Pathways

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. Pravastatin 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. It reduces cholesterol biosynthesis due to the result of a prolonged duration of HMG-CoA reductase inhibition. Reported side effects of Pravastatin 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 actively 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 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 the binding of more circulating free LDL cholesterol and subsequent internalization via endocytosis. Lysosomal degradation of the internalized LDL cholesterol elevates cellular cholesterol levels to maintain homeostasis.

Prazepam is a benzodiazepine used to manage more severe forms of anxiety disorders. Prazepam is a benzodiazepine derivative with anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant activity. It can be found under the brand names Centrac, Demetrin, and Prazene. Benzodiazepines may be habit-forming (causing mental or physical dependence), especially when taken for a long time or in high doses. Prazepam is believed to stimulate GABA receptors in the ascending reticular activating system. Since GABA is inhibitory, receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brain stem reticular formation. Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam. Some side effects of using prazepam may include drowsiness, confusion, coordination problems, and concentration and memory problems.

Prazosin is an alpha-blocker that causes a decrease in total peripheral resistance and is used to treat hypertension. This drug is indicated for the treatment of hypertension (high blood pressure). Prazosin can be given alone or given with other blood pressure-lowering drugs, including diuretics or beta-adrenergic blocking agents. Alpha-adrenergic receptors are essential for the regulation of blood pressure in humans. Two types of alpha receptors, alpha 1 and alpha 2, both play a role in regulating blood pressure. Alpha-1 receptors are postsynaptic (located after the nerve junction, or space between a nerve fiber and target tissue). In this case, the target tissue is the vascular smooth muscle. Activation of the alpha-1 receptor activates the Gq signaling cascade, which activates phospholipase C. Phospholipase C converts phosphatidylinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate (IP3). IP3 activates the IP3 receptor on the sarcoplasmic reticulum, leading to calcium influx into the cytosol from the sarcoplasmic reticulum. Calcium binds to calmodulin and activates myosin light chain kinase. Myosin light chain kinase is responsicle for phosphorylating myosin light chain. Phosphorylated myosin light chain binds to actin and causes muscle contraction. Prazosin inhibits the postsynaptic alpha-1 adrenoceptors. This inhibition blocks the vasoconstricting (narrowing) effect of catecholamines (epinephrine and norepinephrine) on the vessels, leading to peripheral blood vessel dilation. Common side effects of prazosin include dizziness, headache, drowsiness, lack of energy, weakness, palpitations and nausea.

Metabolites of sildenafil are predicted with biotransformer.

Prednicarbate is a relatively new topical corticosteroid. It displays similar potency as hydrocortisone and has a favorable benefit-risk ratio, with an inflammatory action similar to that of a medium potency corticosteroid, but with a low potential to cause skin atrophy. Since prednicarbate is a glucocorticoid receptor agonist. By binding to the glucocorticoid receptor, it influences transcription factors AP-1 and NF-kB to block the transcription of COX-2/prostaglandin G/H synthase 2 which reduces the amount of prostanoids being produced from arachidonic acid. Prostanoids such as PGI2 and thromboxane A2 influence the effects of inflammation through vasoconstriction/dilation, pain sensitivity, and platelet aggregation. Prednicarbate also affects the promoter of annexin-1, an important inflammatory protein as it affects leukocytes and blocks phospholipase A2 which reduces the amount of arachidonic acid being cleaved from the phospholipid bilayer. Reducing the amount of arachidonic acid formed further decreases the concentrations of prostanoids mentioned calming inflammation. This molecule is administered as a topical cream or ointment.