Ionophores are a group of antibiotics produced by the fermentation of fungi ( mainly Streptomyces spp.).
They are used as growth promotants, coccidiostats and as feed additives or slow release bullets (Rumensin®). Ionophores licensed for use in New Zealand include lasalocid, monensin, narasin and salinomycin. The source of poisoning may be from contaminated feed, accidental feeding of ionophore containing calf pellets to horses or dogs mouthing or chewing Rumensin® bullets. Monensin toxicity and death in calves and deer have been reported on several occasions, where monensin has been used as a coccidiostat mixed with feed meal.
Table 54 Acute LD50 for selected ionophores
| Monensin | Lasalocid | Salinomycin | |
|---|---|---|---|
| Horses | 1-2 mg/kg | 21.5 mg/kg | 0.6 mg/kg |
| Sheep | 12 mg/kg | ||
| Swine | 17 mg/kg | ||
| Dog | 20 mg/kg | ||
|
Cattle |
20-80 mg/kg | ||
| Goat | 26 mg/kg | ||
| Chicken | >200 mg/kg | 71.5 mg/kg |
The single oral doses that have been shown to be toxic for lasalocid (not LD50) are 100-125 mg/kg in cattle, 12 mg/kg in sheep, 58 mg/kg in swine, 58 mg/kg in a donkey and 20-30 mg/kg in dogs.
The toxicity of ionophores varies from species to species. Sex differences have been reported for monensin toxicity in rats and dogs where females are more susceptible than males. Dogs and horses are at risk in a small percentage of cases from the pick up of regurgitated capsules before payout is complete. The accidental feeding of cattle feeds containing ionophores and the accidental inclusion of ionophores in horse feeds have been the source of poisoning in horses. Overseas dogs and cats have been poisoned by foods contaminated with salinomycin and lasalocid. Ostriches have been reported to be poisoned by monensin.
Tiamulin prevents the metabolism of monensin, so that pigs which are fed both may get monensin poisoning. This has also been reported for feedlot cattle in the USA.
The antibloat capsules Rumensin and monensin medicated feeds are especially dangerous to dogs because of their inquisitive nature. Horses fed ionophore medicated feeds with as little as 100 ppm of monensin will develop ionophore toxicity.
In mammals the ionophores are molecules that are capable of binding ions; monensin preferentially binds monovalent cations preferring Na+ to K+ or Ca+2. This produces a higher cellular concentration of Na+, loss of K+ and intracellular alkalosis. Lasalocid forms complexes with divalent cations such as Ca+2 and Mg+2 and primary amines e.g. catecholamines. Salinomycin and narasin chelate K+ over Na+ and produces a transient acidosis.
Ionophores interact with the carrier mechanism that regulates potassium transport across mitochondrial membranes, inhibiting ATP hydrolysis and diminishing cellular energy production (see Figure 10). Electron micrographs have confirmed that monensin causes severe mitochondrial damage. Ionophores may alter calcium transport by changing the sodium component of the sodium-calcium exchange diffusion carrier in the cell membrane, leading to the accumulation of calcium in the cell and mitochondria and possibly causing cell death.
Ionophores cause an imbalance in the ion flux across bacterial and protozoal cell membranes, leading to osmotic rupture or intracellular hydrogen ion accumulation and fatal acidification. At the recommended dose ionophores are non toxic to target animals because the extent of gastrointestinal absorption and first pass liver metabolism limit the concentration reaching the general circulation, however overdosing or use in immature ruminants may result in toxicity.
Ionophores are molecules that are capable of binding ions and transporting them through cell membranes. Monensin preferentially binds monovalent cations preferring Na+ to K+ or Ca+2. This produces a higher cellular concentration of Na+, loss of K+ and H+ leading to intracellular alkalosis. Lasalocid forms complexes with divalent cations such as Ca+2 and Mg+2 and primary amines e.g. catecholamines. Salinomycin and narasin prefer K+ to Na+ and produce a transient acidosis.
Cation influx causes depolarisation of muscle cells which leads to increased intracellular Ca+2 concentration. If sustained, this damages various intracellurar organelles including mitochondria and the Golgi apparatus.
Ionophores cause an imbalance in the ion flux across bacterial and protozoal cell membranes, leading to osmotic rupture or intracellular hydrogen ion accumulation and fatal acidification. At the recommended dose ionophores are non toxic to target animals because the extent of gastrointestinal absorption and first pass liver metabolism limit the concentration reaching the general circulation, however overdosing or use in immature ruminants may result in toxicity.
Ionophores potentiate other toxins which disrupt normal ion movement across cell membranes, such as ricin from castor oil plants.
Dogs usually present showing anorexia and muscle weakness with ataxia. The toxicity causes a progressive, bilaterally symmetrical, ascending muscle weakness, which progresses from the hind to forelimbs followed by quadriplegia, hyporeflexia and hypotonia. If the respiratory muscles are affected than dyspnoea and apnoea may be present. The mental status and cranial nerve function tend to remain normal. Pain perception is maintained and the dog will still be able to wag its tail. Diarrhoea may occur. Myoglobinuria, polycythaemia and increased activity of creatinine kinase and lactate dehydrogenase have been reported in ionophore toxicity. Death may be delayed until 7 - 14 days after ingestion.
Ostriches were accidently fed a ration which contained 215 to 224 ppm monensin for 13 days. The initial clinical signs were muscle weakness and ataxia which progressed to recumbency, dyspnoea and death, despite intensive supportive therapy.
The initial signs of toxicity are anorexia, uneasiness, profuse intermittent sweating with or without a fever. Polyuria may occur soon after poisoning but it may be followed by a terminal oliguria.
In the intermediate phase of poisoning the horse develops a progressive ataxia (12 - 36 hours after ingestion) followed by colic, stiffness, posterior paresis with intermittent recumbency then standing as the condition worsens.
The advanced clinical signs include tachycardia, hypotension, hyperventilation and dyspnoea. These indicate impending death.
The clinical signs of acute toxicity are anorexia (24 36 hours post ingestion), depression, weakness, ataxia, dyspnoea and diarrhoea. Sometimes the animal appears to recover only to develop myocardial failure and death especially if the animals are forced to move or are heat stressed.
Dogs ingesting an acutely toxic dose will die with no or few clinical signs or postmortem changes. When death in dogs is delayed (7 - 14 days post ingestion) the cadaver may show the following features:
In delayed deaths there is severe skeletal muscle degeneration and necrosis. The muscles with the highest activity (cardiac, skeletal and diaphragm) are generally worst affected. In dogs, unlike horses, the target muscle is skeletal and not cardiac.
It is possible for animals surviving an acute ionophore dose to develop signs of congestive heart failure. This is especially true of the horse.
In cattle findings may include hydrothorax, ascites, pulmonary oedema and a mild rumenitis. Histological findings include multifocal areas of myocyte necrosis in the heart. Cattle dying within 3 days of overdose may have a marked degranulation of pancreatic acinar cells. In subacute poisoning there is reduced cardiac function and congestive heart failure.
In ostriches the serum activity of the enzymes creatine kinase, aspartate aminotransferase and lactate dehydrogenase was high in the affected birds, indicating significant muscle pathology. Few gross lesions were identifiable postmortem, but widespread lesions of degenerative myopathy were present at the histopathological level. However, these degenerative changes were restricted to the skeletal muscle and there was no evidence of cardiomyopathy in any of the birds examined.
Clinical pathology results need to be interpreted with caution. There are usually very high creatine phosphokinase (CPK) and aspartate animo transferase (AST) levels in dogs with the delayed syndrome. Such clinical biochemistry may be suggestive of ionophore toxicity, but is not pathognomonic and other causes of muscle degeneration need to be eliminated.
In general ionophores may cause an increase in serum alkaline phosphatase (AP), bilirubin after 24 hours, blood urea nitrogen (but may return to normal), haemocrit, creatine kinase levels and aspartate transaminase (AST). Lactate dehydrogenase (LDH) is increased for 36 hours. Serum creatinine is elevated at 24 - 36 hours, but may return to normal. Serum calcium decreases for 12 - 18 hours and potassium decreases after 24 hours.
The diagnosis depends on history, clinical and pathological findings and feed analysis. Feed analysis is used to establish a diagnosis as tissue analysis is difficult to perform and interpret.
In recent ingestions decontamination with activated charcoal and sorbitol (saline cathartic) is recommended. Supportive treatment should include balanced fluid and electrolyte replacement to correct changes in the haematocrit, serum potassium and calcium.
Vitamin E and selenium has been shown to have a protective effect against muscle damage but must be given as soon as possible after ingestion to be of benefit.
Agnew, K. (1996): Ionophore poisoning in dogs. Vetscript. lX No.11 4-5.
Anon, (2001): Monensin: one animal’s additive, another’s poison. NZVA Companion Animal Society Newsletter 12(4) 22-23.
Baird, G.J, Caldow, G.L. Peek, I.S. and Grant D.A. (1997). Monensin toxicity in a flock of ostriches. Veterinary Record. 140(24):624-626.
Boemo, C.M. et al (1991). Monensin toxicity in horses: An outbreak resulting in the deaths of ten horses. Australian Equine Veterinarian Vol.9 No.3 pp 103-106.
Novilla, M.N. (1992). The veterinary importance of the toxic syndrome induced by ionophores. Veterinary and Human Toxicology 34(1):66-70.
Osweiler, G.D. (1996). In Toxicology. Williams and Wilkins Publishers. Pennsylvania.
Segev, G.; Baneth, G.; Levitin, B.; Shlosberg, A.; Aroch, I. (2004) Accidental poisoning of 17 dogs with lasalocid. Veterinary Record 155 (6) : 174-176
Surveillance (2001) 28(2):19 Monensin poisoning in cattle
Surveillance (2003) 30(1):21 Monensin poisoning in calves
Surveillance (2003) 30(3):30 Monensin poisoning in deer
Surveillance (2004) 31(1):21 Ionophore toxicity in calves (Monensin)
Surveillance (2004) 31(1):23 Ionophore toxicity in alpacas
Surveillance (2005) 32(4):16 Monensin toxicity in cattle