ALKALOIDS

2011

These compounds are heterocyclic, contain nitrogen, generally have potent activity and are of limited distribution in nature. Pseudoalkaloids are terpenoids that contain nitrogen or are derived from acetate, such as coniine. Protoalkaloids contain an amine structure but not within a heterocyclic ring, such as ephedrine. The chemical and biological properties of pseudoalkaloids and protoalkaloids are sufficiently similar to those of heterocyclic alkaloid that they are included in this category.

Select Alkaloid-Rich Plants
Aporphine Alkaloids
Peumus boldus (boldo)
Indole Alkaloids
Banisteriopsis spp (ayahuasca)
Catharanthus roseus (Madagascar periwinkle)
Claviceps purpurea (rye ergot)
Celsemium sempervirens (gelsemium)
Pausinystalia yohimbe (yohimbe)
Physostigma venenosum (ordeal bean)
Psilocybe spp
Rauvolfia serpentina (Indian snakeroot)
Strychnos nux vomica (nux vomica)
Tabernanthe iboga (iboga)
Isoquinoline Alkaloids
Berberis spp (barberry)
Cephaelis ipecacuanha (ipecac)
Chelidonium majus (greater celandine)
Coptis spp (goldthread)
Corydalis yanhusuo (yan hu suo)
Eschscholzia californica (California poppy)
Fumaria officinalis (fumitory)
Hydrastis canadensis (goldenseal)
• Jateorhiza palmata (calumba)
Mahonia aquifolium (Oregon grape)
Papaver somniferum (opium)
Xanthorrhiza simplicissima (yellow root)
Zanthoxylum clava-herculis (prickly ash)
Norlupinane Alkaloids
• Sarothamnus scoparius (Scotch broom)
Protoalkaloids
Colchicum autumnale (autumn crocus)
Catha edulis (khat)
Ephedra sinica (ma huang)
Lophophora williamsii (peyote)
Purine Alkaloids (methylxanthines)
Camellia sinensis (tea) folia
Coffea arabica (coffee) semen
Cola nitida (kola) semen
Paullinia cupana (guarana) semen
Ilex paraguayensis (mate) folia
Theobroma cacao (chocolate) semen
Pseudoalkaloids
Cicuta virosa (water hemlock)
Conium maculatum (hemlock)
Pyridine Alkaloids
Lobelia inflata (lobelia)
Nicotiana tabacum (tobacco)
Piper longum (long pepper)
Piper nigrum (black pepper)
Trigonella foenum-graecum (fenugreek)
Quinoline Alkaloids
Cinchona spp (Peruvian bark)
Calipea officinalis (Angostura)
Tropane Alkaloids
Sanguinaria canadensis (bloodroot)
Atropa belladonna (deadly nightshade)
• Datura stramonium (Jimson weed, thornapple)
Erythroxylum coca (Bolivian coca)
Hyoscyamus niger (henbane)
Mandragora officinarum (mandrake)

Alkaloids are synthesized from amino acids (Select Alkaloid-Rich Plants). This is the basis of the biosynthetic and structural groupings of alkaloids commonly referred to in the literature. Certain alkaloid groups tend to be confined to certain plant families. Therapeutic differences may be extensive within a class of alkaloids, so these categories do not necessarily provide a good clinical basis for an understanding of these molecules.

Precursors Alkaloids Included
Ornithine, putrescine, proline Pyrrole, pyrrolizidine, tropane
Lysine Pyridine, norlupinane
Tyrosine, phenylalanine Protoalkaloids, isoquinoline
Tryptophan, tryptamine Quinoline, indole
Histidine, threonine Imidazole
Adenine, purine, xanthine, hypoxanthine Purine
Acetate or mevalonic acid Steroidal and terpenoid pseudoalkaloids

The nitrogen in alkaloids generally acts as a weak base, although this varies according to other functional groups and the exact configuration of the alkaloids. Primary, secondary, and tertiary amines (the nitrogen connected to one, two, or three carbons, respectively), as well as saturated, heterocyclic amines, are the most basic alkaloids. Aromatic and aniline heterocyclic amines are slightly basic. Amides and quaternary amines are neutral, and phenolics are actually acidic.

Alkaloids, particularly amines and other basic alkaloids, are usually found as salts in plants. They remain in salt form when placed in an acidic solution, and any free alkaloid generally becomes salt. This is critical because the salt forms are water soluble and the free alkaloids generally are not. For example, free quinine is 0.1% water soluble, and quinine hydrochloride is 99% water soluble. Acidic and neutral free alkaloids, such as caffeine, tend to be hydrophilic and may not form salts.

Alkaloids are variably bioavailable. They tend to be oxidized by the cytochrome P450 system to form N-oxide compounds, which are water soluble and nontoxic. The N-oxides can be reduced in the body to their parent alkaloids and may cause problems or bring benefits. Alkaloids are irreversibly bound and are precipitated by tannins, making them almost totally unabsorbable. The two should generally be kept separate to avoid this interaction, although tannins can also serve as a useful immediate treatment for acute alkaloid overdose.

Alkaloids generally have a strong bitter taste. They tend to act as digestive stimulants, as was previously discussed with sesquiterpene lactones and iridoid glycosides. Otherwise, they have extremely diverse clinical properties. Several examples are given here to illustrate this diversity. The only rule that is generally true and inherent to the definition of these compounds is that they tend to be potent, meaning that small doses are all that are necessary to produce significant effects.

Atropine [a racemic mixture of (-)- and (+)-hyoscyamine] and scopolamine are tropane alkaloids found in Atropa belladonna (belladonna), Datura spp (thornapple), and Hyoscyamus niger (henbane). These alkaloids are muscarinic receptor antagonists that give these herbs strong anticholinergic activity. They are used to treat smooth muscle spasm, hypersecretion, and pain.

Pyrrolizidine alkaloids (PA) have no clear therapeutic benefit (although at least one, indicine N-oxide, is being studied as an anticancer agent) but are important for their potential toxicity. Actually, only unsatured PA are toxic, and only those structures that are converted, in this case, to more toxic N-oxide forms by hepatic cytochrome P450 enzymes. Thus, although most members of the Asteraceae and Boraginaceae families (and a few other scattered members of various other families) contain pyrrolizidine alkaloids, only a small number definitely contain the unsaturated type that may cause concern. Because these alkaloids do not cause widespread hepatic necrosis (except when extraordinary doses are ingested), monitoring of serum liver enzymes is not an effective screening test. It should also be noted that because unsaturated pyrrolizidine alkaloids readily induce fibrosis, the damage that they cause is cumulative. Different animal species show wide variation in susceptibility to induction of cirrhosis, hepatic venoocclusive disease, and cancer because of unsaturated PA ingestion (Unsaturated Pyrrolizidine Alkaloid-Containing Medicinal Herbs). Even though horses and cows are said to be highly susceptible, Symphytum officinale (comfrey) leaf has been safely and effectively used as fodder for these animals in large quantities, possibly because of low unsaturated pyrrolizidine alkaloids levels in the feed. Differences in susceptibility may result from differences in gut flora, differences in hepatic conversion, differences in hepatic glutathione production, and differences in doses ingested. If unsaturated PA-containing herbs are to be used medicinally or as food, it is recommended that alkaline aqueous, glycerin, or dilute ethanol (<30%) extracts be prepared from aerial

parts. This method generally reduces the amount of pyrrolizidine alkaloids extracted. Also, many supplement companies now provide extracts that are made from strains bred to contain low PA levels, or that have documented low pyrrolizidine alkaloids levels caused by extraction methods.

Unsaturated Pyrrolizidine Alkaloid-Containing Medicinal Herbs
Asteraceae
Eupatorium perfoliatum (boneset), E. purpureum (Joe Pye weed)
Petasites frigidus (butterbur)
Psacalium decomposition (matarique)
Senecio spp (ragworts)
Tussilago farfara (coltsfoot)
Boraginaceae
Borago officinalis (borage)
Cynoglossum officinale (hound’s tongue)
Lithospermum ruderale (gromwell)
Symphytum officinale (comfrey)

Berberine, berbamine, hydrastine, and sanguinarine are isoquinoline alkaloids found in various combinations in several species, including but not limited to Mahonia aquifolium (Oregon grape), Berberis vulgaris (barberry), Hydmstis canadensis (goldenseal), Coptis spp (goldthread), Xanthorrhiza simplicissimia (yellow root), and Sanguinaria canadensis (bloodroot). These alkaloids have been shown in various study systems and clinical trials to have actions including inhibiting oxidation, indirect inhibition of phospholipase A2, killing bacteria and inhibiting their adhesion to cell surfaces, stimulation of bone marrow leukocyte production inhibition of arrhythmias, strengthening of myocardial contractility, inhibition of blood vessel formation by cancer cells, and apoptosis induction in cancer cells. It is important to note that complex, crude extracts of plants containing these alkaloids frequently show activity that is as good as or better than that seen in the alkaloids in isolation.

Alkaloids and herbs that contain significant amounts of them should generally be treated as potentially toxic. This is not always the case, but many alkaloids are extremely potent and overdose is a possibility. No generic reaction to alkaloid overdose can be anticipated — the exact effects depend entirely on the properties of the specific alkaloid in the body.