Pathways

Naldemedine, also known as Symproic, is an opioid receptor antagonist. It is used to treat opioid-induced constipation (OIC). It is a modified form of Naltrexone to which a side chain has been added to increase molecular weight and polar surface area to restrict the blood-brain barrier transportation. This allows it to antagonize only the peripheral effects of opioid drugs such as constipation. It antagonizes mu-, delta-, and kappa-opioid receptors. The binding of opioid agonists to peripheral mu-opioid receptors slows the transit of feces through the intestine resulting in constipation. By antagonizing mu-opioid receptors, naldemedine inhibits this effect in the GI tract. The most common adverse effects of naldemedine are abdominal pain, diarrhea, nausea, vomiting, and gastroenteritis. This drug is administered as oral tablets only. Naldemedine inhibits the mu-opioid receptor located on neurons in the intestine. This inhibits the exchange of GTP for GDP which is required to activate the G-protein complex. This prevents the Gi subunit of the mu opioid receptor from inhibiting adenylate cyclase, which can therefore continue to catalyze ATP into cAMP. cAMP increases the excitability in spinal cord pain transmission neurons which allows the patient to feel pain rather than the analgesic effects of opioids. The inhibition of Mu-type opioid receptors also prevents the Gi subunit of the mu opioid receptor from activating the inwardly rectifying potassium channel increasing K+ conductance which would cause hyperpolarization. Naldemedine also prevents the gamma subunit of the mu opioid receptor from inhibiting the N-type calcium channels on the neuron. This allows calcium to enter the neuron and depolarize. The inhibition of mu-opioid receptors prevents hyperpolarization in the neuron, allowing it to fire at a normal rate. The neuron is able to depolarize and the high concentration of calcium releases acetylcholine and nitric acid into the neuromuscular junction. Acetylcholine binds to nicotinic acetylcholine receptors on the smooth muscles of the intestines, causing muscle contraction. The nitric oxide diffuses into the myocyte and causes muscle relaxation. The rythmic action of the neurotransmitters creates the peristalsis and the good GI transit.

Metabolites of Naldemedine are predicted with biotransformer.

Nalidixic acid is a quinolone antibacterial used to treat urinary tract infections, taken orally. Nalidixic acid acts on gram-negative bacteria including the majority of E. Coli, Enterobacter species, Klebsiella species, and Proteus species. It is an inhibitor of the A subunit of bacterial DNA gyrase. The inhibition of DNA gyrase (topoisomerase II) and causes supercoiling of the bacterial DNA. This prevents DNA replication.

Metabolites of Nalidixic acid are predicted with biotransformer.

Nalmefene is an opioid antagonist used to reduce alcohol consumption and treat and prevent opioid overdose. This drug is a 6-methylene analogue of naltrexone. It acts as an antagonist at the mu (μ)-opioid and delta (δ)-opioid receptors. As an antagonist, nalmefene blocks ligands from binding to the opioid receptor. It is administered as oral tablets, intravenous injections, or in a nasal spray formulation (approved by the FDA in May 2023). Animal studies suggest that kappa-opioid receptor signaling blocks the acute reward and positive reinforcement effects of drugs (like opioids) by decreasing dopamine in the nucleus accumbens. In vivo, studies have demonstrated that nalmefene reduces alcohol consumption, possibly by modulating cortico-mesolimbic functions. Preclinical studies suggest that nalmefene restores alcohol-induced dysregulations of the MOR/endorphins and the KOR/dynorphin system. Nalmefene inhibits the exchange of GTP for GDP which is required to activate the G-protein complex. This prevents the Gi subunit of the mu opioid receptor from inhibiting adenylate cyclase, which can therefore continue to catalyze ATP into cAMP. cAMP increases the excitability in spinal cord pain transmission neurons which allows the patient to feel pain rather than the analgesic effects of opioids. The inhibition of Mu-type opioid receptors also prevents the Gi subunit of the mu opioid receptor from activating the inwardly rectifying potassium channel increasing K+ conductance which would cause hyperpolarization. Nalmefene also prevents the gamma subunit of the mu opioid receptor from inhibiting the N-type calcium channels on the neuron. This allows calcium to enter the neuron and depolarize. The inhibition of mu-opioid receptors prevents hyperpolarization in the neuron, allowing it to fire at a normal rate. The neuron is able to depolarize and the high concentration of calcium releases GABA into the synapse which binds to GABA receptors. GABA receptors inhibits dopamine cell firing in the pain transmission neurons. This prevents the analgesic and depressive effects of opioids, preventing opioid overdose. GABA also inhibits dopamine cell firing in the reward pathway which is the main cause of addiction to opioids and other drugs.

Metabolites of Nalmefene are predicted with biotransformer.

Naloxegol, for PEGylated naloxol, is a peripherally-selective opioid antagonist used to treat opioid-induced constipation. Its pegylated structure allows for high selectivity for peripheral opioid receptors and lack of entry into the central nervous system (through the blood-brain barrier). Naloxegol antagonizes mu, delta, and kappa opioid receptors, having a slightly better affinity to the mu receptor. Antagonism of gastrointestinal mu-opioid receptors by naloxegol inhibits opioid-induced delay of gastrointestinal transit time. This drug is only available as oral tablets. Naloxegol inhibits the mu-opioid receptor located on neurons in the intestine. This inhibits the exchange of GTP for GDP which is required to activate the G-protein complex. This prevents the Gi subunit of the mu opioid receptor from inhibiting adenylate cyclase, which can therefore continue to catalyze ATP into cAMP. cAMP increases the excitability in spinal cord pain transmission neurons which allows the patient to feel pain rather than the analgesic effects of opioids. The inhibition of Mu-type opioid receptors also prevents the Gi subunit of the mu opioid receptor from activating the inwardly rectifying potassium channel increasing K+ conductance which would cause hyperpolarization. Naloxegol also prevents the gamma subunit of the mu opioid receptor from inhibiting the N-type calcium channels on the neuron. This allows calcium to enter the neuron and depolarize. The inhibition of mu-opioid receptors prevents hyperpolarization in the neuron, allowing it to fire at a normal rate. The neuron is able to depolarize and the high concentration of calcium releases acetylcholine and nitric acid into the neuromuscular junction. Acetylcholine binds to nicotinic acetylcholine receptors on the smooth muscles of the intestines, causing muscle contraction. The nitric oxide diffuses into the myocyte and causes muscle relaxation. The rythmic action of the neurotransmitters creates the peristalsis and the good GI transit.