Y

dehydration favoured by oxaloacetate ester y bufadienolide y bufadienolide

1,4-elimination O favouring formation of O conjugated dienone h ri

formation of conjugated system

Figure 5.93

has subsequently taken the general name. Note that in the subsequent formation of hellebrigenin (Figure 5.92), hydroxylation at C-5 occurs with the expected retention of stereochemistry, and not with inversion as seen at C-14.

The fundamental pharmacological activity resides in the aglycone portion, but is considerably modified by the nature of the sugar at C-3. This increases water solubility and binding to heart muscle. The sugar unit may have one to four monosaccharides; many, e.g. D-digitoxose and D-digitalose (Figure 5.94), are unique to this group of compounds. About 20 different sugars have been characterized, and with the exception of D-glucose, they are 6-deoxy- (e.g. L-rhamnose) or 2,6-dideoxy- (e.g. D-digitoxose) hexoses, some of which are 3-methyl ethers (e.g. D-digitalose and D-cymarose (Figure 5.94)). In plants, cardiac gly-cosides are confined to the Angiosperms, but are found in both monocotyledons and dicotyledons. The cardenolides are more common, and the plant

OH D-digitoxose

OH D-digitoxose

D-digitalose

D-cymarose

D-cymarose

D-digitalose

Digitalose

19-norbufalin

19-norbufalin

Figure 5.94

families the Apocynaceae (e.g. Strophanthus)*, Liliaceae (e.g. Convallaria )*, and Scrophulari-aceae (e.g. Digitalis)* yield medicinal agents. The rarer bufadienolides are found in some members of the Liliaceae (e.g. Urginea)* and Ranunculaceae (e.g. Helleborus), as well as toads. Monarch butterflies and their larvae are known to accumulate in their bodies a range of cardenolides, which they ingest from their food plant, the common milkweed (Asclepias syriaca; Asclepiadaceae). This makes them unpalatable to predators such as birds.

Endogenous Digitalis-like compounds have also been detected, albeit in very small quantities, in mammalian tissues. 19-Norbufalin (Figure 5.94) is found in human eye lenses, at higher levels if these are cataract afflicted, and it is believed to regulate ATPase activity under some physiological and pathological conditions.

Digitalis purpurea

Digitalis leaf consists of the dried leaf of the red foxglove Digitalis purpurea (Scrophulariaceae). The plant is a biennial herb, common in Europe and North America, which forms a low rosette of leaves in the first year, and its characteristic spike of purple (occasionally white) bell-shaped flowers in the second year. It is potentially very toxic, but is unlikely to be ingested by humans. Digitalis purpurea is cultivated for drug production, principally in Europe, the first year leaves being harvested then rapidly dried at 60°C as soon as possible after collection. This procedure is necessary to inactivate hydrolytic enzymes which would hydrolyse glycoside linkages in the cardioactive glycosides giving rise to less active derivatives. Even so, some partial hydrolysis does occur. Excess heat may also cause dehydration in the aglycone to A14-anhydro compounds, which are inactive.

Because of the pronounced cardiac effects of digitalis, the variability in the cardiac glycoside content, and also differences in the range of structures present due to the effects of enzymic hydrolysis, the crude leaf drug is usually assayed biologically rather than chemically. Prepared digitalis is a biologically standardized preparation of powdered leaf, its activity being assessed on cardiac muscle of guinea pig or pigeon and compared against a standard preparation. It may be diluted to the required activity by mixing in powdered digitalis of lower potency, or inactive materials such as lucerne (Medicago sativa) or grass. The crude drug is hardly ever used now, having been replaced by the pure isolated glycosides.

The cardioactive glycoside content of Digitalis purpurea leaf is 0.15-0.4%, consisting of about 30 different structures. The major components are based on the aglycones digitoxigenin, gitoxigenin, and gitaloxigenin (Figure 5.95), the latter being a formate ester. The glycosides comprise two series of compounds, those with a tetrasaccharide glucose-(digitoxose)s-unit and those with a trisaccharide (digitoxose)3-unit. The latter group (the secondary glycosides) are produced by partial hydrolysis from the former group (the primary glycosides) during drying by the enzymic action of a p-glucosidase, which removes the terminal glucose. Thus the principal glycosides in the fresh leaves, namely purpureaglycoside A and purpureaglycoside B (Figure 5.95), are partially converted into digitoxin and gitoxin respectively (Figure 5.95), which normally predominate in the dried leaf. These transformations are indicated schematically in Figure 5.96. In the fresh leaf, purpureaglycoside A can constitute about 50% of the glycoside mixture, whilst in the dried leaf, the amounts could be negligible if the plant material is old or poorly stored. The gitaloxigenin-based glycosides are relatively unstable, and the formyl group on the aglycone is readily lost by hydrolysis. Other minor glycosides are present, but neither the fresh nor dried leaf contain any significant quantities of the free aglycones.

Glycosides of the gitoxigenin series are less active than the corresponding members of the digitoxigenin-derived series. Digitoxin is the only compound routinely used as a drug, and it is employed in congestive heart failure and treatment of cardiac arrhythmias, particularly atrial fibrillation.

R = H, purpureaglycoside A
Purpureaglycoside

R = H, lanatoside A R = OH, lanatoside B R = O2CH, lanatoside E

D-glucose

3-acetyl-D-digitoxose

OH D-digitoxose

■ ■

R1 = OH, R2 = H, digoxigenin R1 = OH, R2 = OH, diginatigenin

R1 = OH, R2 =

H, acetyldigoxin

R1 = OH, R2 =

OH, acetyldiginatin

R1 = OH, R2

= H, lanatoside C

R1 = OH, R2

= OH, lanatoside D

Figure 5.95

(Continues)

purpureaglycoside A

Glc-Dig-Dig-Dig-digitoxigenin digitoxin

Dig-Dig-Dig-digitoxigenin lanatoside A

Glc-Dig-Dig-Dig-digitoxigenin Ac acetyldigitoxin

Dig-Dig-Dig-digitoxigenin

Glc-Dig-Dig-Dig-gitoxigenin

- Glc lanatoside B

Glc-Dig-Dig-Dig-gitoxigenin Ac

Ac gitoxin acetylgitoxin

Dig-Dig-Dig-gitoxigenin

Dig-Dig-Dig-gitoxigenin Ac desacetyl-lanatoside C

Glc-Dig-Dig-Dig-digoxigenin

- Ac lanatoside C

digoxin

Dig-Dig-Dig-digoxigenin glucogitaloxin

Glc-Dig-Dig-Dig-gitaloxigenin

Glc gitaloxin

Dig-Dig-Dig-gitaloxigenin

Glc-Dig-Dig-Dig-digoxigenin

- Ac acetyldigoxin

Ac lanatoside E

Glc-Dig-Dig-Dig-gitaloxigenin Ac acetylgitaloxin

Dig-Dig-Dig-gitaloxigenin Ac lanatoside D

Glc-Dig-Dig-Dig-diginatigenin

Ac acetyldiginatin

Ac diginatin

Dig-Dig-Dig-diginatigenin

Digitalis lanata

Digitalis lanata (Scrophulariaceae), the Grecian foxglove, is a perennial or biennial herb from Southern and Central Europe, and differs in appearance from the red foxglove by its long narrow smoother leaves, and its smaller flowers of a yellow-brown colour. It is cultivated in Europe, the United States and South America, and is harvested and dried in a similar manner to D. purpurea. It has not featured as a crude drug, but is used exclusively for the isolation of individual cardiac glycosides, principally digoxin and lanatoside C (Figure 5.97).

The total cardenolide content of up to 1% is two to three times that found in D. purpurea. The main constituents resemble those of D. purpurea, but contain an acetyl ester function on the third digitoxose, that furthest from the aglycone. This acetyl group makes the compounds easier to isolate from the plant material and makes crystallization easier. Drying of the leaf is similarly accompanied by some partial hydrolysis of the original fresh leaf constituents through enzymic action, and both the terminal glucose and the acetyl group may be hydrolysed off, extending the range of compounds isolated. The D. lanata cardiac glycosides are based on five aglycones, digitoxigenin, gitoxigenin, and gitaloxigenin, as found in D. purpurea, plus digoxigenin and diginatigenin (Figure 5.95), which do not occur in D. purpurea. The primary glycosides containing the acetylated tetrasaccharide unit glucose-acetyldigitoxose-(digitoxose)2-are called lanatosides. Lanatosides A and C (Figure 5.95) constitute the major components in the fresh leaf (about 50-70%) and are based on the aglycones digitoxigenin and digoxigenin respectively. Lanatosides B, D, and E (Figure 5.95) are minor components derived from gitoxigenin, diginatigenin, and gitaloxigenin respectively. Enzymic hydrolysis of the lanatosides generally involves loss of the terminal glucose prior to removal of the acetyl function, so that compounds like acetyldigitoxin and acetyldigoxin as well as digitoxin and digoxin are present in the dried leaf as decomposition products from lanatosides A and C respectively. These transformations are also indicated in simplified form in Figure 5.96.

Digoxin (Figure 5.97) has a rapid action and is more quickly eliminated from the body than digitoxin, and is therefore the most widely used of the cardioactive glycosides. Digoxin is more hydrophilic than digitoxin, binds less strongly to plasma proteins and is mainly eliminated by the kidneys, whereas digitoxin is metabolized more slowly by the liver. It is used in congestive r!o

Desacetyl Lanatosid

R1 = Me, R2 = H, medigoxin (metildigoxin) R1 = Glc, R2 = Ac, lanatoside C

R1 = Glc, R2 = H, deslanoside (desacetyl-lanatoside C)

R1 = Me, R2 = H, medigoxin (metildigoxin) R1 = Glc, R2 = Ac, lanatoside C

R1 = Glc, R2 = H, deslanoside (desacetyl-lanatoside C)

" (Continued)

heart failure and atrial fibrillation. Lanatoside C and deslanoside (desacetyl-lanatoside C)

(Figure 5.97) have also been employed, though not to the same extent. They have very rapid action and are suited for treatment of cardiac emergencies by injection. A semisynthetic derivative medigoxin or metildigoxin (methyl replacing the glucose in lanatoside C) (Figure 5.97) has also been available, being more active via better bioavailability.

The cardioactive glycosides increase the force of contractions in the heart, thus increasing cardiac output and allowing more rest between contractions. The primary effect on the heart appears to be inhibition of Na+/K+-ATPase in the cell membranes of heart muscle, specifically inhibiting the Na+ pump, thereby raising the intracellular Na+ concentration. The resultant decrease in the Na+ gradient across the cell membrane reduces the energy available for transport of Ca2+ out of the cell, leads to an increase in intracellular Ca2+ concentration, and provides the positive ionotropic effect and increased force of contractions. The improved blood circulation also tends to improve kidney function leading to diuresis and loss of oedema fluid often associated with heart disease. However, the diuretic effect, historically important in the treatment of dropsy, is more safely controlled by other diuretic drugs.

To treat congestive heart failure, an initial loading dose of the cardioactive glycoside is followed by regular maintenance doses, the amounts administered depending on drug bioavailability and subsequent metabolism or excretion. Because of the extreme toxicity associated with these compounds (the therapeutic level is 50-60% of the toxic dose; a typical daily dose is only about 1 mg) dosage must be controlled very carefully. Bioavailability has sometimes proved erratic and can vary between different manufacturers' formulations, so patients should not be provided with different preparations during their treatment. Individual patients also excrete the glycosides or metabolize them by hydrolysis to the aglycone at different rates, and ideally these processes should be monitored. Levels of the drug in blood plasma can be measured quite rapidly by radioimmunoassay using a specific antibody. A digoxin-specific antibody is available both for assay and also as a means of reversing life-threatening digoxin overdose. It has also successfully reversed digitoxin overdose, thus demonstrating a somewhat broader specificity. The value of digoxin treatment for heart failure where the heartbeat remains regular has recently been called into question. It still remains a recognized treatment for atrial fibrillation.

Many other species of Digitalis, e.g. D. dubia, D. ferruginea, D. grandiflora, D. lutea, D. mertonensis, D. nervosa, D. subalpina, and D. thaspi contain cardioactive glycosides in their leaves, and some have been evaluated and cultivated for drug use.

Strophanthus

Strophanthus is the dried ripe seeds of Strophanthus kombe or S. gratus (Apocynaceae), which are tall vines from equatorial Africa. Strophanthus kombe has a history of use by African tribes as an arrow poison, and the seeds contain 5-10% cardenolides, a mixture known as K-strophanthin. This has little drug use today, though it was formerly used medicinally as a cardiac stimulant. The main glycoside (about 80%) is K-strophanthoside (Figure 5.98) with smaller amounts of K-strophanthin-p and cymarin, related to K-strophanthoside as shown. These are derivatives of the aglycone strophanthidin. Strophanthus gratus contains 4-8% of ouabain (G-strophanthin) (Figure 5.98), the rhamnoside of ouabigenin. Ouabigenin is rather

HO

OMe ■

OH

D-glucose

D-glucose

D-cymarose | ■

strophanthidin

cymarin

K-strophanthin-ß

K-strophanthoside hohO

K-strophanthoside hohO

OH ouabigenin

HO I OH

L-rhamnose

OH ouabigenin al^ O

HO I OH

L-rhamnose

OHC I H

ouabain (G-strophanthin)

strophanthidin convallatoxin

Figure 5.98

unusual in having additional hydroxylation at 1 p and 11 a, as well as a hydroxymethyl at C-10. Ouabain is a stable, crystalline material, which is often employed as the biological standard in assays for cardiac activity. It is a potent cardiac glycoside and acts quickly, but wears off rapidly. It is very polar with rapid renal elimination and must be injected because it is so poorly absorbed orally. It has been used for emergency treatment in cases of acute heart failure. It is still official in many pharmacopoeias.

Convallaria

The dried roots and tops of lily of the valley, Convallaria majalis (Liliaceae/Convallariaceae), contain cardioactive glycosides (0.2-0.3%) and are used in some European countries rather than digitalis. The effects are similar, but the drug is less cumulative. This plant is widely cultivated as an ornamental, particularly for its intensely perfumed small white flowers, and must be considered potentially toxic. The major glycoside (40-50%) is convallatoxin (Figure 5.98), the rhamnoside of strophanthidin.

" (Continued)

Squill

Squill (white squill) consists of the dried sliced bulbs of the white variety of Urginea maritima (formerly Scilla maritima; also known as Drimia maritima) (Liliaceae/Hyacinthaceae) which grows on seashores around the Mediterranean. The plant contains bufadienolides (up to 4%), principally scillaren A and proscillaridin A (Figure 5.99). The aglycone of scillaren A is scillarenin, which is unusual in containing a A4 double bond and thus lacks the cis A/B ring fusion found in the majority of cardiac glycosides. Squill is not usually used for its cardiac properties, as the glycosides have a short duration of action. Instead, squill is employed for its expectorant action in preparations such as Gee's linctus. Large doses cause vomiting and a digitalis-like action on the heart.

Red squill is a variety of Urginea maritima that contains an anthocyanin pigment (see page 150) and bufadienolides that are different from those of the white squill. The main glycosides are glucoscilliroside and scilliroside (Figure 5.99), glucosides of scillirosidin. This chemical variety should not be present in medicinal squill, and has mainly been employed as a rodenticide. Rodents lack a vomiting reflex and are poisoned by the cardiac effects, whilst in other animals and humans vomiting will occur due to the emetic properties of the drug. The use of red squill as a rodenticide is now considered inhumane.

Prepare Scilliroside
Figure 5.99

Toxic Plants

Many plants containing cardioactive glycosides are widely grown as ornamentals and must be considered toxic and treated with due care and respect. These include Digitalis species, Convallaria majalis, Helleborus species, and oleander (Nerium oleander; Apocynaceae).

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