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. 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 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.

Atomoxetine, also known as Strattera, is a selective norepinephrine reuptake inhibitor (SNRI). It is used in the management of attention deficit hyperactivity disorder (ADHD). Although the underlying pathophysiology that causes ADHD remains undefined, evidence suggests that dysregulation in noradrenergic and dopaminergic pathways plays a critical role. Due to atomoxetine's noradrenergic activity, it also has effects on the cardiovascular system such as increased blood pressure and tachycardia. Atomoxetine binds to the sodium-dependent noradrenaline transporter, this prevents the noradrenaline reuptake in the presynaptic neurons. In consequence, there is more norepinephrine available in the synapses and in the brain in general. This will increase the activation of alpha-adrenergic receptors in the postsynaptic neurons. This activation decreases the inattention of ADHD patients. This drug is administered as an oral capsule.

Atomoxetine classified as a selective norepinephrine reuptake inhibitor (SNRI) commonly used in the treatment of attention deficit hyperactivity disorder (ADHD) instead of stimulant medication such as methylphenidate, dextroamphetamine or lisdexamfetamine. Atomoxetine appears to only increase norepinephrine and dopamine levels within the prefrontal cortex without effecting concentration levels in the nucleus accumbens and or the striatum leading to little to no stimulant associated side effects with less abuse potential. It is a selective reuptake inhibitor of norepinephrine transporter (NET) leading to alleviating symptoms of ADHD. Recent studies have also shown that its binds to serotonin transporter (SERT) and also inhibits N-methyl-d-aspartate (NMDA) receptors, although further research is necessary to confirm these interactions. It is metabolized by cytochrome P450 2D6 into its metabolites of 4-hydroxy-atomoxetine which is equipotent as atomoxetine and its mechanism of action. If there is a lack of CYP2D6 enzymes then other cytochrome enzymes break down the drug and results in its minor metabolites being formed with less pharmacological activity. The metabolites are commonly glucuronidated and excreted as 4-hydroxyatomoxetine-O-glucuronide through the urine. During acute or chronic overdoses of atomoxetine, some symptoms observed is gastrointestinal symptoms, somnolence, dizziness, tremor and abnormal behavior. If these symptoms are seen poison control center should be phoned in order to plan a good course of action, as atomoxetine is protein bound and dialysis may not be effective treatment for an overdose.

Metabolites of Atogepant are predicted with biotransformer.

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-1 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. Some side effects of using atenolol may include tiredness, dizziness, nausea, and stomach pain.

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.