Avermectins

Introduction

Avermectins are naturally occurring, potent, macrolide drugs used to treat both intra and extra intestinal parasites and are also used in the treatment of insect pest infestation but lack significant antibacterial or antifungal activities (6). They are broadly considered as blocker of neurotransmitters due to their antiparasitic and anthelmintic activities.

Brief History (1, 2, 4, 5)

• Isolated from a soil sample taken at Kawana, Japan in 1974 as a soil-dwelling actinomycete bacterium in the laboratories of the Kitasato Institute.
• The bacterium was identified as Streptomyces avermitilis and discovered to produce a potent anthelmintic substance (in 1975) in Merck Sharp and Dohme’s Research Laboratories.
• Characterized and the species producing them described by a team at Merck in 1978 (2).
• Commercially introduced in 1981 as an antiparasitic product for veterinary use for the control of endoparasitic nematodes and ectoparasitic arthropods in livestock.
• First used to treat onchocerciasis in humans in 1988 (5).
• This bacterium remains the only source of avermectin (4)
• Here is a detailed history.

                                           Molecular structure of avermectin; image source here

Uses (2,3,4)

*  In humans: majorly used to treat river blindness (onchocerciasis) and strongyloidiasis.
*  In small animals: mostly as monthly heartworm prevention, treat mites and intestinal parasites in dogs and cats.
*  In large animals: used to treat roundworms, eyeworms, lungworms, grubs, mites and horn flies in cattle, sheep,  pigs and horses.
*  They are also used in ant and roach bait.
*  Agriculturally used as pesticides.
Other anthelmintic derived from the avermectin include ivermectin, selamectin, doramectin, eprinomectin, moxidectin, milbemycin and abamectin.

Image source here

Mechanism of action

• Target site of action – glutamate-gated Chloride channels.
• Block transmission of electrical activity in invertebrate nerve.
• Enhance the effect of glutamate at the glutamate chloride channels in invertebrate nerve and muscle cells.
• They cause neuromuscular paralysis in invertebrate and lowers blood pressure. (hypotension) by causing an influx of chloride ions into the cells and increasing serum levels of nitric oxide (NO).
• Mammals such as humans do not have glutamate-gated chloride channels, therefore toxic dose for humans are high (not as toxic) in comparison to invertebrate toxic dose.
• Avermectin stimulate gamma-amino butyric acid (GABA) receptors in the central nervous system of vertebrates, the presence of blood brain barrier in humans prevents high concentrations and accumulation in the brain by using P-glycoprotein efflux pump. This make humans less susceptible to the effects of this toxin.
• Dogs lacks P-glycoprotein which make them susceptible to avermectin toxicities because of their inability to pump these drugs out of the brain.
• Once in the brain, they potentiate the release of GABA and bind to its receptors.

Depiction of the mechanism of action for the avermectin in the brain (after Bloomquist, 1999). Image source here

      Biosynthesis: Involved four pathways (7)

– Biosynthesis of starter units
– Aglycon formed by polyketide synthases
– Modified sugars synthesized to produce avermectin aglycon
– Glycosylation of the modified avermectin aglycon

         Toxicity (8,9,10)

• Wide margin of safety
• Not carcinogenic
• Teratogenic in rats: inter-utero cleft palate
• Not mutagenic
• Affect reproductive functions in rats and men.

Toxicity in humans
• Toxicity in mammals is rare due to blood brain barrier
• Toxicity is usually by accident or suicide attempts.
• Toxicity is mainly by oral route.
• Consumption of large amounts in human is fatal.
• Altered mental status is the first sign in humans.
manifestations include:
 -mild intoxications: nausea, vomiting, diarrhea, and weakness.
 -severe intoxifications: rare and occur mostly in substantial overdose. Symptoms include hypotension, coma and       respiratory failure occur.
 -chronic intoxification: cause infertility in men with effect on semen (10)

 Blood brain barrier. Image source here

Toxicity in animals
Toxicity occurs in animals when given an excessive dose of the medication (10 to 20 times the recommended dose).

• Dilated pupils.
• Loss of appetite.
• Disorientation.
• Tremors/Seizures

Routes of administration

 In humans: Oral is the major route.
 In animals: parenteral, oral and topically as a spot on (flea repellant) are the major routes

Drug Resistance

– Resistance seen in cattle and small ruminant Cooperia Species.
– No known resistance in Canine heartworm parasites (dirofilaria immitis)
– No known resistance in Equine Strongyloides parasites.
– No known resistance in Human Onchocerca volvulus

Genetic susceptibility to avermectin toxicity

o Invertebrates more susceptible than mammals
o Lack of blood brain barrier leads to high susceptibility
o Lack of p -glycoprotein leads to high susceptibility
o Presence of glutamate-gated chloride channels leads to high susceptibility

Diagnosis/Tests

• History of exposure
• Serum level concentration
• Genetic test- MDRI gene mutation test in dogs
• ELISA Test Kit for quantitative analysis of Avermectin in meat, fish, milk and urine samples.

Avermectin Elisa test kit image source here

Treatment

• There is no known antidote
• No specific treatment
• symptomatic management
• supportive treatment includes
– decontamination of any topical sprays with soap and water
– remove oral ingestion by vomiting, followed by activated charcoal with a cathartic
– fluid therapy
– nutritional support
– monitoring of electrolytes
– respiratory (ventilator) support
– Atropine for severe bradycardia.
Signs may continue for weeks and recovery may take days to weeks but with continue supportive care recovery is expected.

References
1. Campbell WC. History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr Pharm Biotechnol. 2012;13(6):853‐865. doi:10.2174/138920112800399095.
2. Burg R.W., Stapley E.O. (1989) Isolation and Characterization of the Producing Organism. In: Campbell W.C. (eds) Ivermectin and Abamectin. Springer, New York, NY.
3. Omura S. Ivermectin: 25 years and still going strong. Int J Antimicrob Agents. 2008;31(2):91‐98. doi:10.1016/j.ijantimicag.2007.08.023.
4. Burg RW, Miller BM, Baker EE, et al. Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob Agents Chemother. 1979;15(3):361‐367. doi:10.1128/aac.15.3.361
5. Crump A, Ōmura S. Ivermectin, ‘wonder drug’ from Japan: the human use perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(2):13‐28. doi:10.2183/pjab.87.13
6. Hotson IK. The avermectins: A new family of antiparasitic agents. Journal of the South African Veterinary Association. 1982 Jun;53(2):87-90.
7. Zhang J, Yan YJ, An J, et al. Designed biosynthesis of 25-methyl and 25-ethyl ivermectin with enhanced insecticidal activity by domain swap of avermectin polyketide synthase. Microbial Cell Factories. 2015 ;14:152. DOI: 10.1186/s12934-015-0337-y.
8. Aminiahidashti H, Jamali SR, Heidari Gorji AM. Conservative care in successful treatment of abamectin poisoning. Toxicology International. 2014 Sep-Dec;21(3):322-324. DOI: 10.4103/0971-6580.155386.
9. Chung K, Yang CC, Wu ML, Deng JF, Tsai WJ. Agricultural avermectins: an uncommon but potentially fatal cause of pesticide poisoning. Ann Emerg Med. 1999;34(1):51‐57. doi:10.1016/s0196-0644(99)70271-4
10. Celik-Ozenci C, Tasatargil A, Tekcan M, et al. Effect of abamectin exposure on semen parameters indicative of reduced sperm maturity: a study on farmworkers in Antalya (Turkey). Andrologia. 2012;44(6):388‐395. doi:10.1111/j.1439-0272.2012.01297.