Module 2

Saponin glycosides
Saponins are a class of natural compounds, found abundantly in more than 100 families of plants, and in a few
marine organisms such as star fish and sea cucumber. They are large molecule which form colloidal solution in
water and produce persistent soapy froth or foam when agitated, and therefore, they are largely used as detergents.
Indeed, the name ‘saponin’ is derived from the Latin word ‘sapo,’ meaning soap, as a soapy lather forms when
plants containing saponins are agitated in water They occur as amorphous glycosides. Chemically, saponins as a
group include compounds that are glycosylated steroids, triterpenoids, and steroid alkaloids. Two main types of
steroid aglycones are known, spirostan and furostan derivatives Saponins are classified as—Triterpene
glycosides, and Steroidal alkaloid glycosides. Being glycosidic plant products, Saponins consist of a sugar moiety
usually containing glucose, galactose, glucuronic acid, xylose, rhamnose or methylpentose, glycosidically linked
to a hydrophobic aglycone (sapogenin) which may be triterpenoid (Fig. 2.1(a)) or steroid (Fig. 2.1[b]) in nature.
The aglycone may contain one or more unsaturated C–C bonds. The oligosaccharide chain is normally attached
at the C3 position (monodesmosidic), but many saponins have an additional sugar moiety at the C26 or C28
position (bidesmosidic). The great complexity of saponin structure arises from the variability of the aglycone
structure, the nature of the side chains and the position of attachment of these moieties on the aglycone. The
complexity of saponin structure is due to the different glycan moieties that are attached to the triterpenoidal or
steroidal aglycones. Two main types of steroid aglycones are known, spirostan and furostan derivatives (Figure
2.2 A, & B, respectively). The main triterpene aglycone is a derivative of oleanane They are widespread in plant
kingdom. Many are non-toxic. Those that are of considerable toxicity are term sapotoxin.

Fig.2.1. Basic structures of sapogenins: a triterpenoid (a) and a steroid (b).

Figure 2.2: Basic structure of steroid aglycones

Saponins are found in a large number of plants and some animals (such as the sea cucumber). In plants, they occur
in different parts such as root, tuber, bark, leaves, seed, and fruit. Triterpenoid saponins are found principally in
dicotyledons while steroidal saponins occur in monocots. However, some plant species contain both triterpenoid
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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
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and steroidal saponins. Saponins occur constitutively in a great many plant species, in both wild plants and
cultivated crops. In cultivated crops the triterpenoid saponins are generally predominant, while steroid saponins
are common in plants used as herbs or for their health-promoting properties. Triterpenoid saponins have been
detected in many legumes such as soyabeans, beans, peas, lucerne, etc. and also in alliums, tea, spinach, sugar
beet, quinoa, liquorice, sunflower, horse chestnut, and ginseng. Steroid saponins are found in oats, capsicum
peppers, aubergine, tomato seed, alliums, asparagus, yam, fenugreek, yucca and ginseng. Young leaves contain
more saponins than mature leaves, but foliage saponins were found to be less haemolytic than root saponins.
Soyasapogenols are mainly concentrated in the axis of the seeds rather than in the cotyledons and seed coat. In
the seedlings, the root (radicle) contains the highest concentration of soyasapogenol A, while the plumule has the
greatest amounts of soyasapogenol B. Generally, saponins are found in tissues that are most vulnerable to fungal
or bacterial attack or insect predation. Therefore, one of their roles is to act as a chemical barrier or shield in the
plant defense system
Mechanisms of action:
The haemolytic action of saponins is believed to be the result of the affinity of the aglycone moiety for membrane
sterols, particularly cholesterol, with which they form insoluble complexes. The amount of glycosides required
for permeabilisation is much lower for cholesterol-rich lipid layers than cholesterol-free membranes. The
hemolytic effect is seen only if the irritant effect is sufficient to allow them to be absorbed into the bloodstream
through an injure gut wall. Interactions between saponin and membrane‐bound cholesterol lead pore formation
and increasing of membrane permeabilizing properties. This specific effect of saponins depends on the
combination of various factors: the membrane composition, the type of saponin, and—especially—the nature of
aglycone.
The model for the mechanism of action of saponins on the membranes is given in Figure 2.3. According to this
model, the spontaneous formation of complexes between saponins and cholesterol in the membranes is followed
by association with a micelle, two-dimensional structure within the membrane. The hydrophilic sugar chains are
oriented towards the center of the micelle complex, leading to the formation of an aqueous pore that, in turn,
would cause an increase in membrane permeability allowing the passage of ions and macromolecules across the
lipid bilayer.

Fig. 2.3: Model of the mechanism of action of saponins on the membranes.

Several mechanisms have been proposed to explain the hypocholesterolaemic activity of saponins. Possible
mechanisms may involve the capacity of saponins to: (i) form insoluble complexes with cholesterol, (ii) affect
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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®
micelle formation, (iii) interfere with bile acid metabolism, (iv) inhibit lipase activity, or (v) regulate cholesterol
homeostasis via monitoring the expression of the key regulatory genes of proteins or enzymes related to
cholesterol metabolism.
Clinical signs: Saponin toxicity leads to photosensitization followed by liver and kidney degeneration in
ruminants and gut problems such as gastroenteritis and diarrhea. When animals suffer from photosensitization,
weeds containing saponins are usually the first suspects, although many toxic weeds or plants have yet to be
analyzed for their saponin content. Most saponins that have been identified in the toxic plants aresteroidal
saponins. Sapotoxin also affects the CNS bringing about stupefaction and paralysis.
Photosensitization is indicated by skin lesions caused by reaction of an exogenous compound in the blood with
UV light, producing free radicals that react with tissue proteins. This is classified as a primary photosensitization.
The affected animals develop photophobia and severe dermatitis. Secondary photosensitization is a result of liver
damage or damage of bile ducts thus impeding the excretion of bile, causing chlorophyll metabolites such as
phylloerythrin to circulate in the blood.
Photosensitization is associated with the appearance of biliary crystals in the bile and in the liver, which has been
identified as the insoluble salts of steroidal sapogenin. Lithogenic (crystal-forming) compounds such as diosgenin
and yamogenin saponins may cause photosensitization, whereas titogenin, neotigogenin, and gitogenin saponins
are nonlithogenic compounds, which do not cause photosensitization.
Some plants containing sapotoxins
Phytolacca dodecandra (African soapberry)
Phytolacca dodecandra (Figure 2.4) is widespread in tropical Africa as well as south Africa and Madagasear.
The bark and roots are very poisonous, the leaves and green fruits less so, while the ripe fruits appear to be
harmless in small quantities. Cattle and sheep eat the soft juicy leaves when grass is scarce in times of drought.
The leaves, fruits and roots contain numerous saponins (triterpenoid glycosides). These compounds cause
haemolysis of red blood cells. The aglycones of the glycosides are mainly composed of oleanolic acid (66%),
bayogenin (15%), hederogenin (9%), and 2-hydroxyoleanolic acid (6.5%). On a dry weight basis the fruit pulp
contains 25% saponins, and the non-saponin fraction contains a lipid fraction (palmitic acid, oleic acid, stearic
acid and a non saponifiable bright orange, waxy material), sugars, starches, pectins and gums and a water
insoluble fraction. The roots contain saponins of the phytolaccoside or esculentoside types.
The seed contains saponin and is known to cause intense GIT irritation leading to vomiting and bloody diarrhea.
In sheep and cattle, it causes salivation, muscular spasms, dypsnoea and bloody stained diarrhea. In human, eating
fruits or leaves may cause acute poisoning resulting in nausea, bloody diarrhoea, intense congestion of the
stomach and intestines, vomiting, weakness, weak and irregular pulse, dilated pupils, swelling of the mucous
membrane in the mouth and stupor; death may occur within a few days. Post mortem findings include hemorrhagic
edema of the lungs and GIT. Others spp of phytolacca such as P. Americana are reported to contain saponine
(phytolaccine) and to have similar effects. In East Africa the pounded plant is also used as a poison to catch fish.
The leaves and stems produce the antiviral protein dodecandrin, which is a ribosome-inactivating protein (RIP),
similar to pokeweed antiviral protein (PAP), isolated from Phytolacca americana

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
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Figure 2.4: Phytolacca dodecandra
Clematis hirsuta
Clematis hirsuta (Figure 2.5) is a climber over trees and rocks and is very common in the savannah. The clematis
is a flowering vine that comes in many vibrant colors. These vines can grow to beautiful proportions if planted in
favorable conditions. They do not need a lot of specific care, making them a popular choice for home gardens.
The leaves is the most toxic component of the plant. Pet owners should be aware of the dangers that hundreds of
types of plants can present to their canine companions; the clematis is one of the garden plants that is mildly to
moderately toxic to pets. It probably contains saponin. Acute gastroenteritis have been reported from experimental
poisoning in cattle. Animals generally avoid the plant because of its bitter taste. Ingestion of the leaves, in
particular, can cause adverse effects in the digestive system, and exposure to the vine and flowers can cause a
dermatologic reaction as well. The plant is known to local herdsmen in Nigeria as being very poisonous to
livestock. Many species of clematis found in India have acid and poisonous properties, some are known to contain
saponin while others contain hydrocyanic acid. Generally the glycoside it contains is protoanemonin

Figure 2.5: Clematis hirsuta

Clinical signs: In dogs, these include nausea, vomiting, diarrhea, salivation, anorexia and pawing at mouth or
face and ulcers or blisters in the mouth and dermatitis. Clematis will have the same effect on other animals too,
including horses, pigs, goats, chickens and other animals on the farm. Most animals will not eat clematis due to
the bitter taste of the leaves. Animals that are lactating may produce the bitter tasting protoanemonin in the milk,
which would give it an unpleasant taste for a short while.
Treatment: Symptom is self-limiting as long as the animals stops intake of the plant, therefore there may not be
need for treatment.

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
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Balanites aegyptiaca (Desert Date)‘aduwa (hausa)
Balanites aegyptiaca (Figure 2.6) is a spiny shrub or tree up to l0 m tall, widely distributed in dry land areas of
Africa and South Asia. It is found in sudan and sahel savannah zone. It is one of the most common but neglected
wild plant species of the dry land areas of Africa and South Asia. It can be found in many kinds of habitat,
tolerating a wide variety of soil types, from sand to heavy clay, and climatic moisture levels. The bark, fruit and
root all contain saponin and are used as fish poisoning and as molluscicide. The crude saponin from plant has
been shown to have hemolytic effect- the unripe fruit has purgative effect which has been observed in horses. The
sapogenins, diosgenin and yamogenin (Figure 2.7) have been found in the bark and seeds/roots of the plant,
respectively. Apart from saponin, the plant also contains tannin, phenols and anthraquinones.

Figure 2.6 : Balanites aegyptiaca (fruits and plant) and dry fruits

Figure 2.7: Structure of diosgenin and yamogenin

Mimusops djave
This is a giant tree of the evergreen forest; the fruit is the size of a fist and is smooth. The pulp has steaky latex
when unripe. When ripe it is mealy, slightly acidic and edible. It contains saponin. The residue after extraction of
the oil from the kernel is known to be poisonous to fowls and animals in general.it is used as fish poisoning. The
seeds are used as ordeal poisoning by some tribes in Cameroon.

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
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 Figure 2.8 : Mimusops djave (plants and fruit)

Cardiac glycosides
As far as the cardiovascular system is concerned, cardiac glycoside-containing plants are important in both lethal
livestock and human poisonings. The cardiac glycosides, which are highly toxic and found in a number of plants,
are usually phytochemicals consisting of an aglycone (structurally related to steroid hormones) linked to one or
more sugar molecules. The aglycones of cardiac glycosides can be divided into two chemical groups, the
cardenolides and bufadienolides (Figure 2.9). They have action like those of digitalis on the heart, its poisoning
they cause arrythmia, bradycardia and cardiac arrest. Cardenolides are classified according to the chemical
composition of their aglycones as lanataglucosides A, B, C, D and E. Only Digitalis lanata, the woolly foxglove
contains all five forms.
The general structure of a cardiac glycoside consists of a steroid molecule attached to a sugar (glycoside) and an
R group. The steroid nucleus consists of four fused rings to which other functional groups such as methyl,
hydroxyl, and aldehyde groups can be attached to influence the overall molecule's biological activity. Cardiac
glycosides also vary in the groups attached at either end of the steroid. Specifically, different sugar groups
attached at the sugar end of the steroid can alter the molecule's solubility and kinetics; however, the lactone moiety
at the R group end only serves a structural function.

Figure 2.9:The general structure of a cardiac glycoside molecule.

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
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In particular, the structure of the ring attached at the R end of the molecule allows it to be classified as either a
cardenolide or bufadienolide. Cardenolides differ from bufadienolides due to the presence of an “enolide,” a five-
membered ring with a single double bond, at the lactone end. Bufadienolides, on the other hand, contain a
“dienolide,” a six-membered ring with two double bonds, at the lactone end. While compounds of both groups
can be used to influence the cardiac output of the heart, cardenolides are more commonly used medicinally,
primarily due to the widespread availability of the plants from which they are derived.
Mechanism of action: the cardiac glycosides have action on heart similar to digitalis. The glycoside toxin attaches
to the -subunit of the Na/K-ATPase pump to inhibit its action (Figure 2.10). Because this pump exchanges
intracellular sodium ions for extracellular potassium ions, inhibition leads to an overall increase in intracellular
sodium ions. Rises in intracellular sodium concentration result in secondary rises in intracellular calcium levels,
explaining the positive inotropic effect of cardiac glycosides. In toxic amounts, the rises in intracellular sodium
and calcium depolarize the cell following repolarization to cause late afterdepolarizations and increased
automaticity typical of cardiac glycoside poisoning. Depolarization of baroreceptors innervated by the ninth
cranial nerve triggers afferent reflexes, which increase vagal tone and produce bradycardia and heart blocks.
Severe poisoning results in hyperkalemia as the ability to pump potassium into the muscle is curtailed. In low
doses, they may have beneficial therapeutic effect like digitalis by increasing the force of contraction, slowing
the heart rate and enhancing cardiac output. But in toxic doses, most cardiac glycosides cause a variety of
arrhythmias and conduction disturbances that results in decreased cardiac output and death. There is also initial
stimulation followed by vagus nerve paralysis. Therefore, cardiac glycosides are very similar to the toxin of
foxglove, thus having positive inotropic, negative chronotropic, and cross reactivity. This includes direct
glycoside poisoning of the sodium-potassium pump of the heart and increased vagotonia.

Figure 2.10: Mechanism of action of cardiac glycosides

Neurotoxicity is also thought to occur as a result of Na/K-ATPase pump inhibition. It has been proposed that this
occurred in both neurons and astrocytes. While this would directly affect impulse transmission of neurons, the
effect on astrocytes might also adversely affect neuronal activity. A major function of the astrocyte is to take up
glutamate and convert it to glutamine, which in turn, is converted to both glutamate and -aminobutyric acid
(GABA). Inhibition of the glutamate transporter GLT-1 would lead to an increase of the excitatory
neurotransmitter, glutamate, and a decrease in the inhibitory GABA. Excitotoxicity would occur, eventually
leading to neuronal and astrocyte death. Evidence also indicates that serotonergic transmission may play a role.

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®
It should be noted that significant interspecies variation occurs in physiological response to cardiac glycosides.
Rodents, for example, tend to be resistant to cardiac effects, while neurotoxicity is more apparent than in humans.
Care should be taken in extrapolating from rodent studies to humans.
Clinical signs: Clinical signs in cardiac glycoside poisoning are almost similar in all species and are related
mainly to the heart and GIT. In peracute toxicity, cattle and less often horses are often found dead because of
profound cardiac effects of the plants. In less severe cases, onset of clinical signs may take few hours after
ingestion of the toxic plant. The affected animal shows signs of weakness with rapid pulse, tachycardia and
arrhythmias. Nausea, vomiting, anorexia, abdominal pain, colic and sweating (horses) may be observed in some
animals. Blood often appears in the faeces at the terminal stages. Other signs include cold extremities, dilated
pupils, muscular weakness, slowed pulse (late stages), ataxia, hypotension, and hypothermia. These are followed
by titanic spasms, drowsiness, unconsciousness, coma and death. Death usually occurs within 24 hours after
clinical signs appear from peripheral circulatory failure.
Morbidity related to cardiac glycosides is made worse by advanced age, renal dysfunction, myocardial ischemia,
hypothyroidism, hypoxia, and electrolyte imbalances, particularly hypokalemia, hyperkalemia, hypomagnesemia,
and hypercalcemia. Plant-specific determinants of morbidity related to cardiac glycoside poisoning include plant
species, part of plant ingested, specific type of glycoside contained, and concentration of glycoside in plant parts
ingested, but mortality is rare
Postmortem findings: PM findings not definitive. There may be severe catarrhal or hemorrhagic gastroenteritis
with congested patches in the stomach and upper portion of the small intestine. Agonal hemorrhages are
commonly seen on the heart and serous and mucous membranes. In less acute but fatal poisoning, multifocal
myocardial degeneration and necrosis is often present.
Diagnosis- History or evidence of plant ingestion, clinical signs and PM lesions. Presence of plant in the stomach
may help in diagnosis. Detection of cardiac glycosides in serum, urine, tissues and stomach or rumen contents
using HPLC may help in diagnosis
Differential diagnosis: Monensin, a feed additive in cattle ration
Treatment and Management: There is no specific treatment for the poisoning, but procedures that are intended
to reduce absorption or improve elimination of the toxin present in digestive tract, such as oral administration of
activated charcoal, can be efficient in the early stages. Tachycardia can be treated by application of the adrenergic
blocking drugs such as propranolol, which can be accompanied by atropine to reverse atrium-ventricular block.
General treatment for poisoning consisting of GIT detoxification followed by administration of activated charcoal
and osmotic diuretic. After they are absorbed into the systemic circulation, cardiac glycosides are secreted into
the gut lumen by the action of P-glycoprotein. The reason for starting multidose-activated charcoal in these
patients is to prevent enterohepatic recycling. In the gut, activated charcoal binds the secreted glycoside and
thereby enhances glycoside excretion and reduces the half-life of the cardenolides. Rumenotomy may be done in
ruminants to remove all traces of the plant from the rumen. Cardiac irregularities may be countered by appropriate
use of antiarrhythmic drugs such as procainamide, and lidocaine. Ventricular tachyarrhythmias may be managed
with lidocaine, and bradyrhythmias may respond to atropine or ventricular pacing. Large doses of Fab-antidigoxin
antibodies correct both rhythm and hyperkalemia in dogs poisoned by oleander. Interestingly, fructose-1, 6-
diphosphate (FDP) is a phosphorylated sugar that has been proven to be effective in treating life-threatening
arrhythmias and reversal of hyperkalemia due to oleander poisoning. It has also been shown to stimulate Na +/K-
-ATPase activity and inhibit potassium efflux from myocardial cells. Other supportive measures should be
instituted while animal is kept away from any form of stress that may impact negatively on the heart.
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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®
Contraindications: IV fluid containing calcium is contraindicated because Ca 2+ augments the toxic effect of
cardiac glycosides. Use of IV fluids should be avoided due to existing hypercalcemia. The role of magnesium is
controversial and it should be avoided. Amiodarone, quinidine, and calcium-channel blockers are contraindicated
because these may increase the concentration of glycosides. Beta blockers are contraindicated because they may
worsen heart block.
Plants containing cardiac glycosides
Adenium obesum (Desert Rose)
Adenium obesum (Figure 2.11) is found in the drier areas and is often grown as ornaments. It is a succulent shrub
and small tree. The plant produces beautiful flowers that are tubular in shape and come in various shades of red,
pink and rose. It also produces follicle-like fruit containing seeds when pollinated. This heat-tolerant plant grows
best in well-drained, sandy or gravelly soil and direct sunlight. Desert rose is a hardy plant and can grow up to
nine feet tall and five feet wide outdoors. It contains the cardiac glycoside adenin, hongeloside G and
hongeloside A. the action is action is analogous to digitations but complicated by an effect on the CNS. The plant
is toxic to ruminants, horses, dogs and cats. Clinical signs of poisoning include vomiting, diarrhea, anorexia,
gastrointestinal pain, depression, irregular heart beat and death from heart failure. The sap can also lead to
blistering and redness of the skin if pup brushes past the plant. The plant is used as arrow and fish poisoning.

Figure 2.11 -Adenium obesum

Strophanthus spp: S. kombei, S. gratus, S. sarmentosus, S. hispidus, S.preussia
They (Figure 2.12) contain cardiac glycoside strophantin, (k-strophantin and g-strophantin~ oubain), (Figure
2.13) which is of therapeutic value. Ouabain is a cardiac glycoside and in lower doses, can be used medically to
treat hypotension and some arrhythmias. They are poisonous when eaten in large quantities. It acts by inhibiting
the Na/K-ATPase. However, adaptations to the alpha-subunit of the Na+/K+-ATPase via amino acid substitutions,
have been observed in certain species, namely some herbivore- insect species, that have resulted in toxin
resistance. Strophantin glycosides are more dangerous than digitalis as they are more rapidly absorbed. All spp
of Strophantus are used as arrow poisons in eastern Africa for both hunting and warfare.

Figure 2.12: Strophantus gratus

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
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Figure 2.13: Chemical structure of strophantin-k and Strophantin-g (Oubain)

Thevetia peruviana (T. nerifolia)

It is native to tropical America (yellow oleander) (Figure 2.14) but grows in various tropical and subtropical areas
around the world, including various parts of Africa, India, and Sri Lanka, where it is widely used as ornaments
for hedges. It contains the cardiac glycoside thevetin (thevetins A and B.) (Figure 2.15) thevetoxin, peruvoside,
cannonigenol, cannogenin, digitoxigenin, neriifolin, acetylneriifolin, thevefolin, and theveneriin. Seed also
contains small quantity of theveside, viridoside and perusitin.

Figure 2.14: Thevetia peruviana leaves, flower and seed.

These cardenolides are not destroyed by drying or heating. All parts of the plants are toxic to humans and animals.
All parts of these plants are toxic (especially the seeds) and contain a variety of cardiac glycosides. The seeds
have been known to poison cattle. Its sap contains cardiac glycosides that are toxic to cardiac muscle and the
autonomic nervous system. The yellow oleander tree contains phytochemicals, known as cardenolides, which are
capable of exerting positive inotropic effects on the heart. The cardiotonic properties of this plant have been used
both therapeutically, as well as in poisoning, since ancient times. Apart from the cardiotoxic effects, nausea,
vomiting diarrhea and convulsion are observed within hours of ingestion. Ingestion of yellow oleander seeds (T.

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®
peruviana) has become a popular method of suicide in Sri Lanka and other countries in Asia. Adult humans have
died after consuming oleander leaves in herbal teas.
Ingestion of seeds causes predominantly cardiovascular effects such as bradycardia, varying degrees of heart
blocks, atrial or ventricular ectopics and ventricular tachyarrhythmias. Hyperkalemia is a life threatening sequalae
which is an indication for treatment with digoxin immune fab [Digibind]. Continuous ECG monitoring is
indicated to detect arrhythmias in patients with severe poisoning
Signs of yellow oleander poisoning in dog may include significant stomach upset to include vomiting and
diarrhea, either with or without blood, depression, anorexia, excessive drooling, hypothermia, weak pulse, a
decrease in gastrointestinal motility, loss of coordination, mydriasis, congested mucus membranes, drowsiness
and weakness, progressive paralysis, cardiovascular dysrhythmias, cold extremities, tremors and death.

Figure 2.14: Chemical structure of Thevetin A and Thevetin B

Nerium oleander
Nerium Oleander (Figure 2.15) is an evergreen shrub reaching four metres in height. Leaves are 10 to 22 cm long
narrow. The plant produces terminal flower heads, usually pink or white, however, 400 cultivars have been bred
and these display a wide variety of different flower colour: deep to pale pink, lilac, carmine, purple, salmon,
apricot, copper, orange. N. oleander is cultivated worldwide as an ornamental plant; it is native only in the
Mediterranean region. It is commonly used as ornamentals for hedges. The primary cause of poisoning is oleander
trimming. Oleander is not readily eaten but poisoning of stocks may result from access to trimmings or when the
plants are accidentally baled with hays/silage. Bored horses may chew on plants close to their paddocks.

Figure 2.15: Nerium oleander

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
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All parts of the plant are toxic and toxicity is retained with drying. The leaves and flowers have the highest
concentrations of toxic cardenolides. As few as 7 average-sized leaves can be lethal to a horse, while as few as
12 leaves can cause death in cattle. N. oleander contains several lethal toxins, neroside, and oleandroside, the
cardiac glycosides nerin, digitoxigenines, folinerines, odorosides, gentiobiosyl, adigosides, oleandrin, olinerin
and oleandrigenin (deglycosylated metabolite of oleandrin), of which oleandrin is the main toxin (Figure 2.16).
The bark contains the toxic substances of rosagenin which causes strychnine-like effects. Several flavones (0.5%)
and volatile oils (unimportant amount), as well as rubber, fats, sugars and hydrocyanic acid, can be isolated from
its leaves.

Figure 2.16: Structure of (a) oleandrin. (b) oleandrigenin.

The leaves and branches from pruning are the most frequent causes of poisoning in animals though they may
graze directly in the plants. Dry leaves are as toxic as the green ones. The plant is a source of danger to children
who like to gather the flowers and may put the flowers or petiole on their mouth. Poisoning has been reported in
humans eating meat grilled with the sticks.
Clinical signs: All species of animals and man are affected. Animals exposed to oleander are often found dead.
If found alive, the animals may have colic, excessive salivation, depression, and anorexia. The poisoning
progresses rapidly as affected animals develop a variety of cardiac signs, including bradycardia and arrhythmias.
At this stage of the disease, the animals may also show tremors and difficulty breathing. Apart from the
cardiotoxic effect, the plant also causes excessive salivation, vomiting, depression, diarrhea, and anorexia. As the
disease progresses, the animal may develop a variety of cardiac signs, including slow and irregular heartbeat. The
electrocardiographic changes related to N. oleander poisoning, including arrhythmias, such as bradycardia,
blockages of first and second grade, premature ventricular complexes, ventricular tachycardia, sinus tachycardia,
and fibrillation have been reported in dogs.
The gastrointestinal tract involvement in ruminants results frequently in abdominal pain, atony and tympanism;
however, diarrhea has been observed in acute accidental oleander poisoning in cattle as well as in other animal
species. It is suggested that such clinical signs are probably due to the direct contact of the oleander toxins with
the mucosa rather than being secondary to nervous or circulatory involvement as reported for humans. Similarly,
the neurological disorders are caused by the direct effect of the toxins, which are able to cross the blood–brain
barrier. However, vascular endothelial damage and acute heart failure are likely to contribute to the central
nervous system impairment.
As oleander contains cardiac glycosides, the heart is the most affected organ. Thus, a meticulous heart auscultation
along with an ECG examination is essential for the diagnosis. Signs observed include 1st degreee atrioventricular
block and other alterations of the cardiac rhythm (i.e., premature ventricular complexes and paroxysmal
ventricular tachycardia with S-T segment slanting) could originate from coronary ischemia and may be
diagnostically indicative of oleander poisoning within a generalized toxicosis. Indeed, it has been reported that in
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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®
experimentally intoxicated goats, the sinus bradycardia and the 2nd degree atrioventricular block usually occur
in the first hours after oleander administration.
Postmortem findings: These include catarrhal or hemorrhagic gastroenteritis and in protracted cases, it causes
dilation of the heart.
Diagnosis: This is based on history, clinical signs, including ECG changes. Diagnosis of oleander poisoning has
improved significantly since the development of several specific analytical methods. Confirmation of the toxic
glycoside oleandrin in biological samples, such as serum, urine and gastrointestinal contents provides invaluable
information to the clinician in directing the clinical course and initiating adequate treatment in confirmed, non-
fatal poisoning cases. Currently available techniques for the detection of Nerium oleander toxic components
include digoxin fluorescence polarization immunoassay, based on the molecular similarities between digoxin and
oleandrin, thin-layer chromatography, high-performance liquid chromatography of the fluorescent derivative, and
LC-MS/MS. However, most analytical methods are not sufficiently sensitive or specific to detect and quantify
oleandrin in biological fluids and tissues. The most recommended method that provides a rapid and unequivocal
determination is LC-MS/MS .
Treatment: Treatment may be successful if it commenced early by veterinarian. The treatment of N. oleander
poisoning is based on the oral or intravenous fluid therapy to reduce the cardiovascular alterations. Calcium-
contained fluids should be avoided because the extra calcium could increase the effect of the cardiac glycosides
on the myocardium. Repeated doses of activated carbon are used to prevent enterohepatic recycling of the toxin.
Antiarrhythmic medications like atropine, atenolol, fentoine, procainamide and lidocaine could be used to control
cardiac alterations. However, the type of arrhythmia should be determined using the electrocardiographic
examination. Blood glucose measurement should be a part of the treatment protocol for a patient intoxicated by
N. oleander. Intravenous insulin with glucose and sodium bicarbonate can be used in life-threatening
hyperkalemia, though the most effective treatment is administration of digoxin-specific Fab.
Digoxin-specific Fab, which is used to treat severe digitalis glycoside poisoning, has been demonstrated to be
effective in the management of oleander poisoning and decreases morbidity and mortality. Digoxin-specific Fab
should be used for patients with significant toxicity characterized by hyperkalemia, symptomatic bradycardia, or
significant ECG changes.
For preventive purposes, animals should be denied access to areas that contain oleander, especially if dried leaves
or clippings are present.

Calotropis procera ('Sodom apple)

As a native plant, C. procera (Figure 2.17) is found in many parts of tropical Africa. This is found abundantly in
the semi arid condition. All parts of the plant are toxic, the stems and roots being more toxic than the leaves. The
milky juice is caustic to the mucus membrane and tender skin, with the horse being quite susceptible. The latex
is said to be toxic in large doses. It retains its toxicity even in solid state for a very long time. Goat and sheep eat
the flowers and withered leaves but not the fresh leaves. It has been suggested that the toxicity of the plants for
animals may depend on biotypes and on the environmental conditions during the plants' growth. It has also been
noted that drying may result in the loss of some of the more toxic components such as flavonoid and cardiotonic
glycosides of the plant material. Additionally, there have been recent efforts to find safe limits to include the
plants in hay and silage as an alternative feed in arid and semi-arid regions. The juice has been reportedly used in
Sudan as an infanticide.

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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®
Figure 2.17: Calotropis procera
The plant has so many trado-medical and economic uses. In India the latex is used as a drastic pudge and emetic,
latex has been used to procure abortion by internal and local applications. in Africa, arrow poisons have been
derived from the plants. The root is especially poisonous to the extent that snakes cannot withstand its smell,
hence the plant is used to ward off snake. The toxic component of the plant include uscharin, calotoxin,
calotropin, calactin, calotropage, proceragenin and 2”-oxovoruscharin. Calotropin (Figure 2.18), like calactin,
calotoxin, and uscharin are derived from calotropogenin

Figure 2.18: Structure of calotropin

Clinical signs: Toxicity of C. procera is reported in sheep in the form of diarrhea and anorexia. Consumption of
this plant leads to severe poisoning to livestock as well as man. Experimental administration of C. procera leaves
revealed tachycardia and transitory cardiac arrhythmias at auscultation 4 h after dosing.
In humans, the plant is known for its toxic properties that include iridocyclites, keratitis and dermatitis, and acts
like a poison to produce lethal effects. Indeed, there have been many case reports of cutaneous and ocular toxicity
with calotropis. Ocular toxicity due to calotropis is thought to be due to the direct acid injury in the early stages
and toxin mediated ocular injury in later stages.
When the calotropis extract is taken for deliberate self-harm patents presented with stomatitis, epigastric burning,
abdominal pain, vomiting, salivation, tetanic convulsions, collapse and death. In humans estimated fatal period is
within 30 min up to 8 h. Attempt to use the leave to treat snake envenomation resulted in almost fatal poisoning
from cardiac failure.
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Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®
Postmortem findings: Exposure to sheep and goat as revealed at necropsy mild ascites, exudates on the trachea,
pulmonary edema, hemorrhage in the liver, hepatic and renal tubular necrosis, hydropericardium, flaccid heart,
ulcers on the omasum and kidneys presenting a pale juxtamedullary cortex.
Diagnosis: Based on history, clinical signs, toxicological anlysis of the serum and rumen for the toxic principles
Treatment: Treatment should be based on clinical signs. Antiarrhythmic agents to counter cardiac arrhthymia,
demulcent for hemorrhagic gastroenteritis. Treatment of injury to the eyes should include water flushing of the
eyes

15
Veterinary Toxicology (VPP 404) Lecture Notes Prepared by Prof. S.F. Ambali©, Dept. of Veterinary Pharmacology and
Toxicology, University of Ilorin, Ilorin: [email protected]; [email protected] 2021®