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.

Naloxegol Pathway References