Browsing Pathways

Levobunolol is a ophthalmic beta-blocker, equally effective at both β(1)- and β(2)-receptor sites. 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, levobunolol 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, levobunolol 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 levobunolol 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. Levobunolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Torasemide is a loop diuretic drug, administered orally or intravenously to treat hypertension and edema associated with heart failure, renal failure, or liver disease. 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. Torasemide is transported from the capillaries into the cells of the loop of henle then transported from the cell into the lumen. Torasemide 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 frequent urination, headache, cough, sore throat, hearing loss, ringing in your ears, upset stomach, constipation, diarrhea, weakness and excessive thirst may occur when taking torasemide.

Paromomycin is an aminoglycoside antibiotic that is commonly used to treat acute or chronic intestinal amebiasis and also used in adjunction for managing hepatic comas. It is produced from Streptomyces rimosus var. paromomycinus and acts to inhibit protein synthesis by binding to 16S ribosomal RNA. This halts protein synthesis as paramomycin binds to the A site which impairs any further addition to the polypeptide chain as the tRNA cannot bind to the A site and take on the growing polypeptide chain whilst also adding the amino acid it carrys to the chain. This leads to early termination of the polypeptide leading to a non functional protein being produced, continously inhibition leads to accumulation of defective proteins and bacterial death.

Antrafenine is a piperazine derivative drug that acts as an analgesic and anti-inflammatory drug used for the relief of mild to moderate pain. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 converts arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Antrafenine inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because antrafenine decrease PGE2 in the CNS, it has an antipyretic effect.

Vindesine is a semi-synthetic vinca alkaloid derived from vinblastine. This drug is used for the treatment of acute leukemia, malignant lymphoma, Hodgkin's disease, acute erythraemia, and acute panmyelosis. It is differentiated from natural alkaloids by its eight-catharanine ring. Administered intravenously, Vindesine acts on tumorous cells in the body to suppress their growth. Its main mechanism of action works by binding microtubules that are formed during the M phase of mitosis. This ceases the polymerization of microtubules, effectively pausing the cell at its G2/M phase. The disarray of microtubules induces two proteins; cellular tumor antigen p53 and cyclin-dependent kinase inhibitor p21. The latter protein works to inhibit cyclin-dependent kinases in the cell, which disrupt the phosphorylation of the apoptosis inhibitor Bcl-2. Bcl-2 suppresses apoptosis by regulating the permeability of the mitochondrial membrane but is unable to do so due to interrupted phosphorylation. The former protein, p53, acts on BAK and BAX to enact conformational changes, creating pores in the mitochondrial membrane that allow the exit of cytochrome c. Cytochrome c further activates caspases in the cell, which cleave essential cellular proteins. In this way, p53 and p21 work alongside each other to promote apoptosis and terminate unhealthy cells. Vindesine is especially valuable as a drug because it binds specifically to mitotic microtubules, likely decreasing its neurotoxicity.

Timolol is a non-selective beta-adrenergic blocker used in the treatment of elevated intraocular pressure in ocular hypertension or open angle glaucoma. Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye.

Statins are a class of medications that lower lipid levels and are administered to reduce illness and mortality in people who are at high risk of cardiovascular disease. Atorvastatin (trade name: Lipitor) is a well-tolerated orally-administered synthetic statin that reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, and very-low-density lipoprotein (VLDL)-cholesterol. It also increases levels of high-density lipoprotein (HDL)-cholesterol. Atorvastatin's efficacy is greater than other statins in reducing total cholesterol and LDL-cholesterol levels. This is theorized to be the result of a prolonged duration of HMG-CoA reductase inhibition. Reported side effects of atorvastatin include constipation, flatulence, dyspepsia (indigestion), abdominal pain, headache, and myalgia (muscle pain). The primary therapeutic mechanism of action of statins is the inhibition of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in hepatocytes. HMG-CoA reductase catalyzes the conversion of HMG-CoA into mevalonic acid, a precursor for cholesterol biosynthesis. Statins bind reversibly to the active site of HMG-CoA reductase and the subsequent structural change in the enzyme effectively disables it. Due to the resulting decrease in intracellular sterol levels, the ER membrane protein INSIG no longer binds to SREBP cleavage-activating protein (SCAP) which is, itself, bound to the transcription factor sterol regulatory element-binding protein (SREBP). Freed from INSIG, SCAP escorts SREBP to the Golgi apparatus from the ER as cargo in COPII vesicles. At the Golgi membrane, two proteases, S1P and S2P, sequentially cleave the SCAP-SREBP complex, releasing the mature form of SREBP into the cytoplasm. SREBP then translocates to the nucleus where it is transported into the nucleoplasm by binding directly to importin beta in the absence of importin alpha. SREBP binds to the sterol regulatory element (SRE) present in the promoter region of genes involved in cholesterol uptake and cholesterol synthesis, including the gene encoding the low-density lipoprotein (LDL) receptor (LDL-R). As a result, LDL-R gene transcription increases which then leads to an increased synthesis of the LDL-R protein. LDL-R localizes to the endoplasmic reticulum for transport and exocytosis to the cell surface. The elevated amount of LDL-R results in more circulating free LDL cholesterol binding and subsequent internalization via endocytosis. Lysosomal degradation of the internalized LDL cholesterol elevates cellular cholesterol levels to maintain homeostasis. This drug is administered as an oral tablet.

Streptomycin is an antibiotic that treats multi-drug-resistant bacterial strains. It is in the aminoglycosides family and it is derived from Streptomyces griseus which was the first effective antibiotic against Mycobacterium tuberculosis. It is now largely a second-line option due to the development of resistance and toxicity. Streptomycin goes through 3 phases in order to infiltrate the bacterial cell and inhibit protein synthesis: the first phase is the binding of polycationic drug to the negatively charged bacterial cell membrane which increases membrane permeability. The second phase is the entry of aminoglycoside through oxygen-dependent active transport into the cell where it then travels and binds to the 16rRNA and 30S ribosomal subunit. The final phase is the inhibition of protein synthesis and the accumulation of Streptomycin in the cell which further exacerbates its inhibition of protein synthesis, elongation, and ribosome recycling. It is mainly used in combination with other antibiotics. It is commonly administered via intramuscular injection or intravenously and is eliminated in the urine 24 hours after its administration into the body. Some caution must be taken with streptomycin as overdose can lead to nephrotoxicity and ototoxicity.

Tacrolimus is a calcineurin inhibitor that is most often used as an immunosuppressive drug for organ transplant patients in order to reduce the activity of the immune system lowering the risk of organ rejection. Tacrolimus is administered orally or through a topical treatment which allows the drug to be absorbed into the bloodstream. Tacrolimus enters T-cells through the ABC or SLC transporters like ABCB1 and works by forming a complex with FKBP12 with inhibits calcineurin with leads to reduced T cell signal transduction and IL-2 transcription. IL-2 is an important mediator for T-cell activation, differentiation and migration which is through mTOR signalling. Lower IL-2 production and signal transduction leads to less activated immune cells leading to a weaker immune system. Tacrolimus also inhibits the transcription for genes encoding IL-3,4,5, GM-SCF, and TNF as well which are also involved in T cell activation. Organ transplant patients take tacrolimus after allogenic organ transplant for liver, kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea and limb transplant.

Statins are a class of medications that lower lipid levels and are administered to reduce illness and mortality in people who are at high risk of cardiovascular disease. Fluvastatin is a well-tolerated orally-administered synthetic statin that reduces total cholesterol levels, low-density lipoprotein (LDL)-cholesterol, triglyceride, and very-low-density lipoprotein (VLDL)-cholesterol. It also increases levels of high-density lipoprotein (HDL)-cholesterol. It reduces cholesterol biosynthesis as a result of a prolonged duration of HMG-CoA reductase inhibition. Reported side effects of fluvastatin include gastrointestinal upset (diarrhea, nausea, constipation, gas, abdominal pain), myotoxicity (myopathy, myositis, rhabdomyolysis), and hepatotoxicity. The primary therapeutic mechanism of action of statins is the inhibition of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in hepatocytes. HMG-CoA reductase catalyzes the conversion of HMG-CoA into mevalonic acid, a precursor for cholesterol biosynthesis. Statins bind reversibly to the active site of HMG-CoA reductase and the subsequent structural change in the enzyme effectively disables it. Due to the resulting decrease in intracellular sterol levels, the ER membrane protein INSIG no longer binds to SREBP cleavage-activating protein (SCAP) which is, itself, bound to the transcription factor sterol regulatory element-binding protein (SREBP). Freed from INSIG, SCAP escorts SREBP to the Golgi apparatus from the ER as cargo in COPII vesicles. At the Golgi membrane, two proteases, S1P and S2P, sequentially cleave the SCAP-SREBP complex, releasing the mature form of SREBP into the cytoplasm. SREBP then translocates to the nucleus where it is transported into the nucleoplasm by binding directly to importin beta in the absence of importin alpha. SREBP binds to the sterol regulatory element (SRE) present in the promoter region of genes involved in cholesterol uptake and cholesterol synthesis, including the gene encoding the low-density lipoprotein (LDL) receptor (LDL-R). As a result, LDL-R gene transcription increases which then leads to an increased synthesis of the LDL-R protein. LDL-R localizes to the endoplasmic reticulum for transport and exocytosis to the cell surface. The elevated amount of LDL-R results in more circulating free LDL cholesterol binding and subsequent internalization via endocytosis. Lysosomal degradation of the internalized LDL cholesterol elevates cellular cholesterol levels to maintain homeostasis. This drug is administered as an oral tablet.