Pathways

Bezitramide is a narcotic analgesic that has been withdrawn due to overdoses. It is taken orally with a long duration of action. Bezitramide binds to 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. Morphine 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.

Bezafibrate is a lipid-lowering fibrate used in the management of primary and secondary hyperlipidaemia, when there is a lack of clinical improvement following lifestyle modifications or correction of the underlying disorder. Bezafibrate acts in the nucleus where is activates the peroxisome proliferator-activated receptor alpha (PPARα). PPARα binds to the retinoic acid receptor alpha (RXRα). This PPARα-RXRα complex regulate gene transcription/translation of proteins and enzymes involved lipolysis, fatty acid transport and biosynthesis, vLDL and HDL synthesis. Fatty acid biosynthesis is decreased due to the decrease expression of the enzyme acetyl-coA carboxylase. This enzyme is involved in one of the first steps in fatty acid synthesis by converting acetyl-coA to malonyl coA. Fatty acid uptake from the plasma into the liver is increased. This is because there is an upregulation of the fatty acid transporter. This decreases the amount of circulating fatty acids. Fatty acid metabolism is also increased due to upregulation of acyl coA synthase, an enzyme involved in fatty acid oxidation. These 3 alterations ultimately decrease fatty acids in the body, making less fatty acids available for triglyceride synthesis. Bezafibrate also increases HDL synthesis by upregulating apolipoprotein A1 (APOA1) and apolipoproteins A2 (APOA2), which forms part of HDL. HDL is considered good cholesterol. VLDL and LDL are considered bad cholesterol. These levels are decreased due to downregulation of APOB which forms part of triglyceride-rich vLDL and LDL. Finally, triglyceride levels are decreased by 30%-60% via upregulation of lipoprotein lipase (LPL). LPL hydrolyses triglyceride, thus breaking it down. Other proteins that affect LPL are also altered. For instance, APOA5 activates LPL and it’s expression is increased with bezafibrate. APOC3 inhibits lipolysis by inhibiting LPL, therefore, bezafibrate decreases the expression of APOC3. Overall, bezafibrate lowers LDL-C, total-C, triglycerides, and Apo B, while increasing HDL-C.

Bevantolol is a beta blocker and calcium channel blocker. It is an oral drug used for the treatment of angina pectoris and hypertension. It targets the myocytes in heart where it acts mainly as a beta-1 adrenergic receptor antagonist, but also an L-type calcium channel blocker. It exerts it’s effects by inhibiting beta-1 adrenergic receptors, which is coupled to the G-protein signaling cascade. Inhibition of this receptor prevents activation of the signaling cascade which activates protein kinase. Protein kinase is required to activate calcium channels in the cell membrane, causing them to open and allow Ca2+ to enter the cell. Ca2+ activates the ryanodine receptor on the sarcoplasmic reticulum, which transports Ca2+ from the sarcoplasmic reticulum into the cytosol. Ca2+ in the cytosol binds to troponin to cause muscle contraction. Since protein kinase activation does not occur, there is a low concentration of Ca2+ in the cell. The low concentration of Ca2+ means that less Ca2+ binds to troponin, reducing inotropy/muscle contraction. In cardiac pacemaker cells a decrease in intracellular Ca2+ decreases the slope of phase 4 of the action potential. The time taken to reach threshold is longer, therefore, the heart rate is decreased. Due to the decreased force of contraction and heart rate, the blood pumped of the heart exerts less force on the blood vessels, thus the blood pressure decreases. This is also effective for treating angina because lowering the heart rate and force of contraction reduces the oxygen demand and how hard the heart has to work. Possible side effects from taking bevantolol include fatigue, headache, dizziness, edema and gastrointestinal upset.

Bevantolol hydrocholride, also known as bevantolol, is a cardioselective beta blocker prescribed to treat angina pectoris and hypertension. Bevantolol is an antagonist of beta-1 adrenoreceptors to block the G protein signalling cascade and inhibit epinephrine induced sympathetic activation such as, increased heart rate. It does not have intrinsic sympathomimetic activity therefore does not stimulate beta-adrenergic receptors. This results in a decrease in preload and blood pressure.

Bevacizumab is a humanized monoclonal antibody administered intravenously to treat cancers such as colorectal cancer; non-small cell lung cancer; glioblastoma; hepatocellular cancer; renal cell carcinoma; cervical cancer; and epithelial ovarian, fallopian tube, or primary peritoneal cancer. It targets vascular endothelial growth factor (VEGF) in the blood. When cancer grows and spreads, the blood and oxygen supplies become insufficient. In response, the tumor cells secrete VEGF which enters the blood and binds the VEGF receptor-1 and VEGF receptor-2 on endothelial cells in the blood vessels. This activates the VEGF signaling pathway in the endothelial cells which promotes the growth of new blood vessels to supply the cancer cells with a greater blood and oxygen supply. Bevacizumab binds to VEGF in the blood and inactivates it, preventing its interaction with the VEGF receptors. The VEGF signaling pathway is not activated and angiogenesis does not occur. The cancer cells are starved of blood and oxygen, preventing the growth and spread of cancer. Bevacizumab may have side effects like epistaxis, headache, dizziness, fatigue, hypertension, rhinitis, dry skin, back pain, excessive bleeding, skin rash, poor wound healing, hemorrhage, thrombosis, renal dysfunction and bowel, stomach or nasal septum perforation.

Bevacizumab is a humanized anti-VEGF monoclonal antibody used in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration, permeability, invasion, and survival. Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability. In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above. Bevacizumab exerts its effect by binding to extracellular VEGF and preventing its binding to receptors on the endothelial cell surfaces. This in turns inhibits the MAP and IP3 and supresses angiogenesis.

Metabolites of Betrixaban are predicted with biotransformer.