Ivermectin
Esther van Praag, Ph.D.
|
Ivermectin is a macrolide antibiotic belonging to the class of
avermectin; it is extracted from a fungus discovered in Japan, Streptomyces avermitilis. Ivermectin
exhibits broad-spectrum activity against many internal or external parasites,
more specifically, nematode and arthropod parasites. Ivermectin acts by
binding the glutamate-activated Cl- channels of the
parasite (Cl- channels do not exist in mammal
cells), preventing their closure. As Cl- flows into
the cells, the cell membrane is hyperpolarized and no nervous signal can be
transmitted. The insect is paralyzed and slowly dies. At higher
concentrations, ivermectin acts as an antagonist of the GABA (g aminobutyric
acid) neurotransmitter. In insects, those GABA neurons and receptors are
primarily located in the PNS (peripheral nervous system); in mammals, they
are located mainly in the CNS (central nervous system). Trematode
and cestode parasitic worms have a natural
resistance against ivermectin, since they do not use GABA as a PNS
neurotransmitter. Secondary effects such
as inhibition of reproduction of the parasites have also been observed. This difference in
location of the GABA receptors may explain ivermectin’s
rather safe use in mammals. It furthermore enables the administration of
ivermectin in pregnant mammals, with the exception of rats. Indeed,
ivermectin has been observed to cross the blood-brain barrier only in
prenatal rats, whose barrier will not become functional until a few days
after birth. This is an exception among mammals (including humans, ruminants,
lagomorphs), which form a functional blood-brain barrier at the embryo stage.
Adult rats show a
general slowdown during 24 h after injection. Some dog breeds (collie and
collie-crosses) have shown increased sensitivity to ivermectin. Rarely, rabbits
show sensitivity to ivermectin. It is suspected that they suffer a defective
blood-brain barrier. When administrated ivermectin, these rabbits will suffer
tremor, seizures. Prognosis is poor and often fatal. In cattle, horses and
rabbits, ivermectin is partially metabolized by the liver (55%); the rest
(45%) is excreted in the feces. The PO administration of ivermectin shows
rapid absorption by the body and high concentration in the blood is reached
relatively rapidly, in contrast to the SC injection of ivermectin (Ivomec), whose half-time absorption rate is 39.2 h (the
absorption rate is highly dependent on the carrier, in this case glycerolformal-propyleneglycol 40:60). The drug is well
distributed in all different tissues and organs, including the mucous layer
of the gastrointestinal tract. High concentrations are usually found in the
lungs, kidneys, skin and ears. In rabbits, ivermectin
is indicated to treat the following parasites of the GI tract: Strongyloides spp., Graphidium
strigosum, Trichostrongylus retortaeformis.
It is also efficient against ectoparasites such as ear mite, Psoroptes
cuniculi; Sarcoptes cuniculii; Notoedres
cuniculi; Cheyletiella parasitovorax ; lice, Haemodipsus ventricosus; and flea, Spilopsyllus cuniculi. Adverse effectsIn horses, injections of ivermectin can lead to edemas, due to
toxins released by dying internal parasites; this last about 5 days. Dogs can
suffer a shock situation for the same reason. Due to lack of detailed studies
of the effects of ivermectin in young animals, its use should be avoided; if
this is not possible, the fact that younger animals are more sensitive to
ivermectin than adults are should be taken into account. Ivermectin toxicosis has been reported
in cattle, horses, pigs, cats, dogs and, anecdotally in rabbits. Toxicosis is mainly related to inappropriate, off-label
use, use of the large-animal formulation in dogs, or overdosage
(LD50: 406 mg/kg; SC), with penetration of the blood-brain barrier. Overdosage (10 to 100 times the therapeutic value) often
leads to ataxia and depression. Further signs are mydriasis
(dilatation of the pupils), coma, tremors, stupor, emesis, drooling and
death. Convulsions and seizures are rarely related to ivermectin toxicosis. There is no safe and specific antidote to ivermectin. Activated
charcoal, intravenous electrolyte fluids, protection of the eyes against
desiccation and treatment of brachycardia are
recommended. Intubation might be necessary to feed the animal. Comatose
animals should be placed on a warm pad and turned regularly to avoid pressure
sores. Picrotoxin has been tested; it is not the
best treatment for ivermectin, and its margin of safety is narrow. Physostigmine has been shown to be beneficial, as
comatose animals show a transient increase in mental alertness, enabling the
diagnosis of ivermectin toxicosis. Ivermectin
interacts with benzodiazepine, each increasing the other’s toxic effect. In
the combination of ivermectin and pyrantel,
however, neither exerts influence on the other. Dosage
Further
information
Ahern GP, Junankar
PR, Pace SM, Curtis S, Mould JA, Dulhunty AF.
Effects of ivermectin and midecamycin on ryanodine receptors and the Ca2+-ATPase in sarcoplasmic
reticulum of rabbit and rat skeletal muscle. J Physiol. 1999; 514 (Pt
2):313-26 Akintunde KC, Pate P, Lansdown AB,
Abraham L. Cheyletid mite infection in laboratory
rabbits. Vet Rec. 1994; 134(21):560. Ali BH. The effect of ivermectin on
some haematological indices in rabbits: influence
of vitamin K treatment. Clin Exp Pharmacol Physiol. 1990; 17(10):735-8. Anantaphruti MT, Nuamtanong S, Waikagul J. Effect of ivermectin on experimental gnathostomiasis in rabbits. Trop
Med Parasitol. 1992; 43(1):65-7. Arafa MA, Wanas MQ. The efficacy of
ivermectin in treating rabbits experimentally infected with Eimeria as indicated parasitologically
and histologically. J Egypt Soc Parasitol.
1996; 26(3):773-80. Bowman DD, Fogelson
ML, Carbone LG. Effect of ivermectin on the control of ear mites (Psoroptes
cuniculi) in naturally infested rabbits. Am J Vet Res. 1992; 53(1):105-9. Buclar H,
Deplazes P, Wolff K. Behandlung des Parasitenbefalls von Igeln, Kaninchen,
Meerschweinchen, Vögeln und Bienen. Merkblatt
Nr TH 6, Copyright Inst Parasitologie Zürich, 1996.
Curtis SK, Brooks DL. Eradication of
ear mites from naturally infested conventional research rabbits using
ivermectin. Lab Anim Sci. 1990; 40(4):406-8. Curtis SK, Housley
R, Brooks DL. Use of ivermectin for treatment of ear mite infestation in
rabbits. J Am Vet Med Assoc. 1990; 196(7):1139-40. Cutler SL. Ectopic Psoroptes
cuniculi infestation in a pet rabbit.
J Small Anim Pract.
1998; 39(2):86-7.
Isingla LD, Juyal PD, Gupta PP.
Therapeutic trial of ivermectin against Notoedres cati
var. cuniculi infection in rabbits. Parasite. 1996; 3(1):87-9. Koopman JP, Scholten PM, van Zutphen T, Hooghof JB. [The effect of ivermectin on Psoroptes ear mange in
rabbits] Tijdschr Diergeneeskd.
1989; 114(15‑16):825-8. Dutch. McKellar QA, Midgley
DM, Galbraith EA, Scott EW, Bradley A. Clinical and pharmacological properties
of ivermectin in rabbits and guinea pigs. Vet Rec. 1992; 130(4):71-3. Nfi AN. Ivomec, a treatment against
rabbit mange. Rev Elev Med Vet Pays Trop. 1992;
45(1):39-41. Pandey VS. Effect of ivermectin on the ear mange mite, Psoroptes
cuniculi, of rabbits. Br Vet J. 1989; 145(1):54-6. Paradis M. Ivermectin in small animal dermatology. Part I.
Pharmacology and toxicology. The Compendium 20: 193-200, 1998. Perrucci S, Cioni PL, Cascella A, Macchioni F.
Therapeutic efficacy of linalool for the topical treatment of parasitic
otitis caused by Psoroptes cuniculi in the rabbit and in the goat. Med Vet Entomol. 1997; 11(3):300-2. Roder JD, Stair EL. An overview of ivermectin toxicosis. Vet Hum Toxicol.
1998; 40(6):369-70. Review. Sutherland IH, Campbell WC.
Development, pharmacokinetics and mode of action of ivermectin. Acta Leiden. 1990; 59(1-2):161-8. Uhlir J. Effect of ivermectin on the development of serum
antibody activity in rabbits infested with Psoroptes cuniculi (Acari: Psoroptidae). Folia Parasitol (Praha). 1991; 38(1):79-82. Uhlir J, Volf P. Ivermectin: its
effect on the immune system of rabbits and rats infested with ectoparasites.
Vet Immunol Immunopathol.
1992; 34(3-4):325-36. Wang CI, Huang XX, Zhang YQ, Yen QY, Wen Y. Efficacy of ivermectin in hookworms as examined in
Ancylostoma caninum
infections. J Parasitol. 1989; 75(3):373-7. Wright FC, Riner JC. Comparative efficacy of injection routes and doses of ivermectin against Psoroptes in rabbits. Am J Vet Res. 1985; 46(3):752-4 |
