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Ivermectin Pharmacology

Pharmacology

Clinical Particulars

Ivermectin is an avermectin structurally related to milbemycins such as Moxidectin.  Avermectins are naturally occurring compounds generated as fermentation products by Streptomyces avermitilis, a soil actinomycete.

Pharmacodynamics

Pharmacokinetics

Mechanism of Action

Invertebrate Nerve Transmission Disruption: Ivermectin targets g-aminobutyric acid (GABA) receptors and ivermectin-sensitive glutamate-gated chloride channel receptors, only found in invertebrates.


  • Chloride Influx: Avermectins interfere with parasite nerve transmission by indirectly opening chloride channels in the post-synaptic membrane of invertebrate nerve and muscle cells. This causes an influx of chloride ions into the cells,  leading to hyperpolarisation and subsequent paralysis of invertebrate neuromuscular systems.

  • Glutamate Enhancement: Pharmacological action is mostly through enhancing the effects of glutamate at the glutamate-gated chloride channels specific to protostome invertebrates. Parasite specificity occurs in most veterinary species, as typical mammalian patients do not possess protostome-specific glutamate-gated chloride channels (Wolstenholme, 2012).

Summary of Applications

Endectocide: Active against many immature and mature nematodes and arthropods. Often employed as a general, non-specific antiparasitic therapy. Mixed target species activity.  Used extensively. Some species and individuals demonstrate extreme sensitivity/toxicity issues.


  • Arthropod Activity: Active against a wide range of immature and mature arthropods, causing flaccid paralysis of parasites.

  • Nematode Activity: Avermectins are effective against a wide range of nematode species and developmental stages,.

  • Cestode Activity: Ivermectin is ineffective against trematodes and cestodes as these species have no macrocyclic lactone binding sites.

Pharmacodynamics

Metabolism

  • Hepatic: Metabolized in the liver via oxidative pathways (Martin and others 2020).

Elimination

  • Faecal: Primarily excreted in the faeces. Less than 5% of the drug (as parent compound or metabolite) is excreted in the urine. Exctreted ivermectin and its metabolites remain toxic to dung-feeding insects but not birds, plants, and earthworms (Lumaret and others 2012; Martin and others 2020). 

Pharmacokinetics

Precautions

Adverse Effects

General Adverse Effects | Neurotoxicity is possible in any patient: Signs of neurotoxicity include but are not limited to ataxia, mydriasis, blindness, tremors, vomiting, seizures, and cardiovascular and respiratory depression.  Chronic and subchronic signs of neurotoxicity are also reported in some canine patients after prolonged dosing (Bissonnette et al., 2009). 

Ivermectin | Species-Specific Adverse Effects

  • Dogs | Neurotoxicity: Collapse coma and death are possible. Signs of toxicity in dogs include GCS> 10, vomiting, hypersalivation, dilated pupils, ataxia and apparent blindness (An absence of both menace responses and pupillary light reflexes). Animals may present panting and depression, hypersalivation, hyperaesthesia, tremors and twitching. Normocardia and normothermia are possible, but some animals may be pyrexic or hypothermic and very depressed, and comatose animals may show abnormal heart rate and rhythm (Bissonnette et al., 2009; Bates et al., 2013; Becker and Young, 2017). 

Rodents

  • Mice and Rats | Neurotoxicity: Ivermectin may cause neurologic toxicity at therapeutic doses (i.e. less than 0.5 mg/kg).

Reptiles

  • Chelonians: Flaccid paralysis and death have been reported in many chelonian species, including red-footed tortoises (Geochelone carbonaria), leopard tortoises (Geochelone pardalis) (Teare and Bush 1983)

  • Skinks, Indigo Snakes, and crocodilians: Species that have suffered profound fatal neurotoxicity (Petritz & Chen 2018).  

Avians

  • Orange-cheeked Waxbill Finches | Budgerigars: Sensitive Species have suffered profound fatal neurotoxity (Petritz & Chen 2018).  

Aquatic Animals

  • Fish and other Aquatic Animals: Ivermectin is highly toxic to aquatic animals, so it should never be released into aquatic environments. However, it binds heavily to soil and rarely drains from land into water courses. 

Contraindications

General Contraindications 

  • Hypersensitivity: Do not administer to animals with known hypersensitivity to the drug

Species-Specific Contraindications

  • Dogs | ABCB1 (MDR-1) mutation: Do not administer to dogs with a strong chance of MDR1 gene mutation (e.g., All types of collies, Australian Shepherd Dogs, Shelties, Long-haired whippets, breeds with “white feet”). These dogs are likely to suffer significant adverse effects. Neurotoxicity is possible. ABCB1 (MDR-1) mutation is a relative contraindication (higher dosages should be avoided and an alternative drug used)

  • Dogs | Neonates: Ivermectin is not recommended for use in puppies < 6 weeks of age

  • Dogs | Active Heartworm Infestation: Ivermectin is not recommended for use in dogs without a current negative heartworm test.

Reptiles

  • Chelonians | Indigo Snakes | Crocodilians | Skinks: Because of serious adverse effects, including neurotoxicity and death, the use in these species is not recommended.

Avians


  • Orange-cheeked Waxbill Finches | Budgerigars: These species are not recommended because of serious adverse effects, including neurotoxicity and death.

Aquatic Animals

  • Fish and other Aquatic Animals: Ivermectin is highly toxic to aquatic animals, so It should never be released into aquatic environments. However, it binds heavily to soil and rarely drains from land into water courses. 

Potentially Significant Interactions

General interactions

  • Benzodiazepines: Effects may be potentiated by Ivermectin; use together is not advised in humans.

Drug Specific Interactions

  • Amiodarone: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Carvedilol: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Clarithromycin: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Ciclosporin: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Diltiazem: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Erythromycin: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Itraconazole: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Ketoconazole: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Loperamide: Caution is advised if other drugs can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation. This allows Loperamide (a P-glycoprotein substrate) to penetrate the CNS and cause profound sedation. 

  • Phenobarbital: Do not use in seizures of toxic causes where the clinical signs are mediated through the GABA channels (Ivermectin and Moxidectin toxicity) as this may exacerbate the seizures 

  • Quinidine: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Spironolactone: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Tamoxifen: Caution is advised if using other drugs that can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation

  • Verapamil: Caution is advised if other drugs can inhibit P-glycoprotein, especially in dogs at risk for MDR1-allele mutation.

Reproduction

  • Pregnancy | Relative Safety: Manufacturers' data indicates no significant adverse effects of Ivermectin on pregnancy in dogs, horses, cattle, or swine. However, high doses appeared to have a teratogenic effect in rats and rabbits.

  • Lactation | Safe: Manufacturers' data indicates that Ivermectin is excreted into breast milk but is unlikely to influence the nursing offspring when used in therapeutic doses. 



Last Update | 220720

5 | Monitoring



Adverse Effects



     Suspected or Proven



Vital Signs



    HR, RR, T etc


    Perfusion parameters


    Body Condition Score



Physiological Changes



    Cardiac Function


    Digestive Function


    Hepatic Function


    Renal Function


    Respiratory Function


    Neurologal Function



Disease Stage



    Continue to stage the primary morbidity.



Clinical Efficacy



    Monitor the patient concerning treatment goals.


    Set a plan to determine the end of a need for treatment.

Precautions

Availability

A significant number of products are listed at the VMD PID | https://www.vmd.defra.gov.uk/productinformationdatabase/search


A significant number of products are listed at the FDA PID | https://animaldrugsatfda.fda.gov/adafda/views/#/search


A significant number of products are listed at the EUD Medicines PID | https://www.ema.europa.eu/en/medicines

Availability

Identifiers

Identifiers

Evidence Base


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  2. Ballent, M., Lifschitz, A., Virkel, G., Mate, L., Lanusse, C., 2010. Pretreatment with the inducers rifampicin and phenobarbital alters ivermectin gastrointestinal disposition. Journal of Veterinary Pharmacology and Therapeutics 33, 252–259. https://doi.org/10.1111/j.1365-2885.2009.01129.x

  3. Bates, N., Chatterton, J., Robbins, C., Wells, K., Hughes, J., Stone, M., Campbell, A., 2013. Lipid infusion in the management of poisoning: a report of 6 canine cases. Veterinary Record 172, 339–339. https://doi.org/10.1136/vr.101036

  4. Becker, M.D., Young, B.C., 2017. Treatment of severe lipophilic intoxications with intravenous lipid emulsion: a case series (2011&ndash;2014). VMRR 8, 77–85. https://doi.org/10.2147/VMRR.S129576

  5. Bissonnette, S., Paradis, M., Daneau, I., Silversides, D.W., 2009. The ABCB1-1Delta mutation is not responsible for subchronic neurotoxicity seen in dogs of non-collie breeds following macrocyclic lactone treatment for generalized demodicosis. Vet Dermatol 20, 60–66. https://doi.org/10.1111/j.1365-3164.2008.00731.x

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  20. Held, S., Gramer, I., Hassdenteufel, E., Neiger, R., Geyer, J., 2012. Lipid-infusion therapy of avermectin-induced neurotoxicosis in two dogs with homozygous nt230(del4) MDR1 mutation. Kleintierpraxis 57, 313–319. https://doi.org/10.2377/0023-2076-57-313

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  22. Jiang, L., Wang, P., Sun, Y.-J., Wu, Y.-J., 2019. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway. J Exp Clin Cancer Res 38, 265. https://doi.org/10.1186/s13046-019-1251-7

  23. Jourdan, G., Boyer, G., Raymond-Letron, I., Bouhsira, E., Bedel, B., Verwaerde, P., 2015. Intravenous lipid emulsion therapy in 20 cats accidentally overdosed with ivermectin. J Vet Emerg Crit Care (San Antonio) 25, 667–671. https://doi.org/10.1111/vec.12371

  24. Juarez, M., Schcolnik-Cabrera, A., Dueñas-Gonzalez, A., 2018. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res 8, 317–331.

  25. Kidwell, J.H., Buckley, G.J., Allen, A.E., Bandt, C., 2014. Use of IV Lipid Emulsion for Treatment of Ivermectin Toxicosis in a Cat. Journal of the American Animal Hospital Association 50, 59–61. https://doi.org/10.5326/JAAHA-MS-5951

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Evidence

Monograph Details

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