PIPERAZINE (derivatives): Safety Summary for Veterinary Use

WHO Acute Hazard classification: Not listed.


Mechanism of action of Piperazine

Pure piperazine itself is unstable in water and to ensure the required stability in human and veterinary medicines various salts are used (e.g. hydrate, citrate, adipate, phosphate, etc.). Each salt contains a different amount of piperazine "base": adipate 37%; chloride 48%; citrate 35%; phosphate 42%; the hexahydrate 44%, the sulphate 46%.

Several modes of action have been described for piperazine. It seems that it acts as a reversible inhibitor of acetylcholinesterase (also known as AchE), an enzyme that hydrolyzes acetylcholine (Ach). AchE is a molecule involved in the transmission of nervous signals from nerves to muscles (so-called neuromuscular junctions) and between neurons in the brain (so-called cholinergic brain synapses). AchE's role is to terminate the transmission of nervous signals where acetylcholine is the neurotransmitter (there are several other neurotransmitters). Inhibition of AchE massively disturbs the motility of the parasites. More recently an agonistic effect on GABA (gamma-aminobutyric acid) neurotransmitters in nerve cells has been also reported.

The bottom line for the parasitic worms is that they are paralyzed and die more or less quickly or are expelled from the gut because they cannot keep themselves attached to the intestinal wall.

It seems that piperazine also inhibits the metabolism of succinic acid in ascarids, which disturbs the energy management of the worms.


Acute Toxicity and Tolerance of Piperazine (base)

  • LD50 acute, rats, p.o. 7900 mg/kg
  • LD50 acute, rats, s.c. 3700 mg/kg
  • LD50 acute, mice, p.o. 11400 mg/kg
  • As a general rule, dogs, cats and livestock tolerate piperazine very well.
  • The safety margin in cats is ~3, in horses ~6
  • In dogs and cats single oral doses ≥110 mg/kg can already cause slight adverse drug reactions; ≥800 mg/kg cause neurotoxic symptoms.

Toxic Symptoms caused by Piperazine Poisoning

  • Intoxication symptoms after piperazine overdose are gastrointestinal and neurological. Most frequent ones are:
    • Salivation (drooling)
    • Vomit
    • Diarrhea
    • Trembling
    • Convulsion
    • Restlessness
    • CNS (Central Nervous System) depression
    • Paresis (partial absence of voluntary movements)
  • Additional symptoms have been described in cats: muscular weakness, head and neck trembling, hyperestesia (abnormal increase in sensitivity to normal stimuli), spasms, delayed pupillary reflex and lethargy
  • In dogs extreme forward extension of the head and of the legs backward have been reported.
  • Typical for piperazine intoxications is their relatively late appearance (~24 hours after administration), and in case of massive overdose their irreversibility.

Piperazine Side Effects, Adverse Drug Reactions (ADRs) and Warnings

  • In dogs and cats diarrhea and vomit may occasionally happen at therapeutic doses, particularly in young animals.
  • In horses therapeutic doses can cause soft feces, particularly in young animals.
  • In human medicine there are reports on convulsions after administration of piperazine to patients with chronic kidney diseases.
  • Piperazine should not be administered to laying hens.
  • Piperazine is contraindicated in animals with liver or kidney disorders or gastrointestinal hypomotility.
  • In case of massive infections with ascarids, administration of piperazine can cause intestinal occlusion and even rupture due to the excessive excretion of dead worms. In these cases it is preferably to use benzimidazoles rather than piperazine.
  • Simultaneous administration of piperazine and phenotiazines can cause convulsions and hyperexcitation.
  • Piperazine should not be used together with levamisolemorantel and/or pyrantel because they have an antagonistic effect that can reduce the anthelmintic efficacy. However there are also reports on a synergistic effect for the combination of piperazine + levamisole against immature Oxyuridae and Strongylus dentatus.
  • The simultaneous use of piperazine and evacuator laxatives accelerates the excretion of piperazine and reduces its anthelmintic efficacy.
  • Piperazine can have an effect on uric acid levels in blood: both false positives and negatives have been reported.

Antidote and Treatment of Piperazine Intoxication

  • There is no specific antidote for piperazine.
  • Treatment consists in supportive and symptomatic measures.
  • After oral intoxication administration of active charcoal and electrolytes is recommended.
  • It is advisable to keep intoxicated animals in a dark room.
  • Most animals recover in 3 to 4 days.

Pharmacokinetics of Piperazine

The pharmacokinetic behavior is similar for all piperazine salts. Following oral administration they are readily absorbed into the bloodstream. Highest plasma levels are reached 1 to 2 hours after administration.

Piperazine excretion is fast. It can be detected in urine already 30 minutes after oral administration. In pigs ~45% of the administered dose is excreted 24 hours after treatment, >70% in laying hens. In pigs it is excreted mainly through urine (~55%) and feces (~16%), mostly as unchanged piperazine (60 to 80%). 

In laying hens piperazine residues can be detected in eggs up to 17 days after administration.


Environmental Toxicity of Piperazine

  • Piperazine is harmful for aquatic organisms.
  • Piperazine is not readily biodegradable nor photodegradable, but it does not bioaccumulate.
  • Nevertheless, it can be assumed that correctly used in dogs, cats and livestock piperazine is unlikely to be detrimental for the environment, including coprophagous insects.

Additional information

Click here for a list and overview of all safety summaries of antiparasitic active ingredients in this site.

  • Piperazine is used in human medicines.
  • Piperazine is not used in crop pesticides.
  • Piperazine is not used in public or domestic hygiene as a biocide.
  • Click here for General safety of antiparasitics for domestic animals.
  • Click here for General safety of antiparasitics for humans.
  • Click here for General safety of antiparasitics for the environment.
  • Click here for technical and commercial information on piperazine.

WARNING

If you intend to use a veterinary drug containing this active ingredient you must carefully read and follow the safety instructions in the product label.  Always ask your veterinary doctor, or pharmacist, or contact the manufacturer. Be aware that the safety instructions for the same veterinary medicine may vary from country to country.

The information in this page must not be confused with the Materials and Safety Datasheets (MSDS) officially issued by manufacturers for active ingredients and many other chemicals. MSDSs target safety during manufacturing, transport, storage and handling of such materials. This safety summary is a complement to the information on product labels and MSDS.

The toxicity of an active ingredient must not be confused with the toxicity of finished products, in this case parasiticidal drugs or pesticides. Finished products contain one or more active ingredients, but also other ingredients that can be relevant from the safety point of view.

All information in this site is made available in good faith and following a reasonable effort to ensure its correctness and actuality. Nevertheless, no this regarding guarantee is given, and any liability on its accuracy, integrity, sufficiency, actuality and opportunity is denied. Liability is also denied for any possible damage or harm to persons, animals or any other goods that could follow the transmission or use of the information, data or recommendations in this site by any site visitor or third parties.

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