Glycosides

• Sugar + non-sugar• In the body they are broken down by enzymes or

acids into:sugars= glycone/ water solublenon sugar= aglycone/ active portion

• Aglycone may be an alcohol, sulfur or phenol compound.

Classification of glycosides

• Based on the nature of the aglycone • Aglycones can be:

phenolsquinonesterpenessteroids

• Huge variety of medicinal activity from one glycoside to the next.

How are they broken down?

• Pro-drugs: glycosides remain inactive until they are hydrolized in the large intestines by the help of specialized bacteria

• This leads to the release of the aglycone which is the active constituent

• The body can absorb some aglycones better than others depending on the herb

Glycosides and Plant Families

• Brassicaceae- glucosinolates• Rosaceae- cyanogenic glycosides• Scrophulariaceae- phenylpropanoid glycosides• Asteraceae- phenylpropanoid, flavinoid

glycosides• Polygonaceae- anthraquinones

Cyanogenic Glycosides

Wild Cherry

Cyanogenic glycosides

• Colorless plant constituent– Hydrogen cyanide was first isolated from Prussian blue dye

• aglycone contains nitrogen• BREAK DOWN:• Cyanogenic glycoside hydrocyanic acid

(prussic acid) cyanide

Cyanogenic Glycosides

• Cyanogenic glycosides are found in pits and seeds of apples, apricots, peaches, plums and elderberries leaves and stems.

• Their function in plants is not really known but they are suspected to be anti-feedants.

Cyanogenic glycosides

• Main cyanogenic glycosides1. Amygdalin- found in bitter almonds and peach kernels

(Chinese herb) - used in to make Marizpan flavoring in cooking.

2. Prunusin- found in wild cherry bark3. Sambunigrin- from the leaves of the elder tree, Sambucus

nigra• Other food plants that contain cyanogenic glycosides

include flaxseed and manioc.– Manioc root must be boiled and the water discarded in

order to remove the toxins.

Cyanogenic glycocides-toxicology

• In large doses hydrogen cyanide (hydrocyanic acid) inactivates respiratory enzymes, shuts down the CNS and leads to death.

• However large doses of raw plant material are needed for toxicity to occur.

• Our bodies can nuetralize cyanides and eliminate them through the urine.

• Cyanogenic glycosides are broken down slowly and are easily detoxified by the body in smaller doses.

• 500mg three times a day to produce a toxic effect, which is A LOT!!- – there are 4-9 mg hydrogen cyanide per bitter almond– You would have to eat 150 bitter almonds a day for a toxic effect!!!

Cyanogenic Glycosides: Properties

• Sedative and expectorant to the respiratory tract.• Wild Cherry Bark (prunus serotina) is a classic prunasin conataining

respiratory herb for dry irritable coughs.• Apricot kernels in Chinese medicine are used for coughs and

asthma.

• Cooling• Hydrocyanic acid cuts down heat at a cellular level.• Ex- peach, apple and pear are all cooling fruits that contain

Cyanogens.

• Anti-cancer• Amygdalin/Laetrile- has been researched as an anti-tumor remedy.

Cardiac Glycosides

Digitalis purpurea

Cardiac Glycosides

• Cardiac glycosides have a long history of use in herbalism

• The famous cardiac glycoside, digitoxin, was isolated in 1785 by William Withering. He found out about the use of foxglove by an elder lady herbalist in his village using it for CHF (dropsy). Of course she gets no credit!

• Digitoxin and other cardiac glycosides from plants day play a large role in modern medicine.

Cardiac Glycosides

• Found in many medicinal plants such as Digitalis purpurea and lilly of the valley (Convallaria majalis)

• Direct action on the heart supporting its strength and rate of contraction when it is failing.

Cardiac Glycosides- Plant protectionPlants and animals create cardiac

glycosides as a strategy for protection against being eaten by other creatures. Some animals, like monarch butterflies, have evolved immunity to the toxins. They consume plants like milkweed (Asclepias syriaca) that are high in cardiac glycosides and store the toxins in their tissues. This makes them poisonous to other predators

• Used as arrow poisons by hunters

Cardiac Glycosides- chemistry

• Steroidal structure- 3 six carbon rings and one five-carbon ring

• The sugar portion of the cardiac glycoside is important in the absorbtion and distribution in the body.

• The aglycone portion is important in binding to Na/K pumps in the heart cells

Cardiac Glycosides

CONDITIONS: Used in arrhythmias and congestive heart failure(dropsy)

• In the past dropsy was the only sign of heart failure. Dropsy (CHF) fluid accumulation in the lower limbs and abdomen due to the heart not being strong enough to handle venous return.

ACTIONS: 1. increase the force and speed of contraction

• Inhibit sodium potassium pump leading to a rise in intracellular calcium which increases contraction of the heart.

2. Decrease heart rate3. Slows conduction velocity in the pace maker- used for

arryhthmias

Cardiac glycosides

• Toxicity- Narrow therapeutic window. The therapeutic dose is not much smaller than the toxic dose.– Too high of a dose can make the pace maker more

sensitive and lead to atrial fibrillation.• Cardiac Glycosides are antagonistic to Potassium. If

person is low in K+ they will be more likely to have digitalis intoxication.– Taraxicum in combition helps to replenish K+

• Digitalis Intoxication- nausea, vomiting, diarrhea, vision disturbances, headache, arrhythmias.

Cardiac Glycosides

• Cardiac remedies in other than drop doses should be used with discretion.

• Digitalis lasts a long time in the body and its effects are cumulative. Half life is over 6 days!

• Convallaria should be considered before digitalis because it has a lower toxicity

Cardiac Glycosides

• Plants containing cardiac glycosides include:• Digitalis purpurea- Used for CHF and edema• Apocyanum cannabinum (Dogbane)• Strophanthus hispidus (Kombe Seed)• Adonis vernalis (False Hellibore)• Urginea Maritima (Squill)• Convallaria margalis (Lily of the Valley)

Isothiocyanate glycosides

Isothiocyanate glycosides (Glucosinolates)

• Found in the Brassicaceae (Mustard) Family.• Sulpher link between the glycone and the

aglycone.• Sulpher is what gives the brassicas their pungent

quality. ( Horseradish clears the sinuses, mustard oil opens the lungs)

• In plants they are used as protection against microbes that disrupt their cell walls.

Isothiocyanate Glycosides

• Therapeutic Actions:• Culinary- black and brown mustard seeds used in

cooking are high in nutrients, stimulate digestion.• Rubefacients- mustard seed oils act as irritants

when applied topically, causing local vasodilation• Mustard poultices over the lungs break up congestion.

• Decongestant for the sinus and bronchial conditions (horseradish, onion and garlic).

• Large doses may have an emetics effect.

Isothiocyanates- goiterogens

• When consumed in excess they inhibit pumping of iodine into the thyroid follicles. This leads to goiter formation especially in those who are iodine deficient.

• pertains more to people who are very iodine deficient like in parts of Asia or central Africa.

• Isothiocyanate botanicals are low enough not to cause a problem.

Isothiocyanate glycosides- Antitumor

• Glucobrassicin is widely distributed amongst the Brassicaceae family

• Glucobrassicin produces indoles when broken down.

• Indole-3-carbinol and diindoylmethane (DIM)

• Indoles are known for their ability to induce tumor inhibiting enzymes. Thus are protective against cancer.

• Indoles do not break down under heat.

Isothyocyanate Glycosides

• Toxicology: External use of should not be sustained for longer than two weeks because of irritating effects.

• mustard seed oils should never be used internally or externally because it toxic to the skin and mucus membranes.

SaponinsWild Yam (Dioscorrea spp.)

Saponins- Definition

• Saponins are glycosides with foaming characteristics.

• Saponin- comes from “sapo” in Latin which means soap.– Historically soap was made from the soapwart

plant.• In plants they are anti-feedants and protect

plants against microbes and fungi

Saponins- synthesis

• Synthesized from acetyl CoA via the mevalonic pathway (similar to cholesterol in animals)– Major economic importance: saponins are used to

synthesize pharmaceutical steroids (corticosteroids, estrogens, progesterone and progestins)

– Agave, fenugreek and wild yam root are examples of plants used for their steroidal properties in the laboratory.

– Human body doesn’t possess the gut flora to interconvert plant steroids to human steroids.

Saponins- classification

• Consist of polycyclic aglycones attached to one or more sugar side chains.

• Two subcategories of saponins– Triterpenoid: pentacyclic structure– Steroidal saponins (phytosterols): tetracyclic

structure

Licorice is a Pentacyclic triterpenoid

Saponins= Suds

• The foaming ability of saponins is caused by the combination of a hydrophobic (fat soluble) aglycone along with the the sugar which is hydrophilic (water loving).

• Allows lipids to dissolve in water• Emulsification in foods that allow water and fat to mix.

• They have a detergent effect on the skin and the mucus membranes.

Saponins

Wound healing herbs contain saponins such as calendula.

Saponins- Actions

• Saponins are bitter or acrid in taste• If injected intravenously they cause hemolysis. Use

only orally!– Destroy the membranes of red blood cells.

• Lower cholesterol:– Because they are structurally similar to cholesterol they

interfere with cholesterol absorption– Increase cholesterol excretion into the bile which then

gets excreted through the feces.– Ex. Trigonella foenum-graecum (fenugreek)

Saponins- Actions

• Medicinally they have many uses:– anti-inflammatory: Licorice, wild yam– anti-viral: licorice, ashwaganda– Digestive: licorice,– Expectorant: lobelia, squill – Adaptogenic: licorice, gensing,ashwaganda

Saponins- reflex expectorants

• Acrid and flavor of saponins make them reflex expectorants

• Reflex expectorants irritate the upper digestive tract causing emesis. This irritation also causes a reflex action via the vagus nerve to promote expectoration.

• Historically herbalists have used emesis to clear the lungs in chronic bronchitis

Saponins- reflex expectorants

• Lobelia inflata• Cephaelis ipecacuanha (Ipecac)• Urginea maritima (Squill)• Verbasum thapsus (Mullein flowers)• Viola spp (Violet flowers)• Glycyrrhiza glabra (licorice)

Steroidal Saponins• Dioscorea villosa (Mexican

wild yam) root– Diosgenin: saponin

aglycone– NOT PROGESTROGENIC in

the body. Complex chemical reactions in the laboratory make it progestrogenic. Naturally it is antispasmodic and anti-inflammatory.

– Human body cannot convert diosgenin into hormones.

Steroidal Saponins

• Panax gensing (Asian) and P.quinquefoium (American gensing):

– Gensenosides: immunomodulating, anti-stress, anti-dementia

– Saponins foam and enhance absorption of other plant constituents.

• Withania somnifra (Ashwaganda) root

– Withanolides: calming and immunomodulating

Panax gensing

Triterpenoid Saponins

• Glycyrrhiza glabra (Licorice)• Glycyrrhizin- reduces toxicity

of other saponins– anti-inflammatory, antiviral,

immunomodulating, hepatoprotective, anti-ulcer

– Used as a synergizer in herbal formulas rendering other ingredients more bioavailabe

• Bupleurum falcatum– Hepatoprotective, antiviral,

immunostimulating

Saponins in medicine making

• Saponins are poorly bioavailable in the human body. Other plant constituents present in the plant aid in assimilation of saponins.

• Saponin rich plants influence absorption of other plant constituents:

• Help lipophilic constituents of plants be absorbed

• Saponins in high doses can cause gastric irritation. Better if they are taken with food.

• Mostly soluble in dilute ethanol (30%), water and lipids

Alkaloids

Alkaloids

• Have had a major impact on humanity• Examples are caffeine, morphine, ephedrine,

atropine, cocaine and many more…

Alkaloids

• Most potent of all plant constituents• alkaloids are seen in pharmaceuticals such as

codeine, morphine, atropine, pseudoepinephrine and vincristine.

• High doses will cause vomiting, diarrhea, immediate central nervous system symptoms and death.

• Important for the herbalists to be careful with herbs that have a high alkaloid content.– Many herbs that contain alkaloids such as berberis and

California poppy are low toxicity.

Alkaloids in the plants

• Why do plants have alkaloids? We don’t know, there are just theories…

• Unclear• alkaloids are a way for plants to excrete excess

nitrogen, like mammals excrete nitrogen though urea in the urine• Alkaloids serve as defenses from predations• Alkaloids are a way for the plant to store nitrogen

which is hard element to come by.

Alkaloids in plants

• Alkaloids are common in plants: 10-15% of all plants have some kind of alkaloid

• May be found in roots, leaves, bark, fruit or seeds.

• Over 40 different alkaloids can be present in one plant, like Vinca major.

Vinca Major

Alkaloids- chemistry

• The word alkaloid is derived from vegetable alkali, which refers to their alkaline nature due to the presence of nitrogen

• Alkaloids are best classified according to their biosynthetic origen.

• Most are synthesized by the plant from amino acids• Psuedoalkaloids- derived from terpenes

Alkaloids-chemistry

• General characteristics • alkaline• Contain a nitrogen• Part of a heterocyclic ring system

Berberine

Alkaloids- Properties

• Most are white in color when extracted, except berberine alkaloids which are yellow

• Bitter in taste• Soluble in alcohol

• Tinctures (45% ethanol) are very effective at extracting alkaloids

• Acetracts extract alkaloids well, such as apple cider vinegar.

• Less soluble in water• This may be a good way to deliver medicine if there is a

potential for giving too high of a dose of alkaloids.

Alkaloids- Properties

• Irreversibly precipitated by tannins.• Alkaloid containing medicines should not be tinctured

with tannins, unless you wish to counteract the alkaloid.• If you want to mix a tincture that has both alkaloids and

tannins use 10% glycerine to the tincture.

• Black tea (Camelia sinensis), cranesbill (Geranium maculatum) or witch hazel (Hamamelis virginiana) are the three remedies for alkaloid poisoning

Alkaloids- Actions

• Analgesics/narcotics- morphine• Mydriatics- atropine• Hypertensives- ephedrine• Hypotensives- reserpine• Stimulants- caffeine, strychnine• Antimicrobials- berberine• Anti-cancer- vinblastine

Alkaloids

• Many different groups of alkaloids exist• The most common groups that we will be

covering in this class are:– Tropane Alkaloids- Belladonna, Henbane ect– Isoquinoline- California poppy, berberis– Pyridine- Tobacco, Lobelia – Pyrrolizidine- Comfrey, Western Coltsfoot– Indole- Peyote, Iboga– Purine- Cacoa, Caffeine

Tropane Alkaloids

• Synthesized from amino acids ornithine or proline.

• Mostly Solanaceae family• Atropa belladona – Deadly nightshade• Datura stramonium- Thornapple• Hyoscymus niger- henbane• Mandragora officianialis- mandrake• Erythroxylum coca - Bolivian coca

Tropane Alkaloids

• Anticholenergics (inhibit parasympathetic nervous system)

• Smooth muscle relaxants– Atropine: dilates pupils, anti-emetic, decreases

salivation– Hyoscamine: bronchial and intestinal

antispasmotic, hallucinagenic– Cocaine: Anesthetic (novacaine), narcotic

Isoquinoline Alkaloids

• Synthesized from amino acid tyrosine• Alkaloid Berberine- Hydrastis canadensis and

Mahonia root• Bitter digestive stimulant• GI tonic• Anti-microbial• Immune stimulant

Hydrastis canadensis

Isoquinoline alkaloids

• Papaver somnifera (opium poppy): papaverine, morphine, codeine

• Analgesic, antitussive, seditave narcotic

• Corydalis spp : corydalin• Analgesic

• Ipecac root: emetine• Emetic in high dose, reflex expectorant in low dose,

anthelmintic

• Sanguinaria candensis (Bloodroot):sanguinarine• Antimicrobial, antineoplastic

Isoquinoline alkaloids

Sanguinaria canadensis

Isoquinoline Alkaloids

Papaver somnifera

Pyridine alkaloids

• Derived from the B vitamin nicotinin acid• Nitrogen atoms in six-membered benzene

rings

Pyridine Alkaloids- Actions

• Lobeline (lobelia inflata leaf): • expectorant, smasmolytic, nicotic agonist

• Nicotine (Nicotiniana tabacum leaf):• Nicotinic agonist, addictive

• Trigonelline (fenugreek seed):• hypolipidemic (lowers blood cholestrol)

• Piperine (Piper longum fruit):• Increases gut permeability, hepatoprotective, used in

combination with other herbs to increase efficacy

Pyrrolizidine alkaloids

• Synthesized from ornithine in plants• Ingested by butterflies to protect them from

invadors• Asteraceae and Boranginaceae families

contain PA- ex) comfrey, echinacea and arnica• Herbal medicine containing PA are

contraversial and have been banned from use in Australia.

Pyrrolizidine Alkaloids

• Hepatotoxic in large doses• PA can cause hepatic venous occlusive disease

if large doses are ingested– When metabolized in liver they cause DNA damage to liver cells which then

fibrose around the venules of the liver. Jaundice and liver failure ensue.

– PA don’t affect everyone equally. Some people may not have sufficient levels of liver enzymes to metabolize PA.

– Intake of over 3 gm/day of PA can cause liver damage within three months.

Pyrrolizidine Alkaloids

• Symphytum off. (Comfrey) has PA• Mucilagenous, anti-inflammatory, heals ulcers

internally and externally.• Has been condemned as toxic by many.• Few cases of injury have been reported and of those

cases people who were poisoned ate the root which is much higher in PA than the leaves.

• Glycyrrhizin (saponin from licorice) has been found to protect the liver from PA

Pyrrolizidine Alkaloids• Other plants that

contain PA:

– Tussilago farfara (Eastern coltsfoot)

– Sencio spp (Life root)

– Borago officianlis ( Borage)

Tussilago farfara

Pyrrolizidine Alkaloids

Senecio spp. (Liferoot or Ragweed)

Indole Alkaloids

• Large number of medicinal alkaloids are found in this group

• Derived from tryptophan or tryptamine in plants.

• Contain 2 nitrogens and often involve multiple rings.

• Form the basis of several hallucinogenic and pharmaceutical drugs.

Indole Alkaloids• Apocynacea family- Rauwolfia, Vinca,

Catharanthus, Iboga• Fungus family- psylocybin mushroom and

ergotimine

Indole Alkaloids- Reserpine

• Reserpine found in Rauwolfia serpentina has been used in Aryuvedic medicine as a hyptotensive, seditave and tranquilizer.

• Reserpine temporarily inhibits noradreniline and depletes the amino acids in the central nervous system.• Hypotensive effects have a slow onset and their

duration is long. • Use cautiously depression and severe hypotension are

indications of overdose.

Indole Alkaloids• Cantharanthus roseus (Madigascar Periwinkle)

• Contain vinblastine and vincristine- antineoplastic used in chemotherapy for childhood luekemia and non-Hodgkin’s lymphoma

• Vinca minor, major (Common Periwinkle)• Vincamine- anti-hemorrhagic and astringent. Does not contain

the anti-cancer alkaloids that cantharanus has.

• Claviceps purpurea (Ergot)• Ergotamine- fungus grows on rye. • Migraine relief• St.Anthony’s Fire- epileptic convulsions and spasms.• LSD is derived from ergot. Similar compounds found in Ipomoea

spp. (Morning Glory)

Other Indole Alkaloids

• Pausinystalia yohimbe ( Yohimbe)• Yohimbine- Aphrodesiac and nerve tonic

• Gelsimium sempervirens (Yellow jasmine)• Gelsemine- heart tonic, nerve seditave, toxic.

• Strycnhos nux vomica (Nux Vomica)• Strychnine- powerful CNS stimulant in low doses. Toxic

• Banisteriopsis caapi ( Ayahuasca)• Harmine- entheogenic

Indole Alkaloids

Banisteriopsis caapi

Purine Alkaloids

• Caffeine, theobromine (chocolate), theophylline (from cacao and tea)

• Methyl xanthines- Derived from the purine nucleotides adenine and guanine with attached methyl groups.

• Mild stimulants and bronchodilators• Theophylline is a drug used for respiratory distress and

asthma.

Purine Alkaloids

Cacao Tree

Purine Alkaloids

• Increase the rate of cardiac contraction• Increase alertness and induce digestive enzyme activity

in the GI • They act by stimulating the Central nervous system and

prolonging the life of hormones, such as adrenaline.

Bitters

Why are bitters important?

• Increase the appetite:– Have been used in aperitifs or to induce appetite in

convalescence• Increase digestive secretions– Low enzymes or stomach acid aid in depressed

digestive ability and leads to proteins from food penetrating into the wall of the gut.

– Increases stomach and pancreatic enzyme secretions and aid the body in breaking down food.

Bitters

– Protect gut tissue: Increase the tone of the lower esophageal sphincter

» Prevent reflux or heart burn, hiatal hernia or esophageal irritation.

– Promote bile flow: reduces toxic load on liver by flushing out toxic accumililations by increasing bile.

– Increases bicarbonate from gallbladder and thins bile

» Gallstone and gallbladder disease

Bitters

• Indicated for symptoms of poor digestions– Belching, loss of appetite, constipation, bloating

and nausea after eating.• Controversy weather bitters are safe to use

with people who have ulcers because too much acid could aggravate the ulcer• Bitters increase secretions of bicarbonate from the

pancreas which protect the stomach from acid.

Some plants containing bitters

• Achillea millefolia (Yarrow)• Artemesia spp. (Wormwood, mugwort..)• Arctium lappa (Burdock)• Tanacetum (Feverfew)• Taraxicum ( Dandilion)• Gentiana lutea (Gentian)• Centaurium minus (Centaury)• Berberis spp (Oregon Grape)• Hammamelis spp (Witch Hazel)• Humuls lupus (hops)• Tussilago farfara ( Coltsfoot)

Acids

• Weak acids constitute a main part of all plant material

• Acids we will cover– Unsaturated fatty acids– Formic Acid– Oxalic Acid– Citric Acid

• Other acids that occur in plants are – Acetic, succinic, benzoic and tartaric

Unsaturated Fatty Acids

• Found universally in plants and less so in animals.

• Linolenic and arachadonic acids- found in seeds and reproductive tissues of the plants

• Linolenic acids- found in the green tissues of plants

• PUFAs (Polyunsaturated fatty acids) are vitally necessary in the diet = ESSENTIAL FATTY ACIDS

Essential Fatty AcidsWhy are they so important?

• Build and repair cell membranes• Form raw material for prostaglandin

production in the body• Prostaglandins are important in smooth muscle

contractions, inflammatory mediators, and raise blood pressure

• Example of PUFA- Evening Primrose (Oenothera biennis) has gamma linolenic acid

Evening Primrose

Used as an anti-inflammatory conditions like rhuematoid arthritis, PMS and eczema

Formic Acid

• The smallest organic acid and the most corrosive to the skin….just like fire ants!

• Used in counterirritants and vesicants• Found in red ants• Formic Acid is the sting in stinging nettles• Oxidizes and is inactive after being exposed to

heat.• Cook your nettles to eat them!!

Oxalic Acid

• Forms insoluble salts with minerals such as calcium.

• Found in foods such as spinach, beets and parsley• Found in the dock and rhubarb families.

• Oxalic acid bound to iron and calcium is what makes Yellow Dock so highly nutritious.

• Care needs to be taken to not consume too many oxalate rich foods if there is a history of oxalate kidney stones.

Citric Acid

• Found widely in fruits and berries, especially citrus fruits

• Cleansing in the body1. Alkalinizing effect:

– citrus breaks down into bicarbonate once in the stomach– Alkalinizing effect in mouth provides the environment

inhospitable to bacteria

2. Increases bile flow from the liver– Explains use of lemon for gallbladder cleanses

Thank you