Ivermectin is a medication belonging to the avermectin class of drugs, which are compounds derived from the bacterium Streptomyces avermitilis. This antiparasitic agent gained significant recognition when its discoverers were awarded the Nobel Prize in Physiology or Medicine in 2015 for their work. Since its introduction in the 1980s, ivermectin has seen widespread use in treating various parasitic infections in both veterinary and human medicine globally. It has become a foundational treatment for numerous conditions caused by worms and arthropods.
Primary Antiparasitic Action
Ivermectin exerts its primary antiparasitic effect by targeting specific neuro-muscular pathways found in invertebrates. The drug selectively binds to glutamate-gated chloride ion channels, often referred to as GluCls, which are present in the nerve and muscle cells of various parasites, including nematodes and arthropods. These channels are distinct from those found in mammals.
Once ivermectin binds to these GluCl channels, it causes them to open permanently. This leads to a sustained influx of chloride ions into the parasite’s nerve and muscle cells. The continuous flow of negatively charged chloride ions results in a hyperpolarization of the cell membranes, making it harder for the cells to generate electrical signals.
The sustained hyperpolarization effectively paralyzes the parasite’s pharyngeal and somatic muscles, affecting feeding and movement. This paralysis prevents the parasite from feeding and moving. The inability to feed leads to starvation, while the muscular paralysis prevents the parasite from maintaining its position within the host, ultimately resulting in its death or expulsion from the body.
Selectivity for Invertebrates
Ivermectin’s effectiveness against parasites while generally maintaining a safety profile in humans at prescribed doses stems from specific biological differences between invertebrates and mammals. A primary reason is that mammals do not possess the same glutamate-gated chloride channels (GluCls) that ivermectin primarily targets in parasitic organisms. This absence means the drug does not directly interfere with a comparable primary target in human physiology.
While mammals do have other types of ligand-gated chloride channels, such as gamma-aminobutyric acid (GABA)-A receptors, ivermectin exhibits a lower affinity for these mammalian channels. This reduced binding affinity means that at therapeutic concentrations, ivermectin is less likely to significantly affect human neurological functions mediated by GABA receptors. However, at much higher concentrations, ivermectin can potentiate mammalian GABA-A gated chloride channels, which contributes to potential neurotoxicity in overdose situations.
A second significant factor contributing to its selective safety is the presence and function of the blood-brain barrier (BBB) in mammals. The BBB acts as a protective filter, regulating the passage of substances from the bloodstream into the central nervous system. A protein located within this barrier, known as P-glycoprotein, actively pumps ivermectin out of the brain, preventing it from accumulating to high concentrations where it could potentially interact with mammalian GABA receptors.
Investigated Cellular Effects
Beyond its established antiparasitic action, ivermectin has demonstrated other cellular effects, primarily observed in laboratory studies. One proposed mechanism involves its potential antiviral properties, where ivermectin has been shown to inhibit the importin (IMP) α/β1 heterodimer. This protein complex acts as a cellular shuttle, facilitating the movement of certain viral proteins into the host cell’s nucleus, a step often necessary for viral replication.
Laboratory studies indicate that ivermectin can bind to importin α, disrupting the IMPα/β1 heterodimer formation. By blocking this cellular transport pathway, ivermectin can prevent viral proteins from reaching the nucleus, thereby impeding the replication cycles of various viruses, including HIV-1, dengue virus, and SARS-CoV-2. These findings highlight a potential broad-spectrum antiviral activity, though the concentrations required for such effects in vitro often exceed those safely achievable in humans.
Ivermectin also exhibits anti-inflammatory properties in cellular and animal models. These effects appear to involve the modulation of pathways that regulate the production of inflammatory molecules. Studies indicate that ivermectin can suppress the activity of the nuclear factor kappa-light-chain enhancer of activated B (NF-κB) pathway. This pathway regulates the immune response and plays a significant role in the production of pro-inflammatory cytokines.
Inhibition of the NF-κB pathway by ivermectin has been associated with a reduction in the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These cytokines contribute to inflammatory responses. While these anti-inflammatory effects have been demonstrated in cell cultures and some animal studies, their consistent clinical relevance and therapeutic application in human inflammatory conditions remain under investigation.
Pharmacokinetics in the Human Body
Following oral administration, ivermectin is absorbed into the systemic circulation, with absorption improved when taken with a high-fat meal. Peak plasma concentrations are reached approximately 3 to 5 hours after ingestion, and these levels are proportional to the administered dose. The drug’s high fat-solubility allows it to distribute widely throughout the body’s tissues.
Ivermectin undergoes extensive metabolism primarily in the liver, with the cytochrome P450 system playing a significant role. The enzyme CYP3A4 is responsible for the drug’s biotransformation. This metabolic process converts ivermectin into various metabolites, which are then prepared for elimination from the body.
The excretion of ivermectin and its metabolites occurs almost exclusively through the feces over about 12 days. Less than one percent of the administered dose is excreted unchanged in the urine. The plasma half-life of ivermectin in humans is approximately 18 hours, indicating a relatively slow elimination process from the bloodstream.