Alkaloids

Alkaloids are a very mixed group of plant constituents that contain a nitrogen-bearing molecule that makes them particularly pharmacologically active. Despite this chemical similarity, the structures and functions vary so widely it would be very silly to link all “alkaloids” together. And though they may be subdivided into various categories based on their structure there is still large variability even within these groups. The major groups of alkaloids are as follows:

• Tropane (or Pyrrolidine)
• Isoquinoline
• Pyridine
• Pyrrolizidine
• Quinoline
• Indole
• Purine

Some are well-known drugs that have a recognized medicinal use. Vincristine for example found in Vinca sp. (Periwinkle) is used to treat some types of cancer. Other alkaloids such as atropine found in Atropa belladonna (deadly nightshade) have a direct effect on the body, reducing spasms, relieving pain, drying up bodily secretions, and dilating the pupils during eye procedures.

Alkaloids are found most commonly in around 20 families of flowering plants. Some of the most important among these are Apocynaceae (the richest family by a large margin), Asteraceae, Berberidaceae, Boraginaceae, Fabaceae, Papaveraceae (a particularly rich source though less than the Apocynaceae), Ranunculaceae, Rubiaceae, Rutaceae and Solanaceae. Alkaloids serve diverse purposes in plants. These include storage and transport of acids, antioxidant protection, and anti-predation effects.

Free alkaloids (bases) are generally soluble in ethanol and other organic solvents, but only slightly soluble in water. In fact, tinctures were largely developed because they are very efficient (using about 45% ethanol) at extracting alkaloids and alkaloid salts from plants.

Alkaloids are readily and irreversibly precipitated by tannins. Therefore alkaloid-containing and significant tannin-containing plants should never be mixed together directly, unless one wishes to counteract the actions of alkaloids. Black tea (Camellia sinensis), cranesbill (Geranium maculatum) or witch hazel (Hamamelis virginiana) are three remedies commonly used for alkaloid poisoning.

Tropane Alkaloids 

Tropane alkaloids are synthesized ultimately from the amino acids ornithine, putrescine (decarboxylated ornithine), or proline. They contain a pyrrolidine and piperidine ring meshed together, and are largely confined to the Solanaceae family, though some are found sprinkled through other families.

Examples and Actions of Selected Tropane Alkaloids

Alkaloid(s)	Source(s)	Action(s)
HyoscyamineAtropineScopolamine	Datura stramonium (Jimson weed, thorn apple)Atropa belladonna (deadly nightshade) folia or radixHyoscyamus niger (henbane)	Anti-cholinergicMydriatic (dilates pupils)SpasmolyticAnti-secretory Anti-emetic
cocaine	Erythroxylum coca (Bolivian coca)	First modern local anesthetic, narcotic

The most well known tropane alkaloids are atropine, hyoscyamine and scopolamine, found exclusively in Solanaceae family plants. These alkaloids are all anticholinergic and are used to decrease smooth muscle spasms and reduce secretions, particularly in the digestive tract. Scopolamine is also used to prevent motion sickness and as presurgical medication because of its unique central nervous system depressing effects, not seen with hyoscyamine. Higher doses of hyoscyamine are hallucinogenic, and these plants have historically been used for ritual purposes. An important bronchodilator drug, ipratropium, is a synthetic derivative of hyoscyamine.

Isoquinoline alkaloids

 There are several important medicinal isoquinoline alkaloids. These alkaloids are all ultimately synthesized from tyrosine in plants.

Examples and Actions of Selected Isoquinoline Alkaloids

Alkaloid(s)	Source(s)	Action(s)
berberine	Hydrastis canadensis (goldenseal) radix–also contains hydrastine and canadineMahonia aquifolium (Oregon grape) radix–also contains berbamine	bitter digestive stimulant, gastrointestinal tonic, antimicrobial, immune stimulant
papaverine, morphine, codeine	Papaver somniferum (opium) latex	analgesic, antitussive, sedative narcotic
corydaline	Corydalis spp	analgesic
emetine	Cephaelis ipecacuanha (ipecac) radix	emetic (high dose), expectorant (low dose), anthelmintic (medium dose)
sanguinarine, etc.	Sanguinaria canadensis (bloodroot) radix	antimicrobial, antineoplastic
palmatine, etc.	Jateorhiza palmata (calumba)	bitter digestive stimulant

Pyridine alkaloids

Pyridine alkaloids are synthesized ultimately from lysine in plants. Some examples of medicinally relevant pyridine alkaloids are listed below.

Alkaloid(s)	Source(s)	Action(s)
lobeline	Lobelia inflata (lobelia) herba	nicotinic agonist, spasmolytic, expectorant
nicotine	Nicotiana tabacum (tobacco) folia	nicotinic agonist, addictive
trigonelline	Trigonella foenum-graecum (fenugreek) semen	possibly hypolipidemic
piperine	Piper longum (long pepper) fructus	increases gut permeability

 Pyrrole alkaloids

 Pyrrole alkaloids are synthesized ultimately from ornithine in plants. No major medicinally important representatives known.

Pyrrolizidine alkaloids

 Pyrrolizidine alkaloids (PA) are synthesized ultimately from ornithine in plants. They are medically relevant due to the existence of significant hepatotoxins among the group. The Asteraceae and Boraginaceae families are notable for widespread presence of PAs. Note: Only PAs with unsaturated necine bases are hepatotoxic. Saturated bases (such as found in Echinacea spp and Arnica spp) are non-toxic.

The toxic unsaturated bases only become dangerous after undergoing liver metabolism to alkylating pyrrole esters by the cytochrome P450 enzyme system in the liver. These electrophilic intermediates readily attack DNA. Since they are formed in the liver, they tend to cause their greatest damage to hepatocytes.

Hepatocytes are destroyed and fibrosis tends to replace them. This damage is greatest around the venules in the liver. With sufficient intake of unsaturated PA, fibrosis can obstruct blood flow through the liver sufficient to cause a condition known as hepatic veno-occlusive disease (HVOD). Jaundice and liver failure can ensue, ending ultimately in death in some people who are particularly sensitive or heavily affected unless liver transplantation is available. Activated unsaturated PAs can have toxic effects on other tissues, particularly the kidneys, if they get into circulation. Thus unsaturated PAs should not be seen solely as hepatotoxins.

PAs do not affect everyone equally. This may be a result of differences in cytochrome P450 activity, differences in levels of intake, or other variables. Even moderately large doses of PA tend to have no acute toxicity, only the chronic problem noted above.

Intake of several milligrams a day of PA is sufficient to cause liver damage in susceptible hosts within three months.

It should also be noted that the hepatoprotective saponin glycoside glycyrrhizin found in Glycyrrhiza glabra (licorice) has been shown to protect rats’ livers from the highly toxic pyrrolizidine alkaloid retrorsine

Examples and Actions of Selected Pyrrolizidine Alkaloids

Alkaloid(s)	Source(s)	Action(s)
various	Senecio spp	hepatotoxic
symphytine, etc.	Symphytum officinale (comfrey) radix	hepatotoxic
various	Tussilago farfara (Eastern coltsfoot) radix	hepatotoxic
Various	Borago officinalis (borage) herba	hepatotoxic

Quinoline alkaloids

Quinoline alkaloids are ultimately synthesized from tryptophan or tryptamine in plants. They are unusual in that they contain two nitrogens, one inside and one outside the main skeleton. One of the first pharmaceutical drugs of global importance, quinine, is a quinoline alkaloid. Crude extracts of Cinchona were used successfully for many years to treat malaria, with isolated quinine eventually replacing them.

Examples and Actions of Selected Quinoline Alkaloids

Alkaloid(s)	Source(s)	Action(s)
quinine, quinidine	Cinchona spp (Peruvian bark) cortex	anti-malarial, febrifuge, relieve muscle cramps, bitter digestive stimulant
cusparine	Galipea officinalis (Angostura) cortex	bitter digestive tonic

Indole alkaloids

Indole alkaloids are derived synthetically from tryptophan or tryptamine in plants. These compounds also contain two nitrogens. Dimeric forms exist (two indoles hooked together) resulting in four nitrogen compounds. A large number of medicinal alkaloids are found in this group, including some of the most spectacularly active agents such as the potent anticancer drugs vincristine and vinblastine.

Examples and Actions of Selected Indole Alkaloids

Alkaloid(s)	Source(s)	Action(s)
vinblastine, vincristine (note: dimeric)	Catharanthus roseus (Madagascar periwinkle) herba	antineoplastic
ergometrine group, ergotamine group, ergotoxine group	Claviceps purpurea (rye ergot) sclerotium	migraine relief, vasoconstriction (anti-hemorrhagic), hallucinogenic
reserpine	Rauvolfia serpentina (Indian snakeroot) radix	indirect hypotensive (medium dose), anti-psychotic (high dose)
physostigmine	Physostigma venenosum (ordeal bean) semen	miotic (pupil constriction), cholinesterase inhibitor (indirect cholinergic stimulant)
yohimbine	Pausinystalia yohimbe cortex	alpha adrenergic antagonist
gelsemine	Gelsemium sempervirens (gelsemium) radix	cardiotonic, anti-neuralgic, toxic
strychnine	Strychnos nux vomica semen	bitter, toxic
beta-carbolines (harmine, harmaline)	Banisteriopsis spp (ayahuasca)	hallucinogenic

 Purine Alkaloids

The so-called “methyl xanthines” are synthesized by plants from the purine nucleic acid xanthine with attached methyl groups.

Examples and Actions of Selected Purine Alkaloids

Alkaloid(s)	Source(s)	Action(s)
caffeine	Camellia sinensis (tea) folia, Coffea arabica (coffee) semen, Cola nitida (kola) semen, Paullinia cupana (guaraná) semen, Ilex paraguaensis (maté) folia	CNS stimulant, diuretic (weak), mildly addictive, bitter
theobromine	Theobroma cacao (chocolate) semen	similar to caffeine, quite bitter, antioxidant?
theophylline	same as caffeine	CNS stimulant, diuretic (strong), antispasmodic