Pathways

Risperidone is a second-generation antipsychotic medication used to treat a number of mental health disorders including schizophrenia, bipolar mania, psychosis, or as an adjunct in severe depression. Paliperidone is the primary active metabolite of risperidone. The two antipsychotics are also metabolized differently, as risperidone is metabolized in the liver mainly by the polymorphic cytochrome P450 2D6 (CYP2D6) to its active metabolite 9-hydroxyrisperidone (paliperidone). Paliperidone, by contrast, is predominantly excreted unchanged in the urine. The main route of risperidone metabolism is in the liver by the enzyme CYP2D6. The major active metabolite, 9-hydroxyrisperidone, contributes to the pharmacological effects of this drug. While risperidone and 9-hydroxyrisperidone are often regarded as equipotent, they display different affinities towards the two target receptors (D2 and 5HT2A), where risperidone appears to be approximately 2-fold more potent than 9-hydroxyrisperidone. There is also a difference in brain distribution; risperidone is distributed more to the CNS. Though its precise mechanism of action is not fully understood, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to result from an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors. Low-affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation. The high-affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptors. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time.

Risperidone is a second-generation antipsychotic medication used to treat a number of mental health disorders including schizophrenia, bipolar mania, psychosis, or as an adjunct in severe depression. Paliperidone is the primary active metabolite of risperidone. The two antipsychotics are also metabolized differently, as risperidone is metabolized in the liver mainly by the polymorphic cytochrome P450 2D6 (CYP2D6) to its active metabolite 9-hydroxyrisperidone (paliperidone). Paliperidone, by contrast, is predominantly excreted unchanged in the urine. The major active metabolite, 9-hydroxyrisperidone, contributes to the pharmacological effects of this drug. While risperidone and 9-hydroxyrisperidone are often regarded as equipotent, they display different affinities towards the two target receptors (D2 and 5HT2A), where risperidone appears to be approximately 2-fold more potent than 9-hydroxyrisperidone. There is also a difference in brain distribution; risperidone is distributed more to the CNS. Though its precise mechanism of action is not fully understood, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to result from an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors. Low-affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation. The high-affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptors. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time.

Ritiometan is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Ritiometan passes through the liver and is then excreted from the body mainly through the kidney.

Ritodrine is a adrenergic beta agonist used for the treatment and prophylaxis of premature labour. Beta-2 adrenergic receptors are located at sympathetic neuroeffector junctions of many organs, including uterus. Ritodrine is beta-2 adrenergic agonist. It stimulates beta-2 adrenergic receptor, increases cAMP level and decreases intracellular calcium concentration. The decrease of calcium concentration leads to a relaxation of uterine smooth muscle and, therefore, a decrease in premature uterine contractions. Ritodrine binds to receptors on outer membrane of myometrial cells. Once ritodrine is administered and it binds to the beta-2 adrenergic receptor, the G protein signalling cascade begins. The alpha and beta/gamma subunits of the G protein separate and GDP is replaced with GTP on the alpha subunit. This alpha subunit then activates adenylyl cyclase which converts ATP to cAMP. cAMP then activates protein kinase A (PKA) which in turn phosphorylates targets and inhibits MLCK through decreased calcium levels causing muscle relaxation. PKA can phosphorylate certain Gq-coupled receptors as well as phospholipase C (PLC) and thereby inhibit G protein-coupled receptor (GPCR) -PLC-mediated phosphoinositide (PI) generation, and thus calcium flux. PKA phosphorylates the inositol 1,4,5-trisphosphate (IP3) receptor to reduce its affinity for IP3 and further limit calcium mobilization. PKA phosphorylates myosin light chain kinase (MLCK) and decreases its affinity to calcium calmodulin, thus reducing activity and myosin light chain (MLC) phosphorylation. Inhibits the phosphorylation of myosin. There are two mechanisms by which KCa++ channels can be activated in these cells, the first being when PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization, and the second being directly by the G proteins by direct gating. Phosphorylation of ATP-sensitive potassium channels occurs as well. Since myosine light chain kinase is not activated, Serine/threonine-protein phosphatase continues to dephosphorylate myosin LC-P, and more cannot be synthesized so myosin remains unbound from actin causing muscle relaxation. This relaxation of the smooth muscles in the uterus causes the uterine muscles to relax which causes a decrease in premature contractions, effectively treating premature labour. In summary, ritodrine is able to complete this through its activation of beta-2 adrenergic receptors, activation of ATP-sensitive potassium channels, and activation of calcium activated potassium channels. Ritodrine is typically administered via intravenous injection, or as an oral tablet. Some side effects of using ritodrine may include chest pain or tightness, dizziness or lightheadedness, flushed and dry skin, and increased urination.

Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection. While ritonavir is not an active antiviral agent against hepatitis C virus (HCV) infection, it is added in combination therapies indicated for the treatment of HCV infections as a booster. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of other protease inhibitors such as Paritaprevir and overall drug exposure. Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as gag and pol. 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. Ritonavir competitively binds to the active site of 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, Ritonavir prevents the virus from reproducing. Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels.

Rivaroxaban is a factor Xa inhibitor used to treat deep vein thrombosis (DVT) and pulmonary embolism (PE). May also be used as thrombosis prophylaxis in specific situations. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Rivaroxaban is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone total hips replacements and total knee replacement surgery; prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); to reduce risk of recurrent DVT and/or PE. Rivaroxaban is also indicated, in combination with aspirin, for reducing the risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Its use is also not recommended in those with severe renal impairment. Rivaroxaban competitively inhibits free and clot bound factor Xa. Factor Xa is needed to activate prothrombin (factor II) to thrombin (factor IIa). Thrombin is a serine protease that is required to activate fibrinogen to fibrin, which is the loose meshwork that completes the clotting process.