Pathways

Remdesivir is a nucleoside analog used to treat RNA virus infections, including COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was granted FDA emergency use Authorization on May 1, 2020, for use in adults and children with suspected or confirmed COVID-19 infection requiring hospitalization. It was fully approved by the FDA on October 22, 2020 for the treatment of COVID-19. The mechanism of the drug were found to be identical between SARS-CoV, SARS-CoV-2, and MERS-CoV. Severe acute respiratory syndrome conronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, and is a respiratory disease that is capable of progressing to viral pneumonia and acute respiratory distress syndrome (ARDS). COVID-19 can be fatal. Like other RNA viruses, SARS-CoV-2 depends on RNA-dependent RNA polymerase (RdRp) for genomic replication. Due to the much higher selectivity of mammalian DNA and RNA polymerases for ATP over remdesivir triphosphate, remdesivir is not a significant inhibitor of these mammalian enzymes. Remdesivir does, however, carry the risks for hypersensitivity reactions, including anaphylaxis, elevated transaminase levels and potential decreased efficacy when combined with hydroxychloroquine or chloroquine. SARS-CoV-2 lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. Viral RNA is released from the mature SARS-CoV-2 virion and translated at the endoplasmic reticulum. SARS-CoV-2 RNA is translated into Replicase polypotein 1ab by host ribosomes. Replicase Protein 1ab is cleaved by SARS-CoV-2 3C-like proteinase nsp5 and Papain-like protease nsp3 into various proteins required for RNA replication, mature virus synthesis, and the enzymes required for the cleavage of the polyprotein. These proteins include host translation inhibitor nsp1, non-structural protein 2, papain-like protease nsp3, non-structural protein 4, 3C-like proteinase nsp5, non-structural protein 6, non-structural protein 7, non-structural protein 8, RNA-capping enzyme subunit nsp9, non-structural protein 10, RNA-directed RNA polymerase nsp12, helicase nsp13, guanine-N7 methyltransferase nsp14, uridylate-specific endoribonuclease nsp15, and 2'-O-methyltransferase nsp16. SARS-CoV-2 RNA that was released from the virus is normally replicated by RNA polymerase which is comprised of nsp7, nsp8, and nsp12. Remdesivir is a phosphoramidite produg of a 1'-cyano-substituted adenosine nucleoside analogue that competes with ATP for incorporation into newly synthesized viral RNA by the RdRp complex. Remdesivir is cleaved to a monophosphate form through the actions of either carboxylesterase 1 or cathepsin A enzymes. Remdesivir nucleoside monophosphate is then phosphylated by undescribed kinases to remdesivir nucleoside triphosphate. Remdesivir Nucleoside Triphosphate inhibits RNA polymerase, by competing with ATP for incorporation into newly synthesized viral RNA. This prevents RNA replication from occurring. Because RNA replication does not occur, mature, infective viruses are unable to be assembled and released.

Metabolites of Remdesivir are predicted with biotransformer.

Remifentanil is a pharmacologically-active, synthetic, small molecule derived from fentanyl and belongs to a class of drugs called opioids. Opioids are therapeutically employed to achieve analgesia. Remifentanial’s rapid mechanism of action primarily involves its agonistic effects on mu-type opioid receptors which are inhibitory G-coupled protein receptors and lead to the inhibition of adenylate cyclase and decrease in cAMP production. Analgesia, anesthesia, and respiratory depression are a function of remifentanial’s action on these mu-type opioid receptors.

Remifentanil is a potent ultra short-acting synthetic opioid given to patients during surgery for pain relief and adjunctive to an anaesthetic. Remifentanil is a specific mu-type-opioid receptor agonist which means it reduces sympathetic nervous system tone, and causes respiratory depression and analgesia. Remifentanil binds to mu opioid receptors, stimulating the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as GABA is inhibited. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability. Remifentanil acts at A delta and C pain fibres in the dorsal horn of the spinal cord. By decreasing neurotransmitter action there is less pain transmittance into the spinal cord. This leads to less pain perception.

Remifentanil is a potent ultra short-acting synthetic opioid given to patients during surgery for pain relief and adjunctive to an anaesthetic. Remifentanil is a specific mu-type-opioid receptor agonist which acts in the brain, spinal cord, and peripherally. This means it reduces sympathetic nervous system tone, and causes respiratory depression and analgesia. Remifentanil binds to mu opioid receptors, stimulating the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as GABA is inhibited. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability. This leads to less activity in the brain which causes an anesthetic effect.

Metabolites of Remifentanil are predicted with biotransformer.