Pathways

Atenolol is a cardioselective beta 1 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, atenolol 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, atenolol 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. Atenolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Atenolol, trade name Tenormin, is a beta blocker prescribed to treat hypertension. Atenolol is a selective beta-1-adrenoceptor antagonist targeting the heart and vascular smooth muscle to inhibit sympathetic activity. Binding of atenolol inhibits the G protein signalling cascade and reduces heart rate, blood pressure, cardiac output and reflex orthostatic hypotension. Beta blockers were once the first line therapy for hypertension, however, current recommendations favour calcium channel blockers and angiotensin converting enzyme inhibitors.

Metabolites of Atazanavir are predicted with biotransformer.

Atazanavir (formerly known as BMS-232632) is an antiretroviral protease inhibitor used in combination with other antiretrovirals for the treatment of HIV in adults and pediatric patients 3 months of age and older weighing at least 5kg. It is used in combination with cobicistat and other antiretrovirals. The HIV virus binds and penetrates the host cell. Viral RNA is transcribed into viral DNA via reverse transcriptase. Viral DNA enters the host nucleus and is integrated into the host DNA via integrase. The DNA is then transcribed, creating viral mRNA. Viral mRNA is translater into the gag-pol polyprotein. HIV protease is synthesized as part of the Gag-pol polyprotein, where Gag encodes for the capsid and matrix protein to form the outer protein shell, and Pol encodes for the reverse transcriptase and integrase protein to synthesize and incorporate its genome into host cells. HIV-1 protease cleaves the Gag-pol polyprotein into 66 molecular species, including HIV-1 protease, integrase, and reverse transcriptase. Atazanavir selectively inhibits HIV-1 protease. This inhibition prevents the HIV virion from fully maturing and becoming infective. Using the lipid bilayer of the host cell, a virus is formed and released. The inhibition of HIV-1 protease prevents the necessary molecular species from forming, therefore preventing maturation and activation of viral particles. This forms immature, non-infectious viral particles, therefore, Atazanavir prevents the virus from reproducing.

Metabolites of Asunaprevir are predicted with biotransformer.

Asunaprevir, also known as BMS-650032, is an NS3 protease inhibitor used to treat hepatitis C genotype 1b. It as been found to be highly effective in dual-combination regimens with daclatasvir in patients with chronic HCV genotype 1b. The lipoviroparticles attach to LDL-R and SR-B1, and then the virus binds to CD81 and subsequently claudin-1 and occludin, which mediate the late steps of viral entry. The virus is internalized by clathrin-dependent endocytosis. RNA is released from the mature Hepatitis C virion and translated at the rough endoplasmic reticulum into a single Genome polyprotein. Asunaprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Asunaprevir inhibits NS3 protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form. At higher concentration above their antiviral half-maximal effective concentration (EC50), NS3 protease cleaves two essential adaptor proteins that initiate signaling leading to activation of IFN regulatory factor 3 and IFN-α/β synthesis, which are mitochondrial antiviral-signaling proteins.