Browsing Pathways

Pafolacianine is a folate analogue used for the treatment of ovarian cancer. It targets the folate receptor in cancer cells where they are overexpressed. Pafolacianine binds to the receptor and is absorbed via receptor-mediated endocytosis. It is an optical imaging drug that binds to the overexpressed folate receptors in cancer cells that allows the visualization of the tumors. The metabolism of pafolacianine is not known, with the knowledge cytochrome P450 enzymes do not metabolize the drug. It is administered intravenously and is eliminated through the urine and feces.

Methylnaltrexone, also known as Relistor, is a μ-opioid antagonist. This drug is used in the treatment of opioid-induced constipation in palliative patients that are not responding to laxative therapy. This drug acts on the gastrointestinal tract to decrease opioid-induced constipation without producing analgesic effects or withdrawal symptoms as it does not cross the blood-brain barrier. Methylnaltrexone is given as a subcutaneous injection or as an oral tablet. Methylnaltrexone is a quaternary derivative of naltrexone. The most common (>5%) adverse reactions reported with methylnaltrexone bromide are abdominal pain, flatulence, nausea, dizziness, diarrhea, and hyperhidrosis. Methylnaltrexone 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. Methylnaltrexone 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.

Alvimopan, also known as Entereg, is an opioid antagonist used to reduce the healing time of the upper and lower GI tract following surgical procedures. It is a μ-opioid antagonist action only on the peripheral receptors and not on the one in the central nervous system. Alvimopan competitively binds to the mu-opioid receptors in the GI tract, alvimopan owes its selectivity for peripheral receptors to its pharmacokinetics. The drug acts in the gastrointestinal tract by competing to bind the mu-opioid receptor. Alvimopan differs from other peripherally acting mu-receptor antagonists such as methylnaltrexone due to only acting on peripheral opioid receptors. It is used to permit a faster recovery of patients after surgical procedures that slow the GI tract transit (postoperative ileus). This drug is administered as an oral capsule. Alvimopan 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. Alvimopan 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.

Pentazocine, the first mixed agonist-antagonist analgesic to be marketed, is an analgesic that can relieve moderate to severe pain. Pentazocine can bind as an antagonist to the mu-type opioid receptors and as an agonist of the kappa-type opioid receptor on neurons of the central nervous system (CNS). The binding of pentazocine on mu-type opioid receptors and kappa-type opioid receptors can lead to decreased levels of neuronal excitability and hyperpolarization. The preponderance of evidence suggests that pentazocine antagonizes the opioid effects by simply competing for the same receptor sites, primarily the opioid mu receptor. This drug is available as an oral tablet or as an injection (intramuscular, intravenous, or subcutaneous). Pentazocine 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. Pentazocine 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.

Felbamate is an anticonvulsant used to treat severe epilepsy, particularly in adults. The mechanism by which Felbamate exerts its anticonvulsant activity is unknown, but in animal tests felbamate has properties in common with other marketed anticonvulsants. In vitro studies have found that it may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate(NMDA) receptor-ionophore complex. This antagonism of the NMDA receptor blocks the glutamate from activating the receptor and prevents calcium from entering the neuron. This causes hyperpolarization of the neuron which increases the threshold for neuron activation, increasing the seizure threshold and decreasing seizure spread. It has also been indicated that Felbamate has inhibitory actions on GABA receptors and benzodiazepine receptors.

Oxprenolol is a non-selective beta blocker. It can be administered orally, where it passes through hepatic portal circulation, and enters the bloodstream and travels to act on cardiomyocytes. In bronchial and vascular smooth muscle, oxprenolol can compete with epinephrine for beta-2 adrenergic receptors. By competing with catecholamines for adrenergic receptors, it inhibits sympathetic stimulation of the heart. The reduction of neurotransmitters binding to beta receptor proteins in the heart inhibits adenylate cyclase type 1. Because adenylate cyclase type 1 typically activates cAMP synthesis, which in turn activates PKA production, which then activates SRC and nitric oxide synthase, its inhibition causes the inhibition of cAMP, PKA, SRC and nitric oxide synthase signaling. Following this chain of reactions, we see that the inhibition of nitric oxide synthase reduces nitric oxide production outside the cell which results in vasoconstriction. On a different end of this reaction chain, the inhibition of SRC in essence causes the activation of Caspase 3 and Caspase 9. This Caspase cascade leads to cell apoptosis. The net result of all these reactions is a decreased sympathetic effect on cardiac cells, causing the heart rate to slow and arterial blood pressure to lower; thus, oxprenolol administration and binding reduces resting heart rate, cardiac output, afterload, blood pressure and orthostatic hypotension. By prolonging diastolic time, it can prevent re-infarction. One potentially less than desirable effect of non-selective beta blockers like oxprenolol is the bronchoconstrictive effect exerted by antagonizing beta-2 adrenergic receptors in the lungs. Clinically, it is used to increase atrioventricular block to treat supraventricular dysrhythmias. Oxprenolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis. Some side effects of using oxprenolol may include lightheadedness, headache, weakness, and irritability.

Lacidipine is a lipophilic dihydropyridine calcium channel blocker with a slow onset of action used to treat hypertension. Lacidipine is a lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity. Due to its long duration of action, lacidipine does not lead to reflex tachycardia. It displays specificity in the vascular smooth muscle, where it acts as an antihypertensive agent to dilate peripheral arterioles and reduce blood pressure. Lacidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure. By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel. Possible side effects of using lacidipine may include dizziness, headache, nausea, and weakness.

Nitrendipine is a dihydropyridine calcium channel blocker indicated in the treatment of arterial hypertension. Nitrendipine is a calcium channel blocker with marked vasodilator action. It is an effective antihypertensive agent and differs from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive. By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nitrendipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. It targets the alpha-1C, alpha-2/delta-1, beta-2, alpha-1D, and alpha-1S subunits of the channel. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Nitrendipine is administered as an oral tablet. Some side effects of using nitrendipine may include headache, flushing, anxiety, and dizziness.

Lercanidipine is a calcium channel blocker of the dihydropyridine class for the management of hypertension. It can be found under the brand name Zanidip. Lercanidipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Lercanidipine is similar to other peripheral vasodilators. Lercanidipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Possible side effects of using lercanidipine may include headaches, palpitations, flushing, and oedema.

Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor belonging to the class of antidepressants called MAOIs. This drug is indicated in the treatment of major depression, dysthymic disorder, and atypical depression. It also is useful in panic and phobic disorders. The monoamine oxidase is an enzyme that catalyzes the oxidative deamination of many amines like serotonin, norepinephrine, epinephrine, and dopamine. There are 2 isoforms of this protein: A and B. The first one is found in cells located in the periphery and breakdown serotonin, norepinephrine, epinephrine, dopamine, and tyramine. The second one, the B isoform, breakdowns phenylethylamine, norepinephrine, epinephrine, dopamine, and tyramine. This isoform is found in the extracellular tissues and mostly in the brain. The mechanism of action of the MAOIs is still not determined, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. MAO A inhibition is thought to be more relevant to antidepressant activity than the inhibition caused by MAO B. Selective MAO B inhibitors have no antidepressant effects. An overdose of this drug will result in insomnia, restlessness, and anxiety. Hypotension, dizziness, weakness, and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. This drug is administered as an oral tablet.