowel syndrome, motion sickness and dyspepsia. In the case of some liver diseases, phytotherapy provides the only effective remedies currently available.

Diarrhoea

Diarrhoea of sudden onset and short duration is very common, especially in children. It normally requires no detailed investigation or treatment, as long as the loss of electrolytes is kept under control. However, chronic serious cases of diarrhoea caused by more virulent pathogens are still a major health threat to the population of poor tropical and subtropical areas. The World Health Organization (WHO) has estimated that approximately 5 million deaths are due to diarrhoea annually (2.5 million in children under 5 years).

The first line treatment is oral rehydration therapy using sugar-salt solutions, often with added starch, and the use of gruel rich in polysaccharides (e.g. rice or barley ‘water’) is an effective measure. The polysaccharides of rice (Oryza sativa) grains are hydrolysed in the GI tract; the resulting sugars are absorbed because the co-transport of sugar and Na+ from the GI lumen into the cells and mucosa is unaffected. Rice suspensions thus actively shift the balance of Na+ towards the mucosal side, enhance the absorption of water and provide the body with energy, and the efficacy of rice starch has been demonstrated in several clinical studies. The treatment of diarrhoea in adults, particularly for travellers, may also include opiates or their derivatives, to reduce gastrointestinal motility. Many classical anti-diarrhoeal preparations contain opium extracts, or the isolated alkaloids morphine and codeine (e.g. kaolin and morphine mixture, codeine phosphate tablets), although these are controlled by law in some countries. Opioid derivatives such as loperamide, which have limited systemic absorption and, therefore, fewer central nervous system side effects, have superseded these agents to some extent but the natural substances are still used and are highly effective. Dietary fibre, including that found in bulk-forming laxatives (qv) can also be used to treat diarrhoea; in this case, the fibre is taken with only a small amount of water. There are other plant drugs which act in varying ways (for review see Palumbo 2006).

Starch (amylum) image

Starch is used for rehydration purposes and may be derived from rice (Oryza sativa L.), maize (Zea mays L.) or potato (Solanum tuberosum L.). Giving starch-based foods (like gruels) has been shown to be therapeutically beneficial and is a first line treatment in minor self-limiting cases. These are also used as excipients for tablet production. Starch particles give a very characteristic microscopic picture, which can be used to differentiate the various types, but chemical analysis is rarely carried out.

Tannin-containing drugs

Tannins are astringent, polymeric polyphenols, and are found widely in plant drugs. The most important herbs used in the treatment of diarrhoea include Greater Burnet, Sangisorba officinalis L., Black Catechu, Acacia catechu Willd., Oak bark, Quercus robur L., Tormentil, Potentilla erecta (L.) Rausch., and even tea and coffee; however, many others are used in different countries (Palumbo 2006). Tannin-containing drugs are generally safe, but care should be taken with concurrent administration of other drugs since tannins are not compatible with alkalis or alkaloids, and form complexes with proteins and amino acids.

Constipation

Constipation is often due to an inappropriate diet and lack of physical activity, for example while being confined to bed during illness, or the result of taking other medication (especially opioids). It is characterized by reduced and difficult bowel movements, and is said to be present when the frequency of bowel movements is less than once in 2 or 3 days. Although the causes are not usually serious in nature, continuous irregularity in bowel movements should be investigated in case there is a risk of malignant disease. The subjective symptoms (straining heavily, hard stools, painful defecation and a feeling of insufficient evacuation) make it one of the most commonly reported health problems. Constipation is often associated with other forms of discomfort such as abdominal cramps, dyspepsia, bloating and flatulence. Alternating diarrhoea and constipation is a symptom of irritable bowel syndrome.

Various types of plant-derived laxative are used: stimulant laxatives (purgatives), which act directly on the mucosa of the GI tract; bulk-forming laxatives, which act mainly via physicochemical effects within the bowel lumen; and osmotic laxatives, which act by drawing water into the gut and thus softening the stool. Osmotic laxatives may be mineral in origin, for example magnesium salts, or derived from natural products such as milk sugars.

Patients generally require rapid relief from constipation, and the immediate effect of stimulant and saline purgatives is very well known. Although there is no problem using them occasionally, or on a short-term basis (less than 2 weeks), or prior to medical intervention such as X-ray (Roentgen) diagnostics, long-term use should be discouraged. The exception is for patients taking opioids for pain management, who may need to use stimulant laxatives routinely. The most important adverse effect of the long-term use of the stimulant laxatives and saline purgatives is electrolyte loss. Hypokalaemia, pathologically reduced levels of potassium (K+), may even worsen constipation and cause damage to the renal tubules. The risk of hypokalaemia is increased with administration of some diuretics and hypokalaemia exacerbates the toxicity of the cardiac glycosides (e.g. digoxin), which are often prescribed for elderly patients. Hyperaldosteronism, an excess of aldosterone production, which leads to sodium (Na+) retention, and again to potassium loss and hypertension, is also a risk. In general, the use of bulk-forming or osmotic laxatives is preferred, unless there are pressing reasons for using a stimulant laxative.

Bulk-forming laxatives

These are bulking agents with a high percentage of fibre and are often rich in polysaccharides, which swell in the GI tract. They influence the composition of food material in the GI tract, especially via the colonic bacteria, which are thus provided with nutrients for proliferation. This in turn influences the composition of the GI flora and the metabolism of the food in the tract (including an increase in gas, or flatus). Fibre-rich food is part of a healthy diet, but processed food and modern life styles have generally reduced fibre intake. Bulk-forming laxatives are generally not digested or absorbed in the GI tract, but pass through it largely unchanged.

Bulking agents can be distinguished from swelling agents in that bulking material contains large amounts of fibre, whereas swelling material is generally composed of plant material (seeds) with a dense cover of polysaccharides on the outside. Both types of medicinal drugs may swell to a certain degree by the uptake of water, but swelling agents in the strict sense include only medicinal plants that form mucilage or gel. The swelling factor (which compares the volume of drug prior to and after soaking it in water) is an indicator of the amount of polysaccharides present in the drug and is generally used as a marker for the quality of bulk-forming laxatives. The European Pharmacopoeia requires a minimal value of the swelling factor for each agent, and the swelling factors of the phytomedicines detailed below are shown in Table 14.1. Preparations of bulk-forming laxatives are always taken with plenty of water. They can, paradoxically, be used to treat diarrhoea if given with very little fluid; they then absorb the fluid from the lumen and increase the consistency of the stool.

Table 14.1 Swelling factors of various bulk-forming laxatives

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Linseed (flax), Linum usitatissimum L. (Lini semen) image

Linseeds are the ripe, dried seeds of flax (Linum usitatissimum, Linaceae), a plant grown for its fibre (used in the clothing industry) and for the seed oil, which is used in paints and varnishes, and to make oil cloth (‘linoleum’). Flax, with its characteristic blue flowers, is an annual, and has long been under human cultivation. The dark brown (less often yellowish-white) seeds are oblong or ovate with a characteristically pointed end. They are tasteless but slowly produce a mucilaginous feel when placed in the mouth. The outer layer of the seed (testa) is rich in polysaccharides, while the inner part of the seed, which contains the endosperm and the cotyledons, is rich in fatty oil. If the seeds are taken whole, the inner layer of the testa is only partially digested in the GI tract and they will be excreted in the entire form, and the fatty acids will not be released. The swelling factor should at least be 4 (entire seeds) or 4.5 (powdered drug). Linseed also possesses cholesterol-lowering properties, and contains phytoestrogenic lignans.

Plantago species

Ispaghula, Plantago ovata Forssk. (Plantaginis ovatae semen) image

The dark brown, glossy seeds from Plantago ovata (Indian fleawort, blond psyllium, Plantaginaceae) are useful in the treatment of chronic constipation. They are broadly elliptical in shape, up to 3.5 mm long, and are practically tasteless, becoming mucilaginous when chewed. They can help to maintain or achieve a regular bowel movement and are also useful in irritable bowel syndrome. The swelling factor should be > 9 for the entire seeds and > 40 for the seed husk, which is the most widely used part. The usage is similar to that of psyllium (fleawort, below).

Psyllium, Plantago psyllium L. and P. arenaria L. (Psyllii semen) image

The brown, shiny, elliptical to ovate seeds (2–3 mm long) are obtained from two species of the plantain family (Plantaginaceae). Plantago psyllium (= Plantago afra L., fleawort, black or dark psyllium, plantain) and P arenaria (= P indica, fleawort, plantain) yield useful and commonly used emollients and bulk laxatives which help in maintaining a regular bowel movement. The seeds are narrower and somewhat smaller than ispaghula seeds. An essential characteristic of high-quality material is a high swelling factor.

Wheat bran, Triticum aestivum L.

Bran is less useful as a laxative (except when taken as a natural part of the diet, e.g. in breakfast cereal), since it contains phytic acid, which in high concentrations can complex with and, therefore, reduce the bioavailability of vitamins and minerals taken at the same time. However, in some patients, wheat bran (the husk from the grains of Triticum aestivum) is more effective than other swelling agents, and preparations containing it are available for prescribing. These are taken in water.

Osmotic laxatives

Osmotic laxatives, such as lactulose or lactose, which are dimeric sugars derived from milk, are a useful and widely used approach to the treatment of long-term constipation. Lactose is split in the GI tract into glucose and galactose, and galactose is not generally resorbed well. Consequently, the bacteria of the colon metabolize this sugar. The resulting acids, including lactic acid and acetic acid, have an osmotic effect, and the bacteria in the colon multiply more rapidly. This results in softening and increasing in the amount of faeces, with a subsequent increase in GI peristalsis.

Stimulant laxatives

Stimulant laxatives are derived from a variety of unrelated plant species, which only have in common the fact that they contain similar chemical constituents. These are anthraquinones such as emodin (Fig. 14.1) and aloe-emodin, and related anthrones and anthranols. Anthraquinones are commonly found as glycosides in the living plant. Several groups are distinguished, based on the degree of oxidation of the nucleus and whether one or two units make up the core of the molecule. The anthrones are less oxygenated than the anthraquinones and the dianthrones are formed from two anthrone units (Fig. 14.2). Studies using dianthrone glycosides such as sennosides A and B suggest that most of these compounds pass through the upper GI tract without any change; however, they are subsequently metabolized to rhein anthrone in the colon and caecum by the natural flora (mainly bacteria) of the GI tract. Anthranoid drugs act directly on the intestinal mucosa, influencing several pharmacological targets, and the laxative effect is due to increased peristalsis of the colon, reducing transit time and, consequently, the re-absorption of water from the colon. Additionally, the stimulation of active chloride secretion results in an inversion of normal physiological conditions and a subsequent increased excretion of water. Overall, this results in an increase of the faecal volume with an increase in the GI pressure. These actions are based on the well-understood effects of chemically defined constituents; consequently, phytomedicines containing them are usually standardized to specified anthranoid content (see Chapter 9).

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Fig. 14.1

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Fig. 14.2

Toxicity of anthranoid drugs

The monomeric aglycones (especially emodin and aloe-emodin) have been shown to have genotoxic and mutagenic effects using bacterial and in vitro systems such as the Ames test, and in mammalian cell lines. The long-term use of anthranoids may result in a (reversible) blackening of the colon (Pseudomelanosis coli), which is due to the incorporation of metabolites of the anthranoids and is thought to be associated with an increased risk of colon carcinoma. In practice, few toxic effects have been described, apart from those involving electrolyte loss described above. More immediate effects of anthranoid-containing drugs are colic and griping pains due to increased spastic contractions of the smooth musculature of the GI tract. Aloes and senna leaves are particularly prone to produce these. A synthetic derivative, danthrone (also known as dantron; not to be confused with the naturally occurring dianthrone), has been developed and, although effective, it is used only in palliative care due to its carcinogenic potential.

Frangula, Rhamnus frangula L. (Frangulae cortex); buckthorn, R. cathartica L. (Rhamni cathartici cortex) and cascara, R. purshiana DC. (Rhamni purshiani cortex) image

The barks of several species of Rhamnaceae are used for their strong purgative effects. Rhamnus frangula (glossy buckthorn, frangula) has a milder action than R. cathartica (European buckthorn) and the berries are used in veterinary medicine. (The fruit also yields a dye, the colour of which depends partly on the ripeness.) The bark of R. purshiana (American buckthorn, known in commerce as Cascara sagrada) is the other main species used medicinally.

R. frangula is a densely foliated, thornless bush or tree, reaching a height of 1–7 m, common in damp environments such as bogs and along streams in North and Central Europe, as well as northern Asia. The cut bark is grey-brown with numerous visible grey-white lenticels. The leaves are broadly elliptical to obovate, about 3.5–5 cm long. The black, pea-sized berries develop from small greenish-white flowers.

Buckthorn (R. cathartica) is a thorny shrub with toothed leaves and a reddish brown bark; the berries are black and globular.

Cascara (R. purshiana) is native to the Pacific coast of North America but grows widely elsewhere. It is found in commerce in quilled pieces, often with epiphytes (lichen and moss) attached.

Constituents

R. frangula. Glucofrangulin A (Fig. 14.3) and B, which are diglucosides differing only in the type of sugar at C6.

R. cathartica. Emodin, aloe-emodin, chrysophanol and rhein glycosides, frangula-emodin, rhamnicoside, alaterin and physcion.

R. purshiana. Cascarosides A (Fig. 14.3), B, C, D, E and F (which are stereoisomers of aloin and derivatives), with minor glycosides including barbaloin, frangulin, chrysaloin, palmidin A, B and C and the free aglycones.

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Fig. 14.3

The anthrone and dianthrone glycosides, which are present in the fresh bark of these species, have emetic effects and may result in colic. In order to oxidize these compounds to anthraquinones with fewer undesirable side effects, the drug has either to be kept for a year or it is ‘aged artificially’ by heating it for several hours to 80–100°C.

Senna, Cassia senna L. and C. angustifolia Vahl (Senna) (Sennae fructus, Sennae folium)image

The genus Cassia (Caesalpiniaceae) is very large, with about 550 species, mostly occurring in warm temperate and tropical climates. The species are not native to Europe and were an important drug of early trading; the name ‘Senna’ is of Arabic origin and was recorded as early as the 12th century. Two shrubs from the genus Cassia (formerly called Senna) yield the drugs senna leaves and senna fruit: Cassia senna L. (syn. C. acutifolia L., Alexandrian senna) and C. angustifolia Vahl (Tinnevelly senna). The common names were derived from their original trade sources and are only applied to the fruits (pods). The second species is considered to be the milder in activity. Both the leaves and the fruits have typical microscopic characteristics, including the highly diagnostic, single-celled warty trichomes and the crystal sheath of calcium oxalate prisms around the fibres, but it is possible to distinguish the two species microscopically.

Constituents

Leaf. Sennosides A and B (Fig. 14.4), which are based on the aglycones sennidin A and sennidin B; sennosides C and D, which are glycosides of heterodianthrones of aloe-emodin and rhein; palmidin A, rhein anthrone and aloe-emodin glycosides and some free anthraquinones. C. senna usually contains greater amounts of the sennosides.

Fruit. Sennosides A and B and a related glycoside sennoside A1. The sennosides, which are dianthrones, differ in their stereochemistry at C10 and C10′, as well as in their substitution pattern. C. senna usually contains greater amounts of the sennosides.

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Fig. 14.4

The structure of sennoside B is given in fig. 14.4. The Eur. Ph. standard is for a glycoside content of not less than 2.5% for the leaf, 3.5% for C. senna

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