Selected Plant Toxicities of the Southwestern U. S.
ACVIM 2008
Edward D. Voss DVM, DACVIM
Gilbert, AZ, USA

"Jimmyweed" (Isocoma wrightii) aka Rayless Goldenrod

Despite being ubiquitous in Arizona, New Mexico and Texas, this plant is an infrequent source of intoxication in the equine, likely due to its unpalatable nature. This two to four foot high deciduous shrub can be readily found along highways, arid pasture ground, river valleys, drainages and surrounding paddocks in rural regions. Rayless goldenrod contains tremetol, like the eastern and mid-western "White Snakeroot" (Eupatorium rugosum), as its toxic component and signs observed in poisoned horses are similar between the two plants. Both green and dry plant material are toxic and it is thought that consumption of approximately 1.5% body weight (acutely or cumulatively) of Jimmyweed will predictably produce clinical signs and possibly death. Tremetol itself is considered a "higher alcohol" or more accurately an impure extraction mixture of three ketones and a sterol. Of the three ketones (tremetone, dihydrotremetone, and hydroxytremetone), tremetone is thought to be the main toxic moiety. However, microsomal activation (esp. via cytochrome p-450) is required to create toxic metabolites from tremetone as the ketones themselves are not directly toxic. Clinical signs of muscle fasciculations, weakness, obtunded attitude, stiffness, reluctance to move, profuse sweating, labored respirations, dark (coffee colored) urine, jugular pulsation, edema and mydriasis are often observed. Clinicopathological findings include elevations in CPK, AST, LDH, ALP, myoglobinuria, proteinuria, glucosuria, metabolic acidosis, and hyperglycemia. Congestive heart failure may ensue. Findings on necropsy often reveal renal tubular degeneration/necrosis, colitis, pulmonary congestion, hepatopathy, pericarditis, myocardial degeneration/necrosis, epicardial and skeletal muscle degeneration. Diagnosis is often presumptive based on clinical signs, exposure to Isocoma, clinicopathologic data and treatment is supportive. Horses can apparently fully recover from poisoning in some cases.

Pyrrolizidine Alkaloids (Amsinckia intermedia Aka Fiddleneck, Senecio longilobus aka Threadleaf Groundsel)

Both Amsinckia int. and Senecio long. are common weeds in the Southwest responsible for intermittent poisoning of horses. Fiddleneck can often be found in grass hays and around irrigated pasture ground whereas threadleaf groundsel frequents early cuttings of alfalfa hay as well as more arid surroundings. Consumption of between 2 and 5 % body weight of these plants is associated with clinical intoxication and the ingestion can be acute or cumulative. Pyrrolizidine alkaloid content of various plants varies and there are many alkaloids that are specific to each species of plant but all alkaloids are thought to be metabolized to toxic pyrrolic derivatives by the hepatic mixed oxidase system requiring cytochrome p-450, NADPH, and oxygen. These dehydro-pyrrolizidine metabolites are highly reactive alkylating agents and they react within the tissue where they are created--usually the hepatocyte. Zonal hemorrhagic necrosis in the liver lobule can occur within 12-48 hours after ingestion. The localization of inflammation in the subintima of central and/or lobular veins can lead to their occlusion which precipitates collapse of the reticulin framework in the central zone of the liver lobule. Necrosis ensues followed by fibrosis/scarring. Repeated dosings contribute to further scarring and megalocytosis, a result of the pyrrollic ester metabolite's inactivation of proteins and binding to nucleic acid crosslinks preventing normal mitosis. Eventually, the hepatic fibrosis and megalocytosis lead to biliary stasis and elevation of GGT and ALP. AST, SDH, ALT and LDH also become increased with hepatocellular damage. Liver biopsy findings are fairly characteristic with periportal fibrosis, biliary hyperplasia, and megalocytosis, Diagnosis hinges on clinical signs, liver biopsy, and exposure to plant. Measurement of pyrrolizidine alkaloids in plant material is readily accomplished via thin layer chromatography, high performance liquid chromatography, gas chromatography, mass spectrometry, nuclear magnetic resonance or Ehrlich reaction but the alkaloids are metabolized so rapidly in the animal that within hours of ingestion, no readily detectable pyrrolizidine alkaloids are present. Progressive hepatopathy is expected and there is no specific therapy.

Oleander (Nerium oleander, Thevetia peruviana)

Oleander is a member of the Apocynaceae (Dogbane family). Other members of this family include the Azaleas, Laurels, Lily of the Valley, Milkweeds, Japanese pieris, foxglove, etc. Named after the Greek "neros" for humidity, it grows well in many parts of the world and is common in the desert Southwest. All parts of this plant are toxic (bark, leaves, roots) and honey made from its flowers or smoke from burning its components are dangerous. Oleander contains cardiac glycosides which are sugars (glyco) attached to a non-sugar "side" which is usually a steroid + lactone ring (genin or glycone). Oleander has been utilized since antiquity as an abortifacient, therapy for leprosy, ringworm, malaria, indigestion, hangovers, venereal disease, and as a method for suicide to name a few. Oleander contains a large number (> 5) of cardiac glycosides (oleandrin, oleandroside, nerin, folinerin, nerifolin, ruvoside, etc.) within the same plant. Seeds and roots contain the highest total glycoside content but the leaves contain the highest oleandrin glycoside. Cardiac glycosides exert activity by inhibiting the Na/K/ATPase pump in the membranes of cells. By reducing the sodium ions that are actively transported out of the cell, intracellular calcium is allowed to accumulate, be stored in the sarcoplasmic reticulum, and prolongation of phases 4 and 0 of the cardiac action potential ensues. Poisoning often leads to variable cardiac arrhythmias (1st, 2nd and 3rd degree AV block, junctional escape beats, ventricular escape and premature beats, etc.), colic, anxiety, mydriasis (less common), toxemia, diarrhea, muscle fasciculations, sweating, obtunded behavior and weakness. Horses often appear lethargic, anorexic and moderately endotoxemic without cardiac arrhythmias in sublethal natural intoxication. Clinical signs often worsen over 24 to 48 hours as cardiac glycosides are excreted in bile and reabsorbed via the enterohepatic route. This tends to concentrate circulating toxin and worsen the clinical picture over this time frame. The toxic dose of Oleander is approximately 30 mg/kg of the green leaf however, fresh material contains saponins that are irritating to mucosa and are rarely ingested voluntarily. Dried leaves are seemingly more palatable and toxicity is not diminished by drying. Additionally, wind can push dried material a fairly long distance away from the primary source into paddocks where oleander is not typically present. Diagnosis hinges on clinical signs, exposure potential (may be misleading), clinicopathologic data and identification of the toxin in feces, GI contents, urine or blood via thin layer chromatography, HPLC, mass spectrometry or radioimmunoassay (digitalis). In the author's experience, a fractional sodium excretion of much greater than 1 % is typical and suggestive of oleander poisoned horses, likely a result of disrupted renal sodium homeostasis. Typical clinicopathologic findings are increased CPK, AST, hyperglycemia, leukopenia, metabolic acidosis, mild to moderate azotemia, and less frequently hyperkalemia, hyponatremia or calcium aberrations. Therapy is largely supportive however, repeat dosages of activated charcoal (1 lb. q 12 hours) is likely useful. Specific Fab (DigibindTM) cross reacts with oleander glycosides at approximately 100:1 and allows for excretion of the Fab/glycoside in urine. Restoration of the N-K-ATPase activity via 1,6 fructose diphosphate may be useful but has not been evaluated in the equine to my knowledge. Steroids such as spironolactone or pregnenolone 16α carbonitrile may decrease toxicity by increasing bile secretion whereas cholestyramine or colestipol hydrophilic resins bind bile acids in GI tract. Neither of these has been evaluated in the horse. ECG monitoring and addressing specific arrhythmias as they arise is prudent due to the progressive and variable nature of arrhythmias with this intoxication. Atropine is not typically indicated as bradycardia is infrequent in natural oleander exposure.

References

1.  Barr AC, Reagor JC. Toxic Plants: What the Practitioner Needs to Know. The Veterinary Clinics of North America, Dec. 2001, 17:3.

2.  Markov AK, et al. Fructose 1,6 diphosphate in the treatment of oleander toxicity in dogs.

3.  Dasgupta A, et al. Stability of oleander extract and oleandrin in sera stored in plastic serum separator tubes. Ann Clin Biochem. 2007 Sep;44(Pt 5):485-7.

4.  Dasgupta A, et al Rapid detection of oleander poisoning using digoxin immunoassays: comparison of five assays. Therapeutic Drug Monitoring 2004 Dec;26(6):658-63.

Speaker Information
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Edward Voss, DVM, DACVIM
Chandler, AZ


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