Browsing Pathways

Tranexamic acid is a synthetic derivative of lysine used as an antifibrinolytic in the treatment and prevention of major bleeding. It targets plasminogen in blood vessels where these clots occur. The clotting process consists of two pathways, intrinsic and extrinsic, which converge to create stable fibrin which traps platelets and forms a hemostatic plug. The intrinsic pathway is activated by trauma inside the vasculature system, when there is exposed endothelial collagen. Endothelial collagen only becomes exposed when there is damage. The pathway starts with plasma kallikrein activating factor XII. The activated factor XIIa activates factor XI. Factor IX is then activated by factor XIa. Thrombin activates factor VIII and a Calicum-phospholipid-XIIa-VIIIa complex forms. This complex then activates factor X, the merging point of the two pathways. The extrinsic pathway is activated when external trauma causes blood to escape the vasculature system. Activation occurs through tissue factor released by endothelial cells after external damage. The tissue factor is a cellular receptor for factor VII. In the presence of calcium, the active site transitions and a TF-VIIa complex is formed. This complex aids in activation of factors IX and X. Factor V is activated by thrombin in the presence of calcium, then the activated factor Xa, in the presence of phospholipid, calcium and factor Va can convert prothrombin to thrombin. The extrinsic pathway occurs first, producing a small amount of thrombin, which then acts as a positive feedback on several components to increase the thrombin production. Thrombin converts fibrinogen to a loose, unstable fibrin and also activates factor XIII. Factors XIIIa strengthens the fibrin-fibrin and forms a stable, mesh fibrin which is essential for clot formation. The blood clot can be broken down by the enzyme plasmin. Plasmin is formed from plasminogen by tissue plasminogen activator. Tranexamic acid competitively and reversibly inhibits the activation of plasminogen via binding at several distinct sites, including four or five low-affinity sites and one high-affinity site. Plasmin is unable to be formed form plasminogen, and therefore, dissolution of the fibrin clot is prevented. Adverse effects such as seizures, headaches, backache, abdominal pain, nausea, vomiting, diarrhea, fatigue, pulmonary embolism, deep vein thrombosis, anaphylaxis, impaired color vision, and other visual disturbances can occur from the use of Tranexamic acid.

Docetaxel is a taxane/taxoid antineoplastic agent used to treat ovarian and breast cancer. In comparison to paclitaxel, docetaxel has a higher binding affinity for tubulin, specifically the beta subunit. Docetaxel binds to tubulin dimers and enhances the polymerization of microtubules which destroys the cell's ability to use its cytoskeleton in a flexible manner. This causes the formation of discrete bundles of stable microtubules and inhibits the cellular replication of cancerous cells. It is administered as an intravenous injection. Docetaxel has dose-limiting toxic properties that cause myelosuppression, neutropenia, peripheral neurotoxicity, and mucositis. Docetaxel is metabolized by CYP3A4 so patients taking docetaxel should avoid grapefruits and other drugs that interfere with CYP3A4 metabolism.

Amikacin is a semi-synthetic aminoglycoside antibiotic that is used to treat infections caused by both positive and negative strains of Gram bacteria, as it is considered bacteriocidal. It is commonly administered intravenously or intramuscular injection, and is used to successfully treat bacterial infections caused by Pseudomonas species, Escherichia coli, species of indole-positive Proteus, indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter species. Amikacin enters the bacterial cell and interacts in the cytosol with the bacterial ribosome 30S subunit, this interferes with mRNA binding and tRNA acceptor sites which halts protein synthesis. With protein synthesis inhibited this leads to the formation of non-functional and defective peptides. The structure of Amikacin allows it to enter the body and minimize enzymatic deactivation, this is helpful as it reduces bacterial resistance to the drug. 94%-98% of Amikacin is eliminated by the kidneys, relatively unchanged within a 24 hour period. Patients with renal impairment have more difficulty clearing Amikacin and doses have to be adjusted accordingly so no harm comes to the patient. If Amikacin accumulates or too much is administered it can lead to nephrotoxicity, ototoxicity, and neuromuscular blockade. Caution should be taken by patients who are pregnant or breastfeeding as the possible effects of Amikacin on fetal development are unknown and could potentially be harmful.

Acebutolol is a cardioselective 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, acebutolol 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, acebutolol administration and binding reduces resting heart rate, cardiac output, afterload, blood pressure and orthostatic hypotension. By prolonging diastolic time, it can prevent re-infarction. Clinically, it is used to increase atrioventricular block to treat supraventricular dysrhythmias. Acebutolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Alprenolol is a non-selective beta blocker for the treatment of hypertension, edema, ventricular tachycardias, and atrial fibrillation. It can be administered intravenously or orally, where it passes through hepatic portal circulation, and enters the bloodstream and travels to act on cardiomyocytes. In bronchial and vascular smooth muscle, alprenolol 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, alprenolol 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 alprenolol 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. Alprenolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Gemcitabine is a nucleoside metabolic inhibitor used as adjunct therapy in the treatment of certain types of ovarian cancer, non-small cell lung carcinoma, metastatic breast cancer, and as a single agent for pancreatic cancer. As a prodrug, gemcitabine is transformed into its active metabolites that work by replacing the building blocks of nucleic acids during DNA elongation, arresting tumor growth and promoting apoptosis of malignant cells. After uptake into malignant cells, gemcitabine is phosphorylated by deoxycytidine kinase to form gemcitabine monophosphate, which is then converted to the active compounds, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA, thereby competitively inhibiting DNA chain elongation. The non-terminal position of dFdCTP in the DNA chain prevents detection of dFdCTP in the chain and repair by proof-reading 3′5′-exonuclease: this process is referred to as "masked DNA chain termination." Incorporation of dFdCTP into the DNA chain ultimately leads to chain termination, DNA fragmentation, and apoptotic cell death of malignant cells. Gemcitabine is cell cycle specific and inhibits the S phase and the progression through the G1/s phase boundary.

Ethacrynic acid is a loop diuretic drug, administered orally or intravenously to treat high blood pressure and edema caused by diseases like congestive heart failure, liver failure, and kidney failure. It targets the nephrons of the kidney, mainly the ascending limb of the loop of henle. The basolateral membrane of the ascending loop of henle contains the Na+/K+ ATPase, Cl- channel and K+/Cl- co-transporter which are essential for the function for ion and water reabsorption. The Na+/K+ ATPase pumps Na+ from the cell into the peritubular fluid and K+ from the peritubular fluid into the cell. The K+/Cl- co-transporter moves K+ and Cl- from the cell into the peritubular fluid and the Cl- channel transports Cl- from the cell into the peritubular fluid. The apical membrane contains the Na+/K+/2Cl- co-transporter (NKCC2) and the K+ channel. The NCKCC2 is responsible for reabsorption Na+, K+ and Cl- from the lumen into the cells of the loop of henle. The K+ channel transports K+ from the cells back into the lumen. Ethacrynic acid is transported from the capillaries into the cells of the loop of henle then transported from the cell into the lumen. Ethacrynic acid binds to NKCC2 transporter and inhibits it, preventing Na+, K+ and Cl- reabsorption from the lumen. The concentration of these ions builds up in the lumen, decreasing the slope of the concentration gradient between the cells and the lumen. Since water reabsorption is linked to ion reabsorption, water reabsorption is also decreased, resulting in a greater volume of water being excreted in urine. This is relieves symptoms such as swelling/ edema and hypertension in patients. Ethacrynic acid may also inhibit sodium and chloride reabsorption in the proximal and distal tubules. Side effects such as nausea, vomiting, loss of appetite, stomach pain, difficulty swallowing, loss of appetite, thirst, muscle cramps, weakness, headache, diarrhea may occur from taking ethacrynic acid.

Bumetanide is a loop diuretic drug, administered orally or intravenously the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. It targets the nephrons of the kidney, mainly the ascending limb of the loop of henle. The basolateral membrane of the ascending loop of henle contains the Na+/K+ ATPase, Cl- channel and K+/Cl- co-transporter which are essential for the function for ion and water reabsorption. The Na+/K+ ATPase pumps Na+ from the cell into the peritubular fluid and K+ from the peritubular fluid into the cell. The K+/Cl- co-transporter moves K+ and Cl- from the cell into the peritubular fluid and the Cl- channel transports Cl- from the cell into the peritubular fluid. The apical membrane contains the Na+/K+/2Cl- co-transporter (NKCC2) and the K+ channel. The NCKCC2 is responsible for reabsorption Na+, K+ and Cl- from the lumen into the cells of the loop of henle. The K+ channel transports K+ from the cells back into the lumen. Bumetanide is transported from the capillaries into the cells of the loop of henle then transported from the cell into the lumen. Bumetanide binds to NKCC2 transporter and inhibits it, preventing Na+, K+ and Cl- reabsorption from the lumen. The concentration of these ions builds up in the lumen, decreasing the slope of the concentration gradient between the cells and the lumen. Since water reabsorption is linked to ion reabsorption, water reabsorption is also decreased, resulting in a greater volume of water being excreted in urine. This is relieves symptoms such as swelling/ edema in patients. Side effects such as peeing more than normal, feeling thirsty and dry mouth, losing a bit of weight (as your body loses water), headaches, feeling confused or dizzy, muscle cramps or weak muscles may occur when taking bumetanide.

Bupranolol is a non cardioselective beta blocker similar to propranolol. 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, bupranolol 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, bupranolol 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 bupranolol 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. Bupranolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Carvedilol is a cardio 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. Carvedilol is a racemic mixture where the S(-) enantiomer is a beta adrenoceptor blocker and the R(+) enantiomer is both a beta and alpha-1 adrenoceptor blocker. In bronchial and vascular smooth muscle, carvedilol 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, carvedilol 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 carvedilol 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. Carvedilol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.