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)

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

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

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

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 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).

Fig. 14.1

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)

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.

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)

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 C_10′, as well as in their substitution pattern. C. senna usually contains greater amounts of the sennosides.

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 fruit and 2.2% for C. angustifolia fruit, calculated as sennoside B. Other secondary metabolites such as flavonoids, tannins and bitter compounds are also present but not defined in the standard. The way in which the plant material is dried has a strong influence on the amount of glycosides and accordingly on the quality of the product (see above).

The other main botanical anthranoid drugs are aloes Aloe vera, A. barbadensis and other species) and rhubarb (Rheum raponticum and others). These are used to a lesser extent nowadays.

Inflammatory GI conditions: gastritis and ulcers

Inflammation of the gastric mucosa, or gastritis, is an acute inflammatory infiltration of the superficial gastric mucosa, predominantly by neutrophils. It is generally treated with antacids (magnesium and aluminium salts) and emollients (alginate, mucilages), but other phytomedicines are still occasionally used (e.g. chamomile and liquorice). These agents, especially liquorice, were used to treat gastritis and ulceration until superseded by the synthetic H₂-receptor-blocking agents (cimetidine, ranitidine, etc. and proton pump inhibitors (omeprazole, lansoprazole). Now that infection with Helicobacter pylori is known to be a causal factor in ulceration, antibiotic therapy is the first-line treatment of choice. Most pharmaceuticals for mild gastric inflammation contain a mixture of an emollient, to line and soothe the mucosa (e.g. an agar suspension), an antacid and possibly a carminative such as peppermint or anise oil (see section on dyspepsia).

Alginate

Alginate, or alginic acid, is an anionic polysaccharide distributed widely in the cell walls of brown algae including Laminaria, and Ascophyllum nodosum. Raw or dried sea weed is washed with acid to remove cross-linking ions that cause the alginate to be insoluble. It is then dissolved in alkali, typically sodium hydroxide, to produce a viscous solution of alginate. The solution is filtered to remove the cell wall debris and leave a clear alginate solution. Alginate binds with water to form a viscous gum and acts as a protective coating over the walls of the stomach and oesophagus.

Chamomile Matricaria recutita L. (Matricariae flos)

German (syn. Hungarian) chamomile flowers are derived from Matricaria recutita (syn. Chamomilla recutita, Matricaria chamomilla, Asteraceae, the daisy family). They have a pleasant aromatic odour. The flower heads have a diameter of approximately 10 mm and are composed of many minute flowers (called florets) which are either tongue-shaped (‘ligulate florets’, found at the margin) or tubular (‘disk’ florets, found in the disk-like centre). True chamomile has a hollow receptacle (the part of the stalk where the flower parts are attached) and is devoid of the small leaf-like structures (stipules) that are common with the non-medicinal members of this genus. Chamomile is grown on a large scale, especially in Eastern Europe, Spain, Turkey, Egypt and Argentina, and has been known as a medicinal plant for several thousands of years. It is used internally for spasmodic and inflammatory illnesses of the GI tract.

Constituents

The flower heads are rich in essential oil. Two types of essential oil are recognized: one rich in bisabolol (levomenol) (Fig. 14.5) and the other in bisabolol oxides. Both contain other terpenoid compounds, including guaianolides such as matricin which are only found in the crude drug. The characteristic, dark blue azulenes (e.g. chamazulene; Fig. 14.5) are produced during steam distillation and only found in the essential oil. Flavonoids (up to 6%), especially apigenin and apigenin-7O-glycoside, caffeic acid derivatives and spiro ethers are also present. The components of the essential oil levomenol (α-bisabolol), its oxides, chamazulene, some unusual spiro ethers and the flavonoids (especially apigenin) are all essential for the pharmacological effects of the drug. The minimum amount of essential oil required by the Eur. Ph. is 0.4%.

Fig. 14.5

Therapeutic uses and available evidence

Anti-inflammatory, spasmolytic, antibacterial and antifungal effects are well established both pharmacologically and clinically (see McKay and Blumberg 2006a). Chamomile is relatively safe, although allergic reactions can occur as with all plants of the family Asteraceae.

Note. The flower heads of Chamaemelum nobile (L.) All. (syn. Anthemis nobilis L., English chamomile, Roman chamomile) have a pharmacological profile similar to that of Matricaria recutita, and are included in the Eur. Ph. However, there is much less scientific and clinical evidence to support their use than for M. recutita.

Liquorice, Glycyrrhiza glabra L. (Liquiritiae radix)

Liquorice (licorice) root is derived from the inner part of the root and underground stem (rhizome) of Glycyrrhiza glabra (Fabaceae, the bean family). The peeled drug is of much higher quality than the root with the bark, and is produced in several south-eastern European countries, Turkey, China and Russia. It has a very characteristic taste and smell, and is used in confectionery. The sweet taste also makes the identification of the drug relatively easy and so adulteration is uncommon. Microscopic identification is possible and uses characteristic crystals of oxalate, especially in the form of a sheath of parenchyma surrounding the phloem fibres, as well as the structure of the parenchyma. Liquorice is used to relieve gastric inflammation, specifically in the case of peptic ulcers and duodenal ulcers, but its use as a GI remedy is controversial because of its mineralocorticoid action. The dose should not exceed 200–600 mg of glycyrrhizin daily and the duration of treatment should be at most 4–6 weeks. More potent synthetic pharmaceuticals are now available, and it is now rarely used for this purpose. Liquorice and its preparations are contraindicated in cholestatic liver disorders, liver cirrhosis, hypertension, hypokalaemia, severe renal failure and pregnancy. With excessive use, liquorice-containing confectionery may result in similar undesired side effects. Liquorice is also used in respiratory complaints as an expectorant, mucolytic and antitussive agent.

Constituents

The most important bioactive secondary metabolite is glycyrrhizic acid (also known as glycyrrhizin; Fig. 14.6), a water-soluble pentacyclic triterpene saponin which gives the drug its characteristic sweet taste (it is about 50 times sweeter than sucrose). The genin (glycyrrhetinic acid or glycyrrhetin), on the other hand, is not sweet but very bitter. Liquorice also contains numerous flavonoids (chalcones and isoflavonoids), coumarins and polysaccharides, which contribute to the activity.

Fig. 14.6

Dyspepsia and biliousness

Dyspepsia and ‘biliousness’ are closely associated with eating habits and are very common complaints. Patients describe the symptoms as nausea, pain and cramps, distension, heartburn and the ‘inability to digest food’, often experienced after rich meals. The condition is treated either with cholagogues or with bitter stimulants. A cholagogue is an agent that stimulates bile production in the liver, or promotes emptying of the gallbladder and bile ducts. Although clinical evidence is largely lacking, plant-based cholagogues are frequently prescribed by family doctors in Germany based on observational evidence and a long tradition of use, but they should not be used in cases of bile duct obstruction or cholestatic jaundice.

Liver disease is not treated as such by conventional medicine, but herbal medicine has a number of clinically proven treatments which help to protect the liver from damage and reverse some of the indicators of liver malfunction. The most important of these is silymarin, but other herbs are widely used for liver disease, although mainly with much less clinical evidence in support.

Phytomedicines used as bitter stimulants, such as Gentian and Wormwood, act directly on the mucosa of the upper part of the GI tract and especially of the bitter receptors on the tongue, stimulating the secretion of saliva and gastric juices and influencing the secretion of gastrin. An aperitif containing ‘bitters’, taken about half an hour before eating, stimulates gastric and biliary secretion; however, it is not known whether these effects are restricted to patients with a reduced secretory reflex, or whether an increase also occurs in healthy people.

Artichoke, Cynara scolymus L. (Cynarae folium)

This well-known member of the Asteraceae yields the globe artichoke (a food common in French cuisine), which is the large flower head of the plant. The medicinal part is the leaf, which is used to treat indigestion and dyspepsia, and to lower cholesterol levels.

Constituents

The leaf contains the bitter sesquiterpene lactone cynaropicrin, several flavonoids and derivatives of caffeoylquinic acid, including cynarin (Fig. 14.7).

Fig. 14.7

Therapeutic uses and available evidence

Antihepatotoxic effects, cholagogue activity and a reduction of cholesterol and triglyceride levels have been reported, and are now known to be due to inhibition of cholesterol biosynthesis. Clinical studies have shown that artichoke leaf extract can improve parameters such as fat intolerance, bloating, flatulence, constipation, abdominal pain and vomiting, and increase bile flow, at a daily mean dose of 1500 mg. For further details, see Bundy et al 2008, and Wider et al 2009. Artichoke extract is also useful in irritable bowel syndrome (Walker et al 2001).

Gentian, Gentiana lutea L. (Gentianae radix)

The yellow gentian (G. lutea, Gentianaceae) is, after ethanol, the most important ingredient of the Alpine beverage Enzianschnaps, used as a digestive stimulant, taken after a large meal. Most medicinal products are made using the rapidly dried and non-fermented drug.

The species is rare (but locally abundant) and distributed in the alpine regions of Europe and western Asia. It is a perennial herb up to 1.4 m high with showy yellow flowers. Because of the high risk of overexploitation (for use as an ornamental and as a medicine) the species is now protected throughout most of its range and attempts are being made to cultivate it. Gentian root in commerce consists of the dried rhizomes and roots of the species. The rhizome is cylindrical and may have a diameter of up to 4 cm, with long roots attached.

Constituents

The compounds responsible for the highly bitter taste are monoterpenoid compounds (Fig. 14.8) such as gentiopicroside – a seco-iridoid with a bitter value of 12,000 – and amarogentin – with a bitter value of 58,000,000, which is only present in minute amounts. The normally white inner part of the rootstock turns yellow during fermentation, due to the formation of xanthones, including gentisin. Chemical analysis is carried out following the method of the Eur. Ph., but the ‘bitter value’ test is also useful. This is a simple and useful measure for establishing the quality of bitter-tasting (botanical) drugs. It is the inverse concentration of the dilution of an extract (or a pure compound) which can still be detected as being bitter to testers with normal bitter taste receptors. In the case of gentian, it should at least be 10,000 (i.e. an extract that has been diluted 10,000 times should still leave a bitter taste).

Fig. 14.8

Therapeutic uses and available evidence

Gentian is indicated for poor appetite, flatulence and bloating, although clinical trial evidence is lacking. Extracts stimulate gastric secretion in cultured rat gastric mucosal cells and gentiopicroside has been shown to suppress chemically and immunologically induced liver damage in mice.

Wormwood, Artemisia absinthium L. (Absinthii herba)

Wormwood is a bitter stimulant derived from the aerial parts of Artemisia absinthium (Asteraceae) and is popularly used as a tea. It is a commonly cultivated garden plant. The liqueur was a popular stimulant in many European countries during the latter part of the 19th century and early part of the 20th century, and gave rise to the condition known as absinthism, a form of mental disorder, reputed to affect the artist Van Gogh. The plant is still commonly grown in Mediterranean gardens. The leaves and young stems are densely covered with characteristic greyish-white hairs, which give the species its typical appearance.

A large number of related species are also used as a food (estragon – A. dracunculus) or medicine (A. annua L. – the source of artemisinine)

Constituents

The essential oil contains β-thujone (Fig. 14.9) as the major components, as well as thujyl alcohol, azulenes, bisabolene and others. Sesquiterpene lactones are also present, especially absinthin, anabsinthin, artemetin, artabsinolides A, B, C and D, artemolin and others, and flavonoids. During the process of distillation, the intensively blue chamazulene is formed, which together with the other constituents gives oil of absinth its characteristic green-blue colour. The sesquiterpene lactone absinthin is responsible for the intensive bitter taste, which according to the Eur. Ph. should be at least 10,000 (Deutsches Arzneibuch 15,000) for the crude extract (see ‘Gentian’ for explanation of bitter value). β-Thujone, a monoterpene, is also partly responsible for the bitterness. The essential oil content should be at least 0.2% and the bitter sesquiterpenoids 0.15–0.4%, according to the Eur. Ph. where the methods are described.

Fig. 14.9

Therapeutic uses and available evidence

It is commonly used as a bitter tonic, a choleretic and also as an anthelmintic. Although its use in the form of a tea is considered safe, the essential oil, and the liqueur ‘absinthe’ distilled from this plant, are harmful in large doses due to the thujone content, and are not now used except where the thujone has been removed. Most of the evidence is empirical and clinical evidence is limited.

Toxicological risks

Thujone, a major component of the essential oil, is neurotoxic and hallucinogenic in large doses and can produce epileptic fits and long-lasting psychiatric disturbances. These are considered to be a problem only with the distilled ethanolic beverage (absinthe). Thujone is found in the essential oil of many unrelated species, including sage (Salvia officinalis) and thuja (Thuja occidentalis), and is still used medicinally with few ill-effects. There is also some dispute as to whether ‘absinthism’ is anything more than plain alcoholism, since thujone levels are not always high enough to be considered as causing such severe damage.

Nausea and vomiting

‘Travel sickness’ or ‘motion sickness’ is particularly common in children and is caused by the repetitive stimulation of the labyrinth of the ear. It is most common when travelling by sea, but also happens in cars, aeroplanes and when horse-riding. Vomiting, nausea, dizziness, sweating and vertigo may occur. Prophylactic treatment includes the use of antihistamines (mainly phenothiazines) and cinnarizine, and natural compounds such as the antimuscarinic alkaloid hyoscine, found the Solanaceae family. Morning sickness of pregnancy is also common but few (if any) synthetic drugs are licensed for such a use because of fears of toxicity to the unborn child. Ginger can be a useful anti-emetic for this condition, as well as for travel sickness.

Ginger, Zingiber officinale Roscoe (Zingiberis rhizoma)

Ginger (Zingiberaceae) is one of the most commonly used culinary spices in the world and has a variety of medicinal uses. The odour and taste are very characteristic, aromatic and pungent. Ginger is cultivated in moist, warm tropical climates throughout south and south-eastern Asia, China, Nigeria and Jamaica. The rhizome is the part used and is available commercially either peeled or unpeeled. African dried ginger is usually unpeeled, and the fresh rhizome, which is widely available for culinary purposes, is always unpeeled. The medicinal use of ginger in Europe has an ancient history and can be traced back to Greek and Roman times. The plant has also been mentioned in Ayurvedic and other religious scriptures dating back to 2000 BC, where it was recognized as an aid to digestion and for cases of rheumatism and inflammation.

Constituents

The rhizome contains 1–3% essential oil, the major constituents of which are zingiberene and β-bisabolene. The pungent taste is produced by a mixture of phenolic compounds with carbon side-chains consisting of seven or more carbon atoms, referred to as gingerols, gingerdiols, gingerdiones, dihydrogingerdiones and shogaols (see Fig. 14.10). The shogaols are produced by dehydration and degradation of the gingerols and are formed during drying and extraction. The shogaols are twice as pungent as the gingerols, which accounts for the fact that dried ginger is more pungent than fresh ginger.

Fig. 14.10

Therapeutic uses and available evidence

Modern uses of ginger are diverse and include as a carminative, anti-emetic, spasmolytic, antiflatulent, antitussive, hepatoprotective, antiplatelet aggregation and hypolipidaemic. Some of these actions are substantiated by pharmacological in vivo or in vitro evidence. Of particular importance is the use in preventing the symptoms of motion sickness and postoperative nausea, as well as vertigo and morning sickness of pregnancy, and there is some clinical evidence for the efficacy of ginger in these conditions (Matthews et al 2010). Ginger consumption has also been reported to have a beneficial effect in alleviating the pain and frequency of migraine headaches, and studies on the action in rheumatic conditions have shown a moderately beneficial effect. Anti-ulcer activity has been described in animals and attributed to the volatile oil, especially the 6-gingesulfonic acid content, and hepatoprotective effects have been noted in cultured hepatocytes, with the gingerols being more potent than the homologous shogaols found in dried ginger. Both groups of compounds are antioxidants and possess free radical scavenging activity. Ginger is well known to produce a warming effect when ingested, and the pungent principles stimulate thermogenic receptors. In addition, zingerone induces catecholamine secretion from the adrenal medulla (for review, see Ali et al 2008). In Oriental medicine, ginger is so highly regarded that it forms an ingredient of about half of all multi-item prescriptions. A distinction is made between the indications for the fresh rhizome (vomiting, coughs, abdominal distension and pyrexia) and the dried or processed rhizome (abdominal pain, lumbago and diarrhoea). This is probably justifiable since the constituents are present in different proportions in the different preparations. Ginger, both in the fresh and dried form, is generally regarded as safe.

Hyoscine (scopolamine)

The alkaloid hyoscine (Fig. 14.11) is usually isolated from Datura or Scopolia spp., although, as the name suggests, it has originally been found in Hyoscyamus niger. It is a popular remedy for motion sickness, given at an oral dose of 400 μg or, more recently, as a transdermal patch containing 2 mg of the alkaloid, which is delivered through the skin over 24 h. Hyoscine is also used as a premedication, usually in combination with an opiate, to relax the patient and dry up bronchial secretions prior to administration of halothane anaesthetics.

Fig. 14.11

Irritable bowel syndrome, bloating and flatulence

Irritable bowel syndrome (IBS) is characterized by pain in the left iliac fossa, diarrhoea and/or constipation. Symptoms are usually relieved to some extent by defecation or the passage of wind, and can be treated successfully by the use of bulk laxatives with or without antispasmodic (carminative) drugs. Natural remedies include peppermint oil and other essential oil carminatives, and some of the tropane alkaloids. Atropine has been replaced by hyoscine, in the form of the N-butyl bromide, which, as a quaternary ion, is poorly absorbed from the GI tract and, therefore, has fewer anti-muscarinic side effects. Artichoke extract is also useful in irritable bowel syndrome (Walker et al 2001); see under dyspepsia and biliousness.

Flatulence, which is the passage of excessive wind from the body, is a condition for which phytotherapy offers useful therapeutic approaches. Carminatives are usually taken with food; they produce a warm sensation when ingested and promote postprandial elimination of gas. Plant-based carminatives are usually rich in essential oil, such as the fruits (‘seeds’) of species of the Apiaceae (celery family) and some members of the Lamiaceae (mint family). Many condiments such as cumin and caraway have carminative effects and are used as spices because of their taste and their pharmacological effect. The clinical validity of carminatives is based on long historical observation and is well established. The effect of many of these botanical drugs is due to their spasmolytic action, for which some in vitro evidence exists (Ford et al 2008), but the precise mechanism of action is unclear. It seems likely that not only is the essential oil responsible for the effect, but that the other components (e.g. the flavonoids) also contribute.

Mint leaves and oils: mentha species

Members of the mint family are widely used for their digestive effects and flavouring qualities. They contain similar compounds, but in differing proportions, which results in subtle differences in their taste and properties.

Peppermint, Mentha × piperita L. (Menthae piperitae folium)

Peppermint is a hybrid of Mentha aquatica and M. spicata, which originated spontaneously and has been known for over 2500 years; the first records are from old Egyptian graves (2600–3200 BC). Peppermint has a very characteristic, strongly aromatic and penetrating smell and taste. All species of the genus Mentha (the mints) have quadrangular (square) stems and decussate, elongated, dentate leaves with a pointed apex, and pinkish-blue flowers up to 5 mm long, and microscopical characteristics include glandular hairs, which are typical of the Lamiaceae. Both the leaves, in the form of a tea, and the oil are used for digestive problems.

Constituents

Peppermint leaf is rich in essential oil (0.5–4%), the main components being (–)-menthol, menthone, menthylacetate and menthofuran. The plant also contains the non-volatile polyphenolics rosmarinic acid and derivatives, flavonoids and triterpenes.

Peppermint oil is derived from the fresh plant by steam distillation and contains approximately 50% (–)-menthol (Fig. 16.4).

Therapeutic uses and available evidence

Peppermint is often taken in the form of a tea, which provides a refreshing beverage as well as a mild digestive soothing effect (see McKay and Blumberg 2006b). The oil can be given well-diluted with water or as an emulsion (2%, v/v, dispersed in a suitable vehicle) for treating colic and GI cramps in both adults and children, and in the form of enteric-coated capsules for IBS, where it is released directly into the intestine and bowel. The antispasmodic effect of peppermint oil has been well established using a series of in vitro models, the effect being marked by a decline in the number and amplitude of spontaneous contractions, and due at least in part to Ca²⁺-antagonistic effects. Peppermint oil has also been shown clinically to enhance gastric emptying. Peppermint water (or emulsion) is generally safe, although must be used with care. A tragic incident with peppermint water caused the death of a young baby, although the toxicity was due to the excipient rather than to the peppermint oil (by adding concentrated chloroform water rather than the diluted form, two pharmacists inadvertently produced a lethal medication).

Japanese mint, Mentha arvensis L.

Japanese mint is rich in menthol (about 80% of the total volatile oil, see below) and is employed as a cheaper substitute for peppermint or for extraction of menthol.

Spearmint, Mentha × spicata L., syn. M. crispa, M. spicata Subsp. crispa

Spearmint gives toothpaste, mouthwash and chewing gum their typical taste and smell. It is an important flavouring agent, but is of limited pharmaceutical importance. Material from this species is easily identifiable from the taste and odour.

Umbelliferous fruits

The fruits (not ‘seeds’ as they are commonly known) of several members of the celery family (Apiaceae or Umbelliferae) are used as carminatives as they are rich in essential oil and have an antispasmodic effect. Many of these species are also important as spices. Flower heads of these species are umbels of white or pinkish flowers, which produce the characteristic schizocarp (double) fruits, in which two mericarps are united to form an easily separated fruit on a carpophor (a stalk which means ‘carrier of fruit’).

Caraway, Carum carvi L. (Carvi fructus)

Caraway is the fruit of a mountain herb common in many regions of Europe and Asia.

Constituents

The essential oil (3–7%) consists mainly of (+)-Carvone and (+)-limonene, accounting for 45–65% and 30–40%, respectively, of the total oil. Carvone (Fig. 14.12) is considered to be the main component responsible for the spasmolytic action.

Fig. 14.12

Therapeutic uses and available evidence

The fruits are used in cases of dyspepsia, minor GI cramps and flatulence. Little modern clinical evidence is available but caraway has long been used in products such as infant gripe water. The aqueous extract, and even more so the essential oil, acts as a spasmolytic and has antimicrobial activity.

Fennel, Foeniculum vulgare Miller (Foeniculi fructus)

The common fennel is a perennial herb yielding fruit and oil that are used for stomach and abdominal discomfort, as well as a spice in sweets and liqueurs. Other varieties yield the commonly used vegetable fennel. Two pharmaceutically important varieties are distinguished: Foeniculum vulgare var. dulce (sweet fennel), which is richer in anethole and has a sweet and aromatic taste, and F. vulgare var. vulgare (bitter fennel), which is rich in fenchone, resulting in a bitter taste. The two varieties are nearly impossible to distinguish microscopically; consequently, taste and smell differentiation, as well as thin layer chromatography (TLC) analysis, are essential for differentiating the two.

Constituents

All of the aerial parts of fennel are rich in essential oil, with bitter fennel fruit containing 2–6%, mostly trans-anethole (> 60% of the oil) and fenchone (> 15%) (Fig. 14.13), and sweet fennel containing 1.5–3%, composed of trans-anethole (80–90%) but with very little fenchone (< 1%). Fatty oil and protein are also found in fennel fruit.

Fig. 14.13

Therapeutic uses and available evidence

Fennel is used empirically as a carminative, for indigestion and colic in children. It is considered to be a very safe drug and is widely used as a health-food supplement as well as a spice. Fennel oil (the distilled essential oil of both varieties of fennel) is used for the same indications and has been shown to be bacteriostatic.

Other fruit drugs used for these indications are anise (Anisi fructus) from Pimpinella anisum, star anise (Anisi stellata fructus) from Illicium verum and coriander (Coriandri fructus) from Coriandrum sativum. These agents are all in the Eur. Ph.

The oils of all of these fruits are the subject of monographs in the Eur. Ph. where quantification of compounds is achieved after separation by gas chromatography. Differentiation between the two types of fennel is possible using the TLC method described in the Eur. Ph. where bitter fennel shows an additional yellow zone after spraying with sulphuric acid.

Liver disease

Liver damage, cirrhosis and poisoning should only be treated under medical supervision. There is, however, a useful phytomedicine derived from the milk thistle, Silybum marianum (L.) Gaertn. (Asteraceae), in the form of an extract known as silymarin. Other herbs, as shown below, are widely used for liver disease, although with less clinical evidence in support. Herbs used for ‘biliousness’ (see section on Dyspepsia and Biliousness) are also used in mild liver disease.

Andrographis, Andrographis paniculata Nees (Andrographis herba)

Andrographis is widely used in many Asian systems of medicine to treat jaundice and liver disorders. There are few clinical studies available to support these uses, although numerous in vitro experiments have shown it has liver protective effects against a variety of hepatotoxins. 14-deoxyandrographolide, a constituent, desensitizes hepatocytes to TNF-alpha-induced signalling of apoptosis (Roy et al 2010). It appears to be well-tolerated but caution should be exercised when given in conjunction with anti-thrombotic drugs. In the West, it is more often used as an immune stimulant (see Chapter 16, Respiratory System, for more detail, including constituents).

Berberis species and other berberine-containing drugs

Berberine (Fig. 14.14) is contained in Berberis species, for example B. vulgaris L., B. aristata DC, in Blood root, Sanguinaria canadensis L., Goldenseal, Hydrastis canadensis L., Gold Thread, Coptis chinensis Franch, and Greater Celandine, Chelidonium majus L.

Fig. 14.14

Berberine has antibacterial and amoebicidal properties and is used either in the form of the pure compound or as a component of plant extracts, to treat dysentery and liver disease (Imanshahidi and Hosseinzadeh 2008). Care should be taken when given together with anticancer drugs and with ciclosporin, since theoretical drug interactions have been described for these combinations, and berberine is known to be a substrate of P-glycoprotein and to affect expression of cytochrome P(CYP) 450 enzymes 3A4 and others.

In many parts of Europe, silymarin is used extensively for liver disease and jaundice. It has been shown to exert an antihepatotoxic effect in animals against a variety of poisons, particularly those of the death cap mushroom Amanita phalloides. This fungus contains some of the most potent liver toxins known (the amatoxins and the phallotoxins), both of which cause fatal haemorrhagic necrosis of the liver. Silymarin has been used at doses of 420 mg daily to treat patients with chronic hepatitis and cirrhosis; it is also partially active against hepatitis B virus, is hypolipidaemic and lowers fat deposits in the liver in animals. This extract can be used not only for serious liver disease, but also for general biliousness and other digestive disorders (see Saller et al 2008).

Schisandra, Schisandra chinensis K. Koch (Schisandrae chinensis fructus)

Schisandra (Schizandra) berries are the fruit of the Magnolia Vine, and are very important in traditional Chinese medicine where they are used to treat liver disorders and many other conditions of general debility. Related species are also used.

Constituents

The active constituents are dibenzocyclooctene lignans, known as schisandrins (schizandrins) and gomisins. The nomenclature is confused and, for example, ‘schisandrin’ is sometimes referred to in the literature as ‘schisandrol A’, and ‘gomisin A’ as ‘schisandrol B’.

Therapeutic uses and available evidence

A great deal of research has been carried out on the pharmacology of this plant (see review by Panossian and Wikman 2008), and liver protectant effects have been observed in animals, but clinical studies are lacking

Turmeric, Curcuma domestica Val. (Curcumae domesticae rhizoma)

Turmeric is used in Asian medicine to treat liver disorders and well as inflammatory conditions. For details regarding the drug and its constituents, see Chapter 21 (Musculoskeletal system). Related species include Javanese turmeric (Curcuma xanthorrhiza Roxb., Eur. Ph.), which is mostly used for dyspepsia and other gastrointestinal problems. Turmeric and the curcuminoids are hepatoprotective against liver damage induced by various toxins, including paracetamol (acetaminophen), aflatoxin and cyclophosphamide; they protect against stomach ulcers in rats, and have antispasmodic effects. Turmeric is also hypoglycaemic in animals, and hypocholesterolaemic effects have been observed both in animal and human clinical studies, although clinical studies for liver disease are lacking. In addition, turmeric is antibacterial and antiprotozoal in vitro. Turmeric is well tolerated but the bioavailability is poor and daily doses of at least 2g are normally used. For reviews see, Rivera-Espinoza and Muriel (2009) and Epstein et al (2010).

References

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Epstein J., Sanderson I.R., Macdonald T.T. Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. Br. J. Nutr.. 2010;103:1545-1557.

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Imanshahidi M., Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother. Res.. 2008;22:999-1012.

Matthews A., Dowswell T., Haas D.M., Doyle M., O’Mathúna D.P. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst. Rev. 2010. 2010 Sep 8:CD007575

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McKay D.L., Blumberg J.B. A review of the bioactivity and potential health benefits of peppermint tea (Mentha piperita L.). Phytother. Res.. 2006;20:619-633.

Palumbo E.A. Phytochemicals from traditional medicinal plants used in the treatment of diarrhoea: modes of action and effects on intestinal function. Phytother. Res.. 2006;20:717-724.

Panossian A., Wikman G. Pharmacology of Schisandra chinensis Bail.: an overview of Russian research and uses in medicine. J. Ethnopharmacol.. 2008;118:183-212.

Rivera-Espinoza Y., Muriel P. Pharmacological actions of curcumin in liver diseases or damage. Liver Int.. 2009;29:1457-1466.