Ivermectin

Ivermectin (22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b) is a broad-spectrum anti-parasite medication, traditionally used against worms (except tapeworms), but more recently found to be effective against most mites and some lice too. It is sold under brand names Stromectol® in the United States, Mectizan® in Canada by Merck and Ivexterm® in Mexico by Valeant Pharmaceuticals International.

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Pharmacodynamics

Ivermectin and the related molecule avermectin (an insecticide most frequently used in home-use ant baits) are macrocyclic lactones derived from the bacterium Streptomyces avermitilis. Ivermectin kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission. The drug binds and activates glutamate-gated chloride channels (GluCls) present in neurons and myocytes (Cully et al., 1994; Cully et al., 1997, Dent et al., 1997), resulting in neuro-muscular paralysis and death. Mutations in GluCls that reduce their response to ivermectin confer ivermectin resistance (Dent et al, 2000, Kane et al., 2000). Although similar in structure to vertebrate ionotropic glycine receptors, glutamate-gated chloride channels are specific to invertebrates (Dent, 2006). The absence of glutamate-gated chloride channels from mammals appears to account in part for the specificity of ivermectin for invertebrate parasites and its relative lack of side effects in mammalian hosts (Lerchner et al., 2007). Invertebrate GABA receptors have been implicated in ivermectin sensitivity although their importance is still unclear (Ludmerer et al., 2002, Blackhall 2003). The principal peripheral neurotransmitter receptor in mammals, the nicotinic acetylcholine receptor, is relatively unaffected by the drug (MSD, 1988), which contributes to its safety.

Pharmacokinetics

Ivermectin can be given either per os or parenterally. It does not readily cross the blood-brain barrier of mammals (Schinkle et al., 1994), although crossing may still become significant if ivermectin is given at high doses (in which case, brain levels peak 2-5 hours after administration).

Toxicity

The main concern is neurotoxicity, which in most mammalian species may manifest as CNS depression, and consequent ataxia, as might be expected from potentiation of inhibitory GABA-ergic synapses (Hayes & Laws, 1991).

In General Use Pesticide (GUP) formulations, these compounds are classified by the United States Environmental Protection Agency as toxicity category IV, or very low. This means that although highly poisonous to insects, mammals should not generally be adversely affected by normal use of avermectin pesticide formulations. As an example, one such formulation was determined to have an oral LD50 (median lethal dose) of 650 mg/kg in rats (qualifies as toxicity category III—low toxicity) [1]. Extrapolated to an 80 kg (180 lb) human, the semi-lethal dose is 52 g (1.9 oz), roughly the weight and volume of an iPod nano, which is considered by the EPA to be a low toxicity amount.

However, pure (as opposed to the diluted GUP formulations) avermectin formulations are both highly toxic to insects and mammals (as well as aquatic life, such as fish). One study reports an oral LD50 of 10 mg/kg in rats (qualifies as toxicity category I—high toxicity) [2].

Some dog breeds, most notably the collie, exhibit signs of ivermectin related central nervous system toxicity at ivermectin doses exceeding 150 to 200 µg/kg. [3] The cause of CNS toxicity in succeptible dogs has been traced to a mutation in a gene responsible for the MDR1 pump protein resulting in a defect in the blood-brain barrier that allows the drug to pass through. [4] This has led some people to conclude that collies should not be treated with ivermectin or any other avermectin. Commonly prescribed veterinary formulations of ivermectin used for heartworm prophyllaxis limit dosages to the range of 6 to 12 µg/kg [5]and are generally considered safe. A severe overdosage of ivermectin is required to produce ivermectin toxicosis. [6] A test is available that checks dogs for sensitivity to ivermectin as well as several other drugs.[7] (See P-glycoprotein)

Indications for use

Humans

Ivermectin is a broad-spectrum antiparasitic agent. It is mainly used in humans in the treatment of onchocerciasis, but is also effective against other worm infestations (such as strongyloidiasis, ascariasis, trichuriasis and enterobiasis). More recent evidence supports its off-label use in the treatment of mites such as scabies, usually limited to cases that prove resistant to topical treatments and/or who present in advanced state (such as Norwegian scabies).

Therapeutic dosage

Adults

Oral: 3 to 12 mg as a single dose per os (about 150 to 200 µg/kg bodyweight) for onchocerciasis and other parasitic infections. (Ex. 45 kg would be about 6.75 mg to 9 mg)

Children

Ivermectin is not given to children weighing less than 15 kg. The dose is 150 µg/kg bodyweight (in children weighing more).

Contraindications

Ivermectin is contraindicated in persons with an immediate hypersensitivity to the drug. It should not be given to mothers who are breast-feeding until the infant is at least three months old (Reynolds, 1993).

Dogs

Ivermectin is the primary ingredient in several types of heartworm preventative, including Heartgard.

It has also been used in treating cases of mange since high doses can kill the mites. Dogs are usually given the drug every day for 2 weeks or until no mites are present in skin scrappings and their symptoms resolve. In demodectic mange, dogs may need to stay on the drug longer.

Unlike other heartworm preventatives, ivermectin is better toleranted by heartworm-positive dogs, making it possible to protect a potentially heartworm-negative dog that needs futher testing in 3 months. In fact there is some evidence that giving ivermectin every day can actually cure heartworm-infected dogs if given every day for many months. The drug slowly kills the worms; however there is risk of serious complications if the worms are killed off too quickly. This method is usually only used on dogs with mild heartworm infections or in those that wouldn't tolerant the usual treatment (such as those with heart conditions). This is off-label use, so vets need to be careful in using the drug this way.

Collies and related breeds (including shelties, border collies, Austrailan shepherds, English shepherds, bearded collies, and others) may be sensitive to ivermectin due to a mutation in the multi-drug resistance gene (Mdr1). Around 80% of collie dogs in the United States may show varying degrees of sensitivity to ivermectin, with 25-33% of collies, that have mutations in both copies of the MDR1 gene, being extremely sensitive. Toxicity is not observed at doses less than 100 microgram/kg even in sensitive breeds. Thus, ivermectin-based heartworm preventatives (which deliver doses in the range of 6 to 13 microgram/kg) may be suitable for dogs with this sensitivity [8] However many vets use caution and prefer giving other heartworm preventatives such as Sentinel, Interceptor (both containing Milbemycin oxime), or ProHeart to their patients that are one of the herding breeds. Regardless these dogs cannot be treated for mites with ivermectin.

Horses

Ivermectin is a very popular ingredient within certain dewormers for horses, with brand names including Bimectin, Equimectrin, Equalvan, and Zimecterin. It is commonly given orally as a paste deposited directly in the animal's mouth via a syringe. Ivermectin protects against most internal parasites of the horse, including their larva, except for tapeworms.

Rodents

A commonly used therapy for rodent fur mite infestations in recent times has been based on oral or parenteral administration of avermectin, a family of macrocyclic lactones produced by fermentation of the soil micro-organism Streptomyces avermitilis. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 µg/kg or less. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activity (Hotson, 1982).

Avermectin therapy is not without its drawbacks. Resistance to avermectins has been reported, which suggests use in moderation (Clark, 1995). Research on ivermectin, piperazine, and dichlorvos in combination also shows potential for toxicity (Toth, 2000). Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, NO, prostaglandin E2, and increase of intracellular concentration of Ca²⁺ (Victorov, 2003). A proven ectoparasite mitigation method that stresses lab animals less than avermectin oral administration is definitely desirable.

Birds

Ivermectin is commonly used to treat mites in birds, usually for scaly eruptions of the face or legs due to the parasite Cnemidocoptes. In many countries this represents an off-label use.

References

• Mectizan Donation Program
• Ivermectin data sheet (source of structural formula)
• Ivermectin for human use
• Site profiling ivermectin and avermectin as pesticides
• Toxicity information for avermectin
• Medline Plus Information
• epocrates.com

• U.S. National Library of Medicine. Hazardous Substances Databank. Bethesda, MD, 1995.10-9
• Lankas, G. R and Gordon, L. R. Toxicology. In Ivermectin and Abamectin. Campbell, W. C., Ed. Springer Verlag, New York, NY, 1989.10-142
• U.S. Environmental Protection Agency. Pesticide Fact Sheet Number 89.2: Avermectin B1. Office of Pesticides and Toxic Substances, Washington, DC, 1990.10-143
• Hotson IK, 1982, The avermectins: A new family of antiparasitic agents, J S Afr Vet Assoc., Jun;53(2):87-90.
• Clark JM, 1995, with Scott JG, Campos F, Bloomquist JR, Resistance to avermectins: extent, mechanisms, and management implications, Annu Rev Entomol, 40:1-30.
• Toth LA, 2000, with Oberbeck C, Straign CM, Frazier S, Rehg JE, Toxicity evaluation of prophylactic treatments for mites and pinworms in mice, Contemp Top Lab Anim Sci., Mar;39(2):18-21.
• Viktorov AV, 2003, with Yurkiv VA, Effect of ivermectin on function of liver macrophages, Bull Exp Biol Med., Dec;136(6):569-71.

• Blackhall, W.J., Prichard , R.K., Beech, R.N., 2003. Selection at a gamma-aminobutyric acid receptor gene in Haemonchus contortus resistant to avermectins/milbemycins. Mol. Biochem. Parasitol. 131(2):137-45.

• Cully, D.F., Vassilatis, D.K., Liu, K.K., Paress, P.S., Van der Ploeg, L.H., Schaeffer, J.M., Arena, J.P., 1994. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature. 371(6499):707-11.

• Cully, D.F., Paress, P.S., Liu, K.K., Schaeffer, J.M., Arena, J.P., 1996. Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin. J.f Biol. Chem. 271(33):20187-91.

• Dent, J.A., Davis, M. Wayne & Avery, L.A., 1997. avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans. EMBO J. 16(19): 5867-5879.

• Dent, J.A., Smith, M., Vassilatis, D.K. and Avery, L., 2000. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Nat. Acad. Sci. USA 97(6): 2674-2679.

• Dent, J.A., 2006. Evidence for a diverse cys-loop ligand-gated ion channel superfamily in early bilateria. J. Mol. Evol.62:523-535.

• Kane, N.S., Hirschberg, B., Qian, S., Hunt, D., Thomas, B., Brochu, R., Ludmerer, S.W., Zheng, Y., Smith, M., Arena, J.P., Cohen, C.J., Schmatz, D., Warmke, J., Cully, D.F., 2000. Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proc. Nat. Acad. Sci. USA 97(25):13949-54.

• Lerchner, W., Xiao, C., Nashmi, R., Slimko, E.M., van Trigt, L., Lester, H.A., and Anderson, D.J., 2007. Reversible silencing of neuronal excitability in behaving mice by a genetically targeted, ivermectin-gated Cl− channel. Neuron, 54(1)1: 35-49.

• Ludmerer, S.W., Warren. V.A., Williams, B.S., Zheng, Y., Hunt, D.C., Ayer, M.B., Wallace, M.A., Chaudhary, A.G., Egan, M.A., Meinke, P.T., Dean, D.C., Garcia, M.L.. Cully, D.F., Smith, M.M., 2002. Ivermectin and nodulisporic acid receptors in Drosophila melanogaster contain both gamma-aminobutyric acid-gated Rdl and glutamate-gated GluCl alpha chloride channel subunits. Biochemistry. 41(20):6548-60.

• Schinkel, A.H. Smit, J.J., van Tellingen, O., Beijnen, J.H., Wagenaar, E., van Deemter, L., Mol, C.A., van der Valk, M.A., Robanus-Maandag, E.C., Riele, H.P., et al., 1994. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 77(4):491-502.

external link

• Stromectol®