ATC Group: N07XX Other nervous system drugs

Amifampridine blocks voltage-dependent potassium channels, thereby prolonging pre-synaptic cell membrane depolarisation. Prolonging the action potential enhances the transport of calcium into the nerve ending. The resulting increase in intra-cellular calcium concentrations facilitates exocytosis of acetylcholine-containing vesicles, which in turn enhances neuromuscular transmission.

Edaravone is a member of the substituted 2-pyrazolin-5-one class. It is used for the treatment of amyotrophic lateral sclerosis (ALS). The mechanism by which edaravone exerts its therapeutic effect in patients with ALS is unknown.

Eplontersen is a N-acetylgalactosamine (GalNAc)-conjugated 2′-O-2-methoxyethyl-modified chimeric gapmer antisense oligonucleotide (ASO) with a mixed backbone of phosphorothioate and phosphate diester internucleotide linkages. The GalNAc conjugate enables targeted delivery of the ASO to hepatocytes. The selective binding of eplontersen to the transthyretin (TTR) messenger RNA (mRNA) within the hepatocytes causes the degradation of both mutant and wild type (normal) TTR mRNA. This prevents the synthesis of TTR protein in the liver, resulting in significant reductions in the levels of mutated and wild type TTR protein secreted by the liver into the circulation.

Fampridine is a potassium channel blocker. By blocking potassium channels, fampridine reduces the leakage of ionic current through these channels, thereby prolonging repolarization and thus enhancing action potential formation in demyelinated axons and neurological function.

Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. It is used for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with Friedreich’s ataxia is unknown. Omaveloxolone has been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. There is substantial evidence that Nrf2 levels and activity are suppressed in cells from patients with Friedreich’s ataxia.

Patisiran is a double-stranded small interfering ribonucleic acid (siRNA) that specifically targets a genetically conserved sequence in the 3’ untranslated region of all mutant and wild-type TTR mRNA. Through a natural process called RNA interference (RNAi), patisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in a reduction of serum TTR protein, a carrier of retinol binding protein which facilitates transport of vitamin A in the blood.

Pitolisant is a potent, orally active histamine H₃-receptor antagonist/inverse agonist which, via its blockade of histamine auto-receptors enhances the activity of brain histaminergic neurons, a major arousal system with widespread projections to the whole brain. Pitolisant also modulates various neurotransmitter systems, increasing acetylcholine, noradrenaline and dopamine release in the brain.

Riluzole is proposed to act by inhibiting glutamate processes. The mode of action is unclear. It is suggested that glutamate (the primary excitatory neurotransmitter in the central nervous system) plays a role for cell death in the ALS disease.

Tafamidis is a selective stabiliser of transthyretin (TTR). Tafamidis binds to TTR at the thyroxine binding sites, stabilising the tetramer and slowing dissociation into monomers, the rate-limiting step in the pathogenesis of transthyretin amyloidosis.

Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system. The precise mechanism by which tetrabenazine exerts its effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Neurotransmitter depletion by a single dose of tetrabenazine is reversible and lasts only a few hours.

SOD1-ALS is a primarily autosomal-dominant disorder affecting approximately 2% of the ALS population. Mutations in the SOD1 gene lead to accumulation of a toxic form of SOD1 protein. Tofersen is an antisense oligonucleotide (ASO) that is complementary to a portion of the 3′ untranslated region (3′UTR) of the mRNA for human SOD1 and binds to the mRNA by Watson-Crick base pairing (hybridisation). This hybridisation of tofersen to the cognate mRNA results in RNase-Hmediated degradation of the mRNA for SOD1, which reduces the amount of SOD1 protein synthesis.

Trofinetide is indicated for the treatment of Rett syndrome. The mechanism by which trofinetide exerts its therapeutic effects is unknown.

The mechanism of action of valbenazine for the treatment of tardive dyskinesia and chorea in patients with Huntington’s disease is unclear, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.

Vutrisiran is covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes. Through a natural process called RNA interference (RNAi), vutrisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in the reduction of variant and wild-type serum TTR protein levels.