The cardiovascular system

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Chapter 15 The cardiovascular system

Cardiovascular (CV) disorders are responsible for many deaths in the Western world, and are a consequence of lifestyle and diet, as well as being hereditary to some extent. Serious conditions such as heart failure should be treated only under the guidance of a qualified physician, but some minor forms of CV disease respond well to changes in diet and taking more exercise, as well as phytotherapy. Cardiology has benefited greatly from the introduction of some newer semi-synthetic drugs based on natural products, including aspirin, an antiplatelet agent derived from salicin, and warfarin, an anticoagulant derived from dicoumarol. Others have been developed using a natural product as a template, for example, verapamil, a calcium channel antagonist used to treat hypertension and angina, is based on the opium alkaloid papaverine, and nifedipine, a calcium channel antagonist and amiodarone, an anti-arrhythmic, were both developed from khellin, the active constituent of Ammi visnaga. Cocaine has cardioactive as well as central nervous system effects, and was the starting material for the development of the anti-arrhythmics procaine and lignocaine, which are more effective and without the unwanted stimulant activity (Hollmann 1992).

Cardiovascular conditions discussed here include heart failure, venous insufficiency, thrombosis and atherosclerosis. Other conditions such as hypertension and cardiac arrhythmias are rarely treated with phytomedicines, although there are some natural products used in their treatment which will be mentioned briefly. Synthetic diuretics are widely used as antihypertensives, but phytomedicines are not suitable for this purpose as they are not sufficiently potent to reduce blood pressure. Instead, they are often incorporated into remedies for urinary tract complaints (see Chapter 20) or to reduce bloating (mild water retention, for example pre-menstrual).

Heart failure and arrhythmias

These conditions can be treated with cardiac glycosides (cardenolides and bufadienolides) such as digoxin, isolated from the foxglove. Lily of the valley (Convallaria majalis) contains convallotoxin (a mixture of cardenolides), and squill (Drimys maritima) contains the bufadienolides scillaren A and proscillaridin, but these are rarely used now. Ouabain, isolated from Strophanthus spp., has been used in emergency cases. The cardiac glycosides have a positive inotropic effect, meaning that they increase the force of contraction of the heart. They are emetic and toxic in large doses and have a cumulative effect and are, therefore, unsuitable for use in the form of herbal extracts. Single isolated compounds for which the pharmacokinetics can be monitored are used instead.

There are, however, other herbal drugs that have beneficial effects upon the heart, the most important of which are hawthorn (Crataegus) and motherwort (Leonurus cardiaca). Hawthorn has anti-arrhythmic activity, and will be discussed briefly below. There is not enough evidence available at present to justify the inclusion of motherwort. In general, however, arrhythmias are treated with isolated compounds, most of which are synthetic, although quinidine (an alkaloid from Cinchona spp.; Fig. 15.1) is still used occasionally. Ajmaline, from Rauvolfia spp., is used as an anti-arrhythmic in some parts of the world; sparteine, from broom (Cytisus scoparius), was formerly employed. Both of these compounds are alkaloids.

Fig. 15.1

Foxglove (digitalis) leaf, Digitalis purpurea L. (Digitalis purpureae folium)

The purple foxglove (Digitalis purpurea) and its close relative the woolly foxglove (D. lanata L., Scrophulariaceae), yield cardiac glycosides. These plants are very common; they are indigenous to Europe and cultivated elsewhere. They do not have a long history of herbal use because of their toxicity, although the famous surgeon William Withering described their use for ‘dropsy’ (an old term for congestive heart failure) in 1870, and this was the first time an effective treatment for this condition had been found. The leaves are the source of the drug and are usually gathered in the second year of growth.

Constituents

Both species contain cardenolides, which are glycosides of the steroidal aglycones digitoxigenin, gitoxigenin and gitaloxigenin. There are very many cardiac glycosides, but the most important is digoxin (Fig. 15.2) and to a much lesser extent digitoxin, and the purpurea glycosides A and B. Digitalis lanata contains higher concentrations of glycosides, including digoxin and lanatosides, and is the main source of digoxin for the pharmaceutical industry.

Fig. 15.2

Therapeutic uses and available evidence

Digoxin increases the force of myocardial contractility and reduces conductivity within the atrioventricular node. It is used primarily in the treatment of supraventricular tachycardia and heart failure and is given as a once-daily dosage in the range 62.5–250 μg. Digitalis glycosides increase the force of contraction of the heart without increasing the oxygen consumption, and slow the heart rate when atrial fibrillation is present. Due to their cumulative effect, the glycosides can easily give rise to toxic symptoms, such as nausea, vomiting and anorexia, especially in the elderly, thus blood levels should be monitored.

Hawthorn, Crataegus spp. (Crataegi folium cum flore, Crataegi fructus)

Hawthorn is a common plant found in hedgerows and gardens throughout Europe and elsewhere; it is sometimes known as mayflower or whitethorn. The flowers, leaves and berries of at least two species are used: Crataegus oxycanthoides Thuill. and C. monogyna Jacq. (Rosaceae). These are hairless, thorny, deciduous shrubs with 3–5 lobed leaves, bearing white, dense clusters of flowers, followed by deep red fruits containing one seed (in C. monogyna) or two seeds (in C. oxycanthoides). The flowers appear in early summer and the berries or ‘haws’ in early autumn. Jams and wines are often made from the fruit.

Constituents

The main constituents of the leaf are flavonoids, including vitexin, vitexin-4-rhamnoside, quercetin and quercetin-3-galactoside, hyperoside, rutin, vicentin, orientin; the fruit contains flavonoids, procyanidins, catechins and epicatechin dimers, as well as phenolic acids such as chlorogenic and caffeic acids. Amines such as phenethylamine and its methoxy derivative, as well as dopamine, acetylcholine and tyramine, have also been isolated. It is thought that a mixture of active constituents may be necessary for the therapeutic effect. The drug prepared from hawthorn is often standardized to contain 4–30 mg of flavonoids, calculated as hyperoside, or 30–160 mg of procyanidins, calculated as epicatechin. In the Eur. Ph., the leaf and flower, and also the berries, are identified using thin layer chromatography (TLC) with the hyperoside, rutin and chlorogenic acid as reference standards. The assays are different, however; whereas the leaf and flower use the flavonoid content, the berries are assayed for anthocyanin content.

Therapeutic uses and available evidence

Hawthorn is used as a cardiac tonic, hypotensive, coronary and peripheral vasodilator, anti-atherosclerotic and anti-arrhythmic. Animal studies have shown beneficial effects on coronary blood flow, blood pressure and heart rate, as well as improved circulation to the extremities (Alternative Medicine Review (Crataegus) 2010). Hawthorn extract inhibits myocardial Na⁺, K⁺-ATPase and exerts a positive inotropic effect and relaxes the coronary artery. It blocks the repolarizing potassium current in the ventricular muscle and so prolongs the refractory period, thus exerting an anti-arrhythmic effect. It seems to protect heart muscle by regulating Akt and HIF-1 signalling pathways (Jayachandran et al 2010), and reducing oxidative stress (Bernatoniene et al 2009, Swaminathan et al 2010). There are as yet few clinical trials of the drug, although a recent double-blind pilot study indicated a promising role for hawthorn extract in mild essential hypertension (Walker et al 2002). However, other studies have found that tolerance to exercise was not improved in patients with class II congestive heart failure (Zick et al 2009). It seems likely that hawthorn can be used as an adjunct or sole treatment only in milder cases of heart disease. The usual recommended dose of standardized extract (see Constituents, above) is 160–900 mg daily. Few side effects have been observed, and both patients and physicians rated the tolerance of the drug as good, although nausea and headache have been reported infrequently.