Vitamin A toxicity

Vitamin A is necessary for the health of normal skin and periocular tissue. Chelonians (turtles and tortoises) are particularly sensitive to vitamin A deficiency. Turtles with hypovitaminosis typically show ocular discharge, palpebral edema and blindness, hyperkeratosis of skin and mouth parts, and aural abscesses. Patients can improve with vitamin A supplementation (2000 IU/kg q 7 days) and improved dietary management.¹

Excessive iatrogenic administration of vitamin A can cause a separate set of problems. Hypervitaminosis A can cause inappetence, full-thickness skin sloughing, secondary bacterial infection, discoloration of the skin, and extreme lethargy. Generally this occurs at doses of 10,000 IU/kg or higher given IM as a single injection. Treatment involves ceasing vitamin A administration, antibiotics, fluid therapy, wound management, and nutritional support. Skin lesions may heal slowly, but animals managed supportively can recover completely.

Vitamin D toxicity

Excesses of water-soluble vitamins can be excreted into the urine. This makes their margin of safety very large. For fat-soluble vitamins, such as vitamin A and vitamin D, this is not the case. Owners, breeders, and veterinarians often oversupplement captive reptiles with disastrous results. Doses of 50 to 1000 times the minimum daily requirement are often given for weeks to months. This can be insidious, particularly when the minimum daily requirement of most vertebrates for vitamin D is only 10 to 20 IU/kg body weight.²

The mechanism of action of the toxicity of vitamin D is related to the hypercalcemia it induces. This prolonged hypercalcemia causes dystrophic calcification of the gastrointestinal tissue, the kidneys, lungs, heart, blood vessels, and joints.³ Complete removal of vitamin D–containing supplements and cortisone may help control hypercalcemia, but resolution of soft-tissue calcification may not be successful.

In light of the inherent calcium problems of captive reptiles, it is incumbent on veterinarians to counsel clients about proper husbandry, nutrition, and dietary requirements and to ensure that no supplements are given to animals without veterinary approval.

Antimicrobial toxicity

Selection of antibiotics should be made judiciously. Selection depends on experience of the clinician, empirical considerations, the type of infection present based on culture and sensitivity and Gram stains, and, last but not least, the size, age, species, and condition of the reptilian patient. There is no antibiotic that can be relied upon to be effective for all situations. In addition, antibiotics are no substitute for good wound management, nursing care, nutrition, or husbandry.

Metronidazole

Metronidazole is used as an antibacterial, an antiprotozoal, an antiparasitic, and an appetite stimulant in reptiles. It is formulated as a suspension, as an injectable, and as tablets.

The activity of metronidazole is specific for anaerobic bacteria and protozoa. It is specific, particularly for Giardia organisms. Metronidazole disrupts DNA in target microbes through reaction with intracellular metabolites.¹⁰

The most severe side effect of metronidazole is dose-related central nervous system (CNS) toxicity. High doses can cause ataxia, inability to walk, nystagmus, opisthotonos, tremors of the lumbar muscles and hindlimbs, seizures, and death.^11,12 Treatment is symptomatic and supportive.

Metronidazole has been recommended for a variety of conditions in reptiles. Particular care must be given when this drug is used regarding dose, duration, and size of the animal.

Antifungal toxicity

A variety of fungal infections have been documented in reptiles. Ranging from dermatophytes to systemic mycotic infections, these conditions are treated with a variety of antifungal medications. Often caused by the small size of the reptilian patient, the mechanism of action of these drugs, and idiosyncrasies of reptilian physiology, treatment with antifungals can lead to serious intoxications.

Organophosphates and carbamates

Organophosphates are the most commonly used insecticide worldwide. In the United States alone, 250 million pounds of organophosphates are used annually at a cost of $2.4 billion to produce.²⁰ They are found in agriculture, in the home, and on or around various domestic animals. Some organophosphates are meant to stay on surfaces to which they are applied, and others are absorbed and become systemic in animals. They are the active ingredients in a long list of products. For animal use as insecticides, they are formulated as dips, sprays, topical medications, systemic parasitic agents, and flea collars. This group of insecticides includes chlorpyrifos (Dursban), dichlorvos, diazinon, cythioate (Proban), fenthion (ProSpot), malathion, ronnel, parathion, metrifonate, and vapona. Their cousins, the carbamates, include aldicarb, carbaryl (Sevin), bendiocarb, methiocarb, propoxur, and carbofuran. As newer, safer insecticides are marketed, these two groups are involved in fewer accidental poisonings, but still account for a large number of intoxications.

Organophosphates and carbamates interfere with metabolism and breakdown of acetylcholine at synaptic junctions.²¹ Acetylcholinesterase is the enzyme responsible for breaking down the neurotransmitter at these sites. Acetylcholinesterase is inhibited by organophosphates and carbamates at these cholinergic sites. As a result, acetylcholine accumulates at the synapses, which at first excites and then paralyzes transmission in these synapses, giving it the characteristic “nerve gas” signs associated with organophosphate toxicity.²² This inhibition of the synapse is irreversible with organophosphates and reversible with carbamates. Organophosphates are readily absorbed by all routes: dermal, respiratory, gastrointestinal, and conjunctival. Overdose with organophosphates may happen more readily if given together with imidothiazoles, such as levamisole.

Clinical signs seen in reptiles include salivation, ataxia, muscle fasciculations, inability to right themselves, coma, and respiratory arrest. Death results from massive respiratory secretions, bronchiolar constriction, and effects upon respiratory centers in the medulla leading to the cessation of breathing.

Animals with dermal exposure should be washed with a mild dishwashing detergent and copious amounts of water. Animals should be dried after rinsing to prevent further uptake of the insecticide. The need for fluid therapy to counter dehydration and electrolyte imbalances should be considered. The specific physiological antidote, the muscarinic antagonist atropine, should be given (0.4 mg/kg intramuscular [IM]). This should help with salivation, bronchospasm, and dyspnea. Diazepam may be given as needed for seizures. Use of antihistamines to treat insecticide poisonings is controversial and most likely not that effective. Prognosis is dependent upon dose, duration of exposure, and size of the animal. Therapies both more effective and safer than organophosphates and carbamates exist for treatment of parasites in captive reptiles. These therapeutic regimens are outlined in detail elsewhere in various sources dealing with reptilian parasitology.

Pyrethrins and pyrethroids

Pyrethrin is the oldest used botanical insecticide. It is made from the dried and ground flowers of Chrysanthemum cinerariifolium. Pyrethroids are synthetic derivatives of pyrethrin and are widely available. Pyrethroid insecticides have enhanced stability, potency, and half-life compared with the parent molecule. A variety of dilute pyrethrin- and pyrethroid-containing sprays have been recommended for reptiles.

The mechanism of action of both pyrethrins and pyrethroids is the same. These molecules affect parasites by altering the activity of the sodium ion channels of nerves. These poisons prolong the period of sodium conductance and increase the length of the depolarizing action potential.²³ This results in repetitive nerve firing and death. With the right conditions or at higher doses, these compounds can intoxicate host animals. Because of the potential for transcutaneous absorption, pyrethrin and pyrethroid sprays must be thoroughly rinsed from the animal immediately after their application. Rinsing with lukewarm water is usually sufficient.

Like ivermectin, organophosphates, and carbamates, pyrethrins and pyrethroids should never be given concurrently with cholinesterase-inhibiting compounds.

Clinical signs have been reported for pyrethrins and pyrethroids, particularly if sprays used also contain insect growth regulators (e.g., methoprene). Signs can develop in animals within 15 minutes of application. Signs include salivation, ataxia, inability to right themselves, and muscle fasciculations.²⁴ Idiosyncratic reactions to pyrethrins can happen at much lower doses than expected. A small percentage of animals appear to be extremely sensitive to pyrethrins and pyrethroids.

If caught early enough, treatment for pyrethrin and pyrethroid toxicity involves dermal decontamination (bathing in copious amounts of water), isotonic fluids, and diazepam for seizures. Care must be taken to keep pyrethrin and pyrethroid sprays away from the reptile’s eyes and mouth to prevent intoxication. Prognosis depends on the strength of the agent used, the duration of the exposure, and the size of the animal involved. Animals do best that are treated early.

A variety of pyrethrins and pyrethroids have been recommended for use against reptile parasites. If used prudently, they are both safe and effective. Animals are sometimes saturated with the spray. As soon as the parasiticide is applied, it should be rinsed off. Gently running lukewarm tap water should be used to wash off the insecticide. This very brief exposure is enough to kill the parasites. Pyrethrin and pyrethroid sprays should not be left on so as to prevent absorption and systemic toxicity in host animals. In smaller animals that have larger surface-to-volume ratios, most sprays should be diluted to the smallest effective dose to prevent accidental intoxication from transcutaneous absorption.

Ivermectin

Ivermectin is an antiparasitic from a family of chemicals called avermectins. These are macrocyclic lactones made from the fermentation broth of the fungus Streptomyces avermitilis.²⁵ The macrolide ivermectin is available as an injectable, a spray, and an oral formulation. It has activity against a variety of parasites including nematodes, arthropods, and arachnids.

Avermectins work by potentiating the effects of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). They stimulate release of GABA by presynaptic sites and increase GABA binding to postsynaptic receptors. This causes neuromuscular blockage. Avermectins also open chloride channels in membranes of the nervous system and further depress neuronal function. These actions cause paralysis and death of susceptible parasites. Ivermectin is absorbed systemically by host tissue. When parasites bite the host they then absorb the ivermectin. Ivermectin is active against intestinal parasites, mites, microfilaria, and developing larva. Concurrent treatment with diazepam, which also works through GABA potentiation, may heighten deleterious effects.

Ivermectin can cause depression, paralysis, coma, and death in chelonians.²⁶ Species susceptible to ivermectin toxicosis may have a blood-brain barrier more permeable than in nonsensitive species. This greater permeability may be due to p-glycoprotein mutation in membranes of the CNS. Another theory postulates the existence of a specific protein receptor only present in the brains of ivermectin-sensitive species. This has not yet been demonstrated. Ivermectin toxicity has also been reported in several species of lizards and snakes.²⁷ Ball pythons (Python regius) in particular may show mild neurological signs when treated. As a result if there is any question regarding safety, it may be more prudent to use ivermectin only as a topical.

There is no known antidote or physiological antagonist for ivermectin. Treatment is supportive and should include decontaminating any topical sprays with soap and water, providing fluid therapy, nutritional support, monitoring electrolytes, and respiratory support. Recovery may take days to weeks. One debilitated tortoise recovered fully after 6 weeks. We have seen two box turtles completely recover in 4 weeks.

Ivermectin, and similarly related compounds, should never be given to chelonians, pregnant animals, or neonatal individuals. Also, for particularly tiny species, other therapies should be investigated. If there is any question, use it only as a topical or find an alternative.

Fenbendazole

Fenbendazole is a benzimidazole type of antiparasitic drug.²⁸ It is safe and effective against many helminth parasites in animals. Fenbendazole inhibits glucose uptake in the parasites. Because of its wide range of activity, its high degree of efficacy, and its broad margin of safety, this anthelmintic is frequently prescribed by veterinarians. Fenbendazole has a good margin of safety and has been reported to be well tolerated, even at six times recommended dose and three times recommended duration. It has been extensively used as an anthelmintic therapy in reptiles at a dosage of 50 to 100 mg/kg PO once (repeated in 2 weeks) or 50 mg/kg PO q 24 hours for 3 to 5 days.^30,31

Toxic effects have been reported in birds, rats, cats, and dogs.^32–36 Recently, evidence of fenbendazole overdose has been reported in individuals of a small snake species given an exceedingly large dose of the drug. Four adult Fea’s vipers (Azemiops feae) died after being administered single doses of fenbendazole ranging from 428 mg/kg to 1064 mg/kg.²⁹ Necropsy findings were suggestive of intestinal changes consistent with fenbendazole toxicity. Fenbendazole is regarded as a safe anthelmintic drug at recommended therapeutic doses.

Chlorhexidine toxicity

Soaking living animals in any solution can be potentially life threatening. Recently, turtles soaked for 1 hour in chlorhexidine scrub were shown to become intoxicated.³⁷ Cutaneous absorption of the solution and possible oral ingestion of these soaks have been postulated as the cause of the problem. Before using any substances as a soak, review the literature for preferred usage, dose, and duration of the soak. Affected animals should be removed from the soak, rinsed, and supported with warmth and fluids. Remember to never leave any reptile unattended in a bath. Animals can drown much faster than anticipated. Also, particular attention must be paid to the depth of fluids reptiles are bathed and soaked in.

Bleach

Various hypochlorite bleach solutions can be found in most households. Typically, these are 3% to 6% hypochlorite solutions in water.³⁸ Bleaches are moderately irritating. If contact with skin is prolonged, the damage is worsened. Bleaches can be very effective in treating cage parasites of reptiles, but should never be applied to live animals. Bleach can cause alkali burns if splashed in the eyes of lizards and turtles. Immediate irrigation of the eye with copious amounts of water minimizes the damage done by the bleach. Skin exposed to bleach should be washed with a mild soap and lukewarm water. Animals should be kept out of recently bleached cages a minimum of 24 hours to prevent respiratory tract irritation. Cages should be allowed to air out, and residual disinfectant removed by wiping with a clean cloth or towel.