Mechanism of Action of Ivermectin
Ivermectin works primarily by binding selectively to glutamate-gated chloride ion channels in invertebrate nerve and muscle cells, causing hyperpolarization, paralysis, and death of parasites. 1
Primary Mechanism of Action
Ivermectin, a member of the avermectin class of antiparasitic agents, has a unique mode of action that explains its effectiveness against various parasites:
- Binds with high affinity to glutamate-gated chloride ion channels found in invertebrate nerve and muscle cells 1
- Increases cell membrane permeability to chloride ions, resulting in hyperpolarization 1
- Causes paralysis and death of the parasite through this hyperpolarization 1, 2
- May also interact with other ligand-gated chloride channels, such as those gated by gamma-aminobutyric acid (GABA) 1
The selective activity of ivermectin against parasites is due to:
- Mammals do not have glutamate-gated chloride channels 1
- Ivermectin has low affinity for mammalian ligand-gated chloride channels 1
- The drug does not readily cross the blood-brain barrier in humans 1
Molecular Interactions
Research has provided detailed insights into how ivermectin interacts with its target receptors:
- Binds to the transmembrane domain in a cleft at the interface of adjacent subunits of glutamate-gated chloride channels 3
- Forms hydrogen bonds that help attach ivermectin to its binding site 3
- Due to its lipophilic nature, likely accumulates in the membrane and binds to its site 3
- Induces a global conformational change that propagates from the transmembrane domain to the neurotransmitter binding site 3
Pharmacokinetics
Understanding the pharmacokinetics of ivermectin helps explain its clinical efficacy:
- After oral administration, plasma concentrations are approximately proportional to the dose 1
- Peak plasma concentrations occur approximately 4 hours after dosing 1
- Metabolized in the liver primarily by CYP3A4 1
- Excreted almost exclusively in feces over approximately 12 days, with less than 1% excreted in urine 1
- Plasma half-life is approximately 18 hours following oral administration 1
- Bioavailability increases approximately 2.5-fold when administered with a high-fat meal 1
Clinical Applications
Ivermectin's mechanism of action makes it effective against:
- Intestinal strongyloidiasis (Strongyloides stercoralis) 1
- Onchocerciasis (river blindness) caused by Onchocerca volvulus 1
- Microfilariae of Wuchereria bancrofti and Brugia malayi (lymphatic filariasis) 4
- Crusted (Norwegian) scabies and head lice 4
Important Caveats
- Ivermectin can cause toxicity by binding to glutamate, GABA, and glycine receptors in humans, though this typically occurs at much higher doses than therapeutic levels 5
- Common adverse effects include edema, rash, headache, and ocular complaints 4, 5
- Risk of severe adverse events is high in individuals with high Loa loa microfilarial loads (>8000 microfilaria/ml) 6
- Ivermectin is a substrate for P-glycoprotein; genetic polymorphisms or co-administration of P-glycoprotein inhibitors may increase neurotoxicity 5
- Despite in vitro antiviral effects at very high concentrations, ivermectin is not recommended for COVID-19 treatment due to insufficient clinical evidence and safety concerns 4, 5
Resistance Concerns
- Reports of O. volvulus responding poorly to the anti-fecundity effect of ivermectin in some regions suggest possible emergence of resistance 6
- Genetic studies have shown polymorphisms or changes in specific genes responsible for suboptimal responses in parasite populations exposed to years of ivermectin treatment 6
- Genome-wide analysis revealed that evolution of suboptimal responses to ivermectin is determined by selective sweeps of pre-existing quantitative trait loci 6
Understanding ivermectin's mechanism of action is crucial for appropriate clinical use and for developing strategies to address potential resistance.