What is the Advantage and Disadvantage of Praziquantel Overdose Dog

Fluralaner is a potent acaricide and insecticide from the isoxazoline drug class. A single dose of Bravecto® administered orally to dogs provides at least twelve weeks of flea- and tick-control [10]. This prolonged activity of the active compound may be explained by its pharmacokinetic properties. It is readily absorbed after single-dose oral administration reaching Cmax within one day, shows long half-life, long mean residence time, relatively high apparent volume of distribution, and low clearance with enterohepatic re-circulation [11].

Fluralaner inhibits arthropod glutamate-gated chloride channels (GluCls) and GABA-gated chloride channels (GABACls) [12], which structurally belong to the class of so-called Cys-loop receptors [13, 14]. Arthropod Cys-loop receptors are targeted by many different antiparasitic drugs, including fipronil, ivermectin, and fluralaner [2]. Single experiments on housefly-head and rat-brain membranes as well as on recombinantly expressed individual receptors point to a significantly lower binding affinity of fluralaner to vertebrate receptors compared with arthropod receptors [1, 5, 15]. Nevertheless, it cannot be excluded that fluralaner also interacts with one of the vertebrate Cys-loop receptors in vivo, which are highly or even exclusively expressed in the central nervous system [16, 17]. Based on the molecular pharmacology of fluralaner, it has to be discussed if the neurological dysfunction seen in the Kooikerhondje dog in the present case may result from blocking of one of these receptors, which would explain the occurrence of generalized ataxia, myoclonic jerks, tremor of head and body, muscle twitching and oral dysphagia. Of note, the onset of the neurological dysfunction was reported exactly at the time of the expected Cmax of fluralaner in dogs [11].

However, as fluralaner has a generally good safety profile and neurologic adverse events only occur in very rare cases, individual factors increasing the drug concentration in the brain or increasing the susceptibility of CNS Cys-loop receptors may come into account. However, currently only few factors are known that affect the pharmacokinetic profile and brain penetration of fluralaner. One of them is a defect of the multidrug resistance (MDR1) drug efflux carrier at the blood-brain barrier (commonly referred to as MDR1 nt230(del4)), frequently present in Collie, Australian Shepherd, Shetland Sheepdog, Longhaired Whippet, White Swiss Shepherd and some other breeds [18], which leads to increased drug penetration into the brain [19]. This can provoke neurological toxicity in MDR1 mutant dogs even at standard dosage, as it is well known for drugs like ivermectin [20]. Very recently, significantly increased brain penetration of fluralaner was demonstrated in an mdr1 mutant mouse model, indicating that MDR1-mediated drug efflux normally prevents fluralaner entry into the brain [21]. Although this breed is not suspected to carry this gene mutation, MDR1 genotyping of the Kooikerhondje dog was performed and revealed an MDR1 intact MDR1+/+ genotype, excluding increased brain penetration of fluralaner due to MDR1 nt230(del4) mutation in the present case. Nevertheless, occurrence of other mutations in the MDR1 gene or related drug efflux carrier at the blood-brain barrier can not be excluded. Furthermore, the premedication of the dog with milbemycin oxime plus praziquantel one month prior to Bravecto® treatment may have increased brain penetration of fluralaner, e.g. by inhibition of MDR1-mediated fluralaner efflux by the premedication via drug-drug interaction. However, fluralaner was shown to be safe when administered concurrently with milbemycin oxime + praziquantel [22].

Furthermore, a combination of different individual factors might have affected the bioavailability, pharmacokinetics and brain penetration of fluralaner in the Kooikerhondje dog and thus may have provoked the neurological dysfunction. These could include inter-individual variability in gastrointestinal pH, time of gastric emptying, duration of intestinal transit, plasma protein binding as well as age and sex of the animal [23, 24]. Additionally, breed-related differences in body constitution might play a role for the margin of safety of drugs [25]. However, in pivotal effectiveness studies of fluralaner [7], various dog breeds and mongrels were included and no obvious differences in drug safety across breeds were noted.

Another factor influencing the pharmacokinetics of fluralaner might be the prandial state of the dog at the time of drug application, as it is well known that feeding affects gastrointestinal physiology and thereby may affect drug absorption and bioavailability [26, 27]. A study investigating the influence of concurrent feeding on fluralaner pharmacokinetics revealed that there were no dramatic differences between fasted and fed dogs, but that food significantly increased the bioavailability of fluralaner from the Bravecto® chewable tablets [28]. As the recommendation of the manufacturer is to administer Bravecto® at or around feeding, as it was performed in the Kooikerhondje dog, feeding is suggested to play a minor role in the present case.

Of note, neurological signs were transient and resolved without any treatment in the Kooikerhondje dog. This might be explained by increased drug levels in the brain around the fluralaner plasma Tmax, reached within one day on average in beagle dogs after administration of Bravecto® [11]. In this case, improvement of the dog’s condition and disappearance of neurological dysfunction might simply be explained by drug elimination and decline of the relevant drug concentration in the brain. Therefore, in the current case no particular treatment was necessary and cannot be recommended until the molecular mechanisms behind the observed signs of neurological toxicity in dogs are better understood. Based on the supposed mechanism of blocking Cys-loop receptors, GABAA receptor agonists such as benzodiazepine drugs or propofol might be a treatment option [29], but until now there is no clinical experience with that at all. Furthermore, administration of an intravenous lipid emulsion (ILE) might be helpful. This treatment was previously administered in cases of intoxications with lipophilic drugs, such as ivermectin in dogs [30]. In order to prevent enterohepatic re-circulation of fluralaner, administration of activated charcoal might also be useful. Overall, depending on the severity of the neurologic adverse events and the patient’s general health condition, symptomatic treatment and supportive care are recommended as it was performed in the present case.

Praziquantel (Droncit)

(For veterinary information only)

WARNING
The size of the tablet/medication is NOT an indication of a proper dose. Never administer any drug without your veterinarian's input. Serious side effects or death can occur if you use drugs on your pet without your veterinarian's advice. 

It is our policy not to give dosing information over the Internet.

Brand Name: Droncit, Interceptor Plus, Milbemax, Profender, Drontal, Drontal Plus, Sentinel Spectrum, Iverhart Plus, Virbantel, Iverhart Max

Available as injectable; 23 mg tablets for cats and 34 mg tablets for dogs; as a topical dewormer combined with emodepside; tablets for dogs combined with milbemycin and lufenuron; tablets for dogs including ivermectin and pyrantel pamoate

How this Medication is Used 

A member of the Taenia genus of tapeworms. Photo courtesy of CDC.

Praziquantel is primarily used against parasites known as cestodes (tapeworms). The common tapeworm of dogs and cats, Dipylidium caninum, is the usual target of this medication although praziquantel is also effective against less common types of tapeworms such as Taenia species and the more dangerous Mesocestoides species and Echinococcus species. Praziquantel is also effective against flukes.

A single treatment of praziquantel should clear a Dipylidium caninum infection although a second treatment is sometimes recommended if it is felt that immediate re-infection is likely. Immediate re-infection might take place if a heavy uncontrolled flea problem is in the pet's environment; Dipylidium caninum is contracted when an infected adult flea harboring a tapeworm larva is eaten.

Praziquantel is also available in combination with other single use oral dewormers as well as with more comprehensive monthly worm protection products. (Numerous brands are available. See the list above.) Such products provide regular deworming against assorted worm parasites. Plain praziquantel is available in non-prescription tablets that may be purchased at pet supply stores. Brand name products, combination products as described above, and injections are available only through veterinarians as they are prescription drugs.

As of late 2007, praziquantel is also available in a topical combination with the anti-parasite drug emodepside. This combination product is applied to the cat's shoulder area and is effective against the tapeworms of the above types as well as hookworms (Ancylostoma tubaeformae) and roundworms (Toxocara cati). The brand name of this product is Profender® and is available by prescription. Unlike other roundworm/hookworm dewormers, only a single dose is necessary for this product.

Praziquantel is available in non-prescription tablets that may be purchased at pet supply stores. Brand name products, combination products, and injections are available only through veterinarians as they are prescription drugs.

How this Medication Works 

Praziquantel acts by damaging the parasite's skin internally such that the parasite disintegrates and is removed by the host's immune system. Unlike the situation with roundworms, dead tapeworms generally will not be seen passing from the host after deworming.

Side Effects 

Injectable praziquantel tends to sting more than most injections and it is not unusual for a pet to scratch at the site or express discomfort immediately following injection.

The oral form of praziquantel tastes bitter and approximately 5% of patients taking it experience nausea.

It has been reported that approximately one cat in ten will experience weakness, salivation, or nausea after a tapeworm injection with praziquantel, but such reactions have been seen far less frequently. This is generally of minor significance and resolves on its own.

Adult Dipylidium. The segments are easily seen. The thick end is the tail, where segments drop off. Photo by CDC.

Interactions with other Drugs

The following medications can increase the blood levels of praziquantel: cimetidine (an antacid), ketoconazole (an antifungal), and itraconazole (another antifungal).

Cautions and Concerns 

Praziquantel is felt to be safe for use in pregnant patients.

Praziquantel should not be used in puppies under age 4 weeks or kittens under age 6 weeks. The topical Profender product described above is approved for feline use only and is not approved for kittens under age 8 weeks.

Fasting is not necessary prior to praziquantel use and oral praziquantel can be given with or without food.

Tablets should be stored at room temperature away from light exposure.

It is our policy not to give dosing information over the Internet.