Ivermectin

Ivermectin (22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) 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.

Pharmacodynamics
Ivermectin and the related molecule avermectin (an insecticide most frequently used in home-use ant baits) are 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&mdash;low toxicity). 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&mdash;high toxicity).

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. The cause of CNS toxicity in succeptible dogs has been traced to a mutation in a gene responsible for the MDR1 pump protein. 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 and are generally considered safe. A severe overdosage of ivermectin is required to produce ivermectin toxicosis. A test is available that checks dogs for sensitivity to ivermectin as well as several other drugs. (See P-glycoprotein)

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.

Collies and related breeds 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 being extremely sensitive. Due to this sensitivity, veterinarians may prescribe other types of heartworm preventative for breeds of dogs with known MDR1 mutations. However, the dosage of ivermectin contained in monthly heartworm preventatives such as Heartgard is generally considered to be safe for all breeds when used as recommended. 

Horses
Ivermectin is a very popular ingredient within certain dewormers for horses, with brand names including 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.