Pathways

Trabectedin is an antineoplastic from the alkylating agent drug class. It is derived from a marine-derived antitumor molecule discovered in the Caribbean tunicate Ecteinascidia turbinata. This drug is indicated in the treatment of advanced soft tissue sarcoma (liposarcoma or leiomyosarcoma) in Europe, Russia, and South Korea. It is also approved as an orphan drug by the FDA for the treatment of soft tissue sarcomas and ovarian cancer. Trabectedin binds covalently to the DNA minor groove. This molecule binds and alkylates guanine bases to the N2 position with its two rings in its structure, causing the equivalent of a functional interstrand crosslink. The third ring protrudes from the DNA strand which lets it interact with nearby nuclear proteins. It affects various transcription factors involved in cell proliferation via the transcription-coupled nucleotide excision repair system (NER). With this mechanism of action, trabectedin blocks the cell cycle at the G2 phase, resulting in the apoptosis of the cancerous cell, This drug is administered as an intravenous injection.

Tramadol is an analgesic drug consisting of two enantiomer forms (+)-Tramadol and (-)-Tramadol. Both contribute to pain relief by inhibiting pain transmission in the spinal cord via different mechanisms. (+)-Tramadol is a selective agonist of the mu receptor (OP3) inhibiting serotonin reuptake, while (-)-Tramadol inhibits norepinephrine reuptake in the central nervous system. Although tramadol is structurally related to codeine and morphine, it’s affinity for the mu receptor compared to other opioids is significantly less. Therefore tramadol is used when treatment with strong opioids is not necessary since it’s pharmacodynamic and pharmacokinetic properties suggest the low likelihood of patients becoming dependent.

Tramadol (also named Ultram) is a class of opioid pain medication that used for treating pain. Metabolism of tramadol mainly happened in liver cell. The N-demethylation of tramadol is catalyzed by the cytochrome CYP3A4 and CYP2B6 to form N-Desmethyltramadol, which further metabolized to N,N-Didesmethyltramadol through CYP3A4 and CYP2B6 and to N,O-Didesmethyltramadol through CYP2D6. The O-demethylation of tramadol is catalyzed by the cytochrome CYP2D6 to form O-Desmethyltramadol, which further metabolized to O-Desmethyltramadol glucuronide through UDP-glucuronosyltransferase 2B7 and UDP-glucuronosyltransferase 1-8. O-Desmethyltramadol can also be metabolized to N,O-Didesmethyltramadol through CYP2D6.

Tramadol is a centrally acting synthetic opioid agonist and SNRI used for the management of moderate to severe pain in adults. It is structurally related to codeine and morphine. It main mechanism of action is on mu-opioid receptors and SNRIs, but it also known to effect pain modulators such as adrenoreceptors, neurokinin receptors, voltage-gated sodium channels, capsaicin receptors, muscarinic receptors (M1 and M3), NMDA receptors, adenosine receptors, and nicotinic acetylcholine receptors. Tramadol diffuses across the blood-brain barrier after being absorbed by the intestine. It then inhibits NMDA receptors in the brain. This prevents glutamate from binding to NMDA receptors, which prevents calcium from entering the postsynaptic neuron which leads to hyperpolarization.

Tramadol is a centrally-acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain in adults. Tramadol 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. O-desmethyltramadol 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.

Trandolapril is an angiotensin-converting enzyme (ACE) inhibitor for the conversion of angiotensin I into angiotensin II. Angiotensin II is a critical circulating peptide hormone that has powerful vasoconstrictive effects and increases blood pressure. Trandolapril is used to treat hypertension, high blood pressure, congestive heart failure, and chronic renal failure as it decreases blood pressure. Trandolapril is converted into trandolaprilat through the liver after being ingested which travels in the blood to inhibit ACE which is from the lungs. Angiotensin has many vasoconstrictive effects by binding to angiotensin II type 1 receptor (AT1) in blood vessels, kidneys, hypothalamus, and posterior pituitary. In blood vessels, AT1 receptors cause vasoconstriction in the tunica media layer of smooth muscle surrounding blood vessels increasing blood pressure. Less angiotensin II that is circulating lowers the constriction of these blood vessels. AT1 receptors in the kidney are responsible for the production of aldosterone which increases salt and water retention which increases blood volume. Less angiotensin II reduces aldosterone production allowing water retention to not increase. AT1 receptors in the hypothalamus are on astrocytes which inhibit the excitatory amino acid transporter 3 from up-taking glutamate back into astrocytes. Glutamate is responsible for the activation of NMDA receptors on paraventricular nucleus neurons (PVN neurons) that lead to thirst sensation. Since angiotensin II levels are lowered, the inhibition of the uptake transporter is not limited decreasing the amount of glutamate activating NMDA on PVN neurons that make the individual crave drinking less. This lowers the blood volume as well. Lastly, the AT1 receptors on posterior pituitary gland are responsible for the release of vasopressin. Vasopressin is an anti-diuretic hormone that cases water reabsorption in the kidney as well as causing smooth muscle contraction in blood vessels increasing blood pressure. Less angiotensin II activating vasopressin release inhibits blood pressure from increasing. Overall, Trandolapril inhibits the conversion of angiotensin I into angiotensin II, a powerful vasoconstrictor and mediator of high blood pressure so decreasing levels of angiotensin will help reduce blood pressure from climbing in individuals. Overdose symptoms are due to severe hypotension leading experiencing effects such as cough, headache, and dizziness.