More than two thousand prescriptions, over the counter medications and vaccines with labelled indications for veterinary patients exist. A number of those products pose a health hazard to humans.

Several veterinary medicinal products (VMPs) have potential human health hazards upon accidental or intentional exposure or ingestion in humans. Moreover, animal production medicines are often not stored or disposed of safely.

Some VMPs are common in a small animal practice (such as ketamine, misoprostol and pimobendan), some are common in production animal medicine (such as clenbuterol, cloprostenol, tilmicosin and testosterone/estradiol), and some are exclusive to exotic and wildlife practices (such as carfentanil).

Those hazards range from mild to life-threatening in terms of severity, and include bronchospasm, CNS depressants, cardiovascular abnormalities, induction of miscarriage, and sudden death. Many veterinarians are unfamiliar with the human hazards those medications may pose, both to themselves and to others.

It is important to physicians – especially those practising in rural areas where pergolide use may be more prevalent – to understand the clinical effects and management of toxicity. Those exposed to human health hazards by VMPs include owners, farmers, handlers, carers, veterinarians and veterinary nurses, and sometimes people can have adverse events after giving a medicine to an animal or after accidentally touching or taking an animal medicine. Personnel administering VMPs or adjuvants (such as mineral oil used in some vaccines to enhance cellular immune response) to livestock represents a substantial cohort of individuals at risk of harm during, and in the immediate time following, exposure.

A need exists for increased awareness of the potential hazards of veterinary medications for humans. Our profession is to care for our animal patients, but at the same time, you have got to protect human health.

Accidental ingestion of pergolide mesylate-based (methanesulfonate ester) products for horses has demonstrated significant human toxicity at doses used in horses. The VMD (2023) drew attention to human adverse events regarding accidental ingestion of one particular brand of pergolide tablets, while the French Agency for Veterinary Medicinal Products also reported 37 cases of adverse events in humans after accidental exposure since 2012, the date of its marketing. These pergolide tablets are the second-most common VMP, immediately following external antiparasitics, involved in cases of human accidental exposure.

Use of pergolide

Pergolide is a diamine, semi-synthetic ergot alkaloid derivative and potent, long-acting dopamine agonist (half-life of about 21 hours in humans), used extensively to manage pituitary pars intermedia dysfunction (PPID), also known as equine Cushing’s disease, in older horses (15 years or older) and ponies (which are more affected). It is estimated that between 20% and 30% of horses and ponies develop PPID. Clinical signs include hypertrichosis, laminitis, muscle atrophy, pendulous abdomen, polydipsia, polyuria, abnormal fat deposition, hyperhidrosis and recurrent infections.

PPID is an endocrine disturbance due to loss of dopaminergic inhibition of the pars intermedia, leading to excessive production of the normal hormones from the pituitary gland, including adrenocorticotropic hormone, melanocyte-stimulating hormone, and beta-endorphin. As with other dopamine agonists, pergoline also inhibits the release of prolactin and can interfere with lactation.

The pituitary pars intermedia in horses with PPID contains one-eighth of the dopamine found in normal horses. Oral administration of dopamine agonists, such as pergolide, is necessary, which counteracts the loss of dopamine in the neurons of the hypothalamus.

The initial treatment of PPID should be starting at a dose of 2µg/kg, orally, once per day. Dosage may be adjusted to effect up to 4µg/kg daily. These are reported to be effective in 65% to 85% of cases. This drug was originally used to treat Parkinson’s disease in humans (reduced dopamine synthesis in the brain) at dosage of 1mg to 3mg daily. In 2007, pergolide was withdrawn from the US market after several studies revealed a link between the drug and increased rates of valvular heart disease.

Pergolide is available in a branded tablet form to be administered orally to the affected horse once per day. It is administered either by placing the tablet directly into the horse’s mouth or mixing it with its feed. However, palatability of the tablet is poor, and some horses are refractory to daily oral administration. A molasses-flavoured pergolide paste preparation has been shown to be safe and effective in horses that are refractory to treatment with the tablets.

Pergolide is an unstable molecule. Storage at room temperature (25°C) or exposure to light results in excessive degradation (the structure of pergolide is the aromatic ring). The compounding formulations of pergolide mesylate are not stable when the aqueous vehicle for oral solution contains 37% purified water or, for oral suspension, 97% of water. This instability is due to the hydrolysis of the methanesulfonate ester portion of the molecule. For convenience, the tablet is often hidden in a small amount of food (such as apples, apricot, carrots and banana) relished by horses. Since it is usually prepared in advance, a lapse of time occurs during which an uninformed person may unintentionally eat the food.

Dopamine is an endogenous, monoamine catecholamine involved in regulating hormone levels and modulation of cardiovascular function. Dopamine gains access to the pituitary gland via the hypophyseal portal circulation. Dopamine receptors are located at different sites within the CNS and peripheral nervous system.

Dopaminergic agonists such as pergolide act directly on dopamine receptors, mimicking endogenous dopamine. Two families of dopamine receptors exist: D₁-like and D₂-like. They are all G protein-coupled receptors. D₁ and D₅ receptors belong to the D₁-like family, and the D₂-like family includes D₂, D₃ and D₄ receptors. D₁ dopamine receptors on vascular smooth muscle cells mediate vasodilation, leading to lowered blood pressure. Pergolide also has high affinity and activity to D₂ and D₃ dopamine receptors located in all brain areas, and in the substantia nigra in the thalamus, respectively, are potential roles in nausea and vomiting (emetogenic receptors). Pergolide binds and activates dopamine receptors, as well multiple other receptors such as alpha-adrenergic and serotonergic (5-hydroxytryptamine; 5HT) receptors. The alpha-1 adrenergic receptors (α1A, α1B, α1D subtypes) located in cardiac myocytes play an important role in cardiac function. Pergolide also activates serotonergic receptors – particularly 5-HT_2B subtypes – affecting the structure, integrity and function of the cardiac valves (blood leaks through the leaflets that do not close correctly).

Adverse effects and treatment in humans

Pergolide mesylate, liposoluble compound (logP 4,23), is absorbed rapidly and onset of the adverse events in humans occurs rapidly within one hour of ingestion.

Serious human adverse events reported with accidental pergolide ingestion are due to excessive dopaminergic activity, including neurological (dizziness, sleepiness, headaches), digestive (nausea, vomiting, abdominal pain) and cardiovascular (bradycardia, palpitations, hypotension, restlessness, collapse) clinical signs.

Healthy human subjects have higher sensitivity to adverse effects of pergolide than those afflicted with Parkinson’s disease, possibly because of a higher sensitivity of the dopaminergic system in individuals who do not have focal degeneration of dopaminergic neurons. Children or people with pre-existing heart conditions may be more at risk.

In case of accidental ingestion, seek immediate medical advice and assistance, and show the package leaflet or the label to the physician. Avoid driving or operating machinery following pergolide ingestion.

To reduce the risk of accidental ingestion by the person administering pergolide products for horses, special precautions to be taken include the following.

Store and handle this product separately away from human medicinal products, and handle it with great care to avoid accidental ingestion.

Tablet parts should be returned to the open blister space. Blisters should be inserted back into the outer packaging and kept in a safe place.

Prepare the treatment at the last minute, immediately before administering it to the horse, and do not leave it unattended.

Children should not come into contact with the veterinary medicinal product. Carefully keep the VMP out of reach (a locked cabinet).

Pergolide may cause eye irritation, an irritating smell, or headache after splitting. Minimise exposure risks when splitting tablets. Tablets should not be crushed (increased human exposure).

Avoid human exposure and skin contact when preparing tablets for horses. In case of contact with skin, wash exposed skin with water.

Avoid contact with the eyes and inhalation when handling the tablets. In the event of pergolide exposure to the eye, flush the affected eye immediately with water and get medical advice.

Pregnant or lactating women should wear gloves when administering pergolide products.

For nasal irritation, move to fresh air and seek for medical attention if breathing difficulty develops. Wash hands after use. Wash skin thoroughly after handling.

Do not eat, drink or smoke when using this VMP.

People with known hypersensitivity to pergolide or other ergot derivatives should avoid contact and should not administer it.

Do not flush pergolide into surface water or sanitary sewer systems.

• Use of some of the drugs in this article is under the veterinary medicine cascade.
• Article appeared in Vet Times (2025), Volume 55, Issue 26, Pages 18-19.