Repositioning Candidate Details
| Candidate ID: | R0120 |
| Source ID: | DB00335 |
| Source Type: | approved |
| Compound Type: | small molecule |
| Compound Name: | Atenolol |
| Synonyms: | 1-p-Carbamoylmethylphenoxy-3-isopropylamino-2-propanol; 2-(p-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide; 4-(2-Hydroxy-3-((1-methylethyl)amino)propoxy)benzeneacetamide; Atenolol |
| Molecular Formula: | C14H22N2O3 |
| SMILES: | CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 |
| Structure: |
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| DrugBank Description: | Atenolol is a cardioselective beta-blocker used in a variety of cardiovascular conditions. Sir James Black, a Scottish pharmacologist, pioneered the use of beta-blockers for the management of angina pectoris in 1958 for which he received the Nobel Prize. Beta-blockers quickly became popular in clinical use and where subsequently investigated for use in myocardial infarction, arrhythmias, and hypertension during the 1960s. Later they continued to be investigated for use in heart failure throughout the 1970-1980s. Atenolol itself was developed early on in this history by Alvogen Malta under the trade name Tenormin and received FDA approval in September, 1981. Despite being one of the most widely prescribed beta blockers, evidence suggests atenolol may not significantly reduce mortality, and only modestly reduce the risk of cardiovascular disease in patients with hypertension. A Cochrane review of patients being treated for primary hypertension shows that atenolol shows a risk ratio of 0.88 for cardiovascular disease risk and a risk ratio of 0.99 for mortality. Similar results have been found in other meta-analyses. A meta-analysis of over 145,000 patients showed the risk of stroke in patients taking atenolol may depend on the age of the patient. The use of atenolol may need to be based on more patient factors than hypertension alone. |
| CAS Number: | 29122-68-7 |
| Molecular Weight: | 266.3361 |
| DrugBank Indication: | **Indicated** for: 1) Management of hypertension alone and in combination with other antihypertensives. 2) Management of angina pectoris associated with coronary atherosclerosis. 3) Management of acute myocardial infarction in hemodynamically stable patients with a heart rate greater than 50 beats per minutes and a systolic blood pressure above 100 mmHg. **Off-label** uses include: 1) Secondary prevention of myocardial infarction. 2) Management of heart failure. 3) Management of atrial fibrillation. 4) Management of supraventricular tachycardia. 5) Management of ventricular arrythmias such as congenital long-QT and arrhythmogenic right ventricular cardiomyopathy. 6) Management of symptomatic thyrotoxicosis in combination with . 7) Prophylaxis of migraine headaches. 8) Management of alcohol withdrawal. |
| DrugBank Pharmacology: | Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control. |
| DrugBank MoA: | Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G<sub>s</sub> coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA). In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca<sup>2+</sup> ATPase to increase reuptake of calcium into the SR. It also phophorylates troponin I to reduce affinity of the protein for calcium. Both of these events lead to a reduction in contraction which, when coupled with the initial increase in contraction, allows for faster cycling and consequently higher heart rate with increased contractility. L-type calcium channels are also a major contributor to cardiac depolarization and their activation can increase frequency of action potentials and possibly the incidence of ectopic potentials. Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G<sub>q</sub> coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction. |
| Targets: | Beta-1 adrenergic receptor antagonist; Beta-2 adrenergic receptor antagonist |
| Inclusion Criteria: | Therapeutic strategy associated |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I07 | 1936 | Arteriosclerosis | Build-up of fatty material and calcium deposition in the arterial wall resulting in partial or complete occlusion of the arterial lumen.https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C35768 | disease of anatomical entity/cardiovascular system disease/ vascular disease/ artery disease | Details |
| I08 | 114 | Cardiovascular system disease | A disease of anatomical entity which occurs in the blood, heart, blood vessels or the lymphatic system that passes nutrients (such as amino acids and electrolytes), gases, hormones, blood cells or lymph to and from cells in the body to help fight diseases and help stabilize body temperature and pH to maintain homeostasis. http://en.wikipedia.org/wiki/Circulatory_system | disease of anatomical entity | Details |
| I12 | 10763 | Hypertension | An artery disease characterized by chronic elevated blood pressure in the arteries. https://en.wikipedia.org/wiki/Hypertension, https://www.ncbi.nlm.nih.gov/pubmed/24352797 | disease of anatomical entity/ cardiovascular system disease/vascular disease/ artery disease | Details |
| I16 | 6713 | Cerebrovascular disease | An vascular disease that is characterized by dysfunction of the blood vessels supplying the brain. http://en.wikipedia.org/wiki/Cerebrovascular_disease, http://www.ncbi.nlm.nih.gov/books/NBK378/ | disease of anatomical entity/ cardiovascular system disease/ vascular disease/cerebrovascular disease | Details |
| I17 | 1596 | Mental depression | Mental depression | disease of mental health/ cognitive disorder/ mood disorder | Details |