Chlorothiazide , sold under the brand name Diuril among others, is an organic compound used as a diuretic and as an antihypertensive .
81-486: It is used both within the hospital setting or for personal use to manage excess fluid associated with congestive heart failure . Most often taken in pill form, it is usually taken orally once or twice a day. In the ICU setting, chlorothiazide is given to diurese a patient in addition to furosemide (Lasix). Working in a separate mechanism from furosemide and absorbed enterically as a reconstituted suspension administered through
162-723: A nasogastric tube (NG tube), the two drugs potentiate one another. It was patented in 1956 and approved for medical use in 1958. It is on the World Health Organization's List of Essential Medicines . The research team of Merck Sharp and Dohme Research Laboratories of Beyer, Sprague, Baer, and Novello created a new series of medications, the thiazide diuretics, which includes chlorothiazide. They won an Albert Lasker Special Award in 1975 for this work. The structure has been determined by X-ray crystallography . Congestive heart failure Heart failure ( HF ), also known as congestive heart failure ( CHF ),
243-585: A cause (e.g., aortic stenosis ) or as a consequence (e.g., mitral regurgitation ) of heart failure. Reverse insufficiency of the left ventricle causes congestion in the blood vessels of the lungs so that symptoms are predominantly respiratory. Reverse insufficiency can be divided into the failure of the left atrium, the left ventricle, or both within the left circuit. Patients will experience shortness of breath (dyspnea) on exertion and, in severe cases, dyspnea at rest. Increasing breathlessness while lying down, called orthopnea , also occurs. It can be measured by
324-465: A decrease in intracardiac pressures or in ejection during systole , reducing cardiac output to the rest of the body. The filling failure and high intracardiac pressure can lead to fluid accumulation in ventricles of the heart. This manifests as water retention and swelling due to fluid accumulation ( edema ) called congestion . Impaired ejection can lead to inadequate blood flow to the body tissues, resulting in ischemia . Congestive heart failure
405-630: A member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure . The 2022 American Diabetes Association (ADA) standards of medical care in diabetes include SGLT2 inhibitors as a first line pharmacological therapy for type 2 diabetes (usually together with metformin), specifically in patients with chronic kidney disease , cardiovascular disease or heart failure . A systematic review and network meta-analysis comparing SGLT-2 inhibitors, GLP-1 agonists , and DPP-4 inhibitors demonstrated that use of SGLT2 inhibitors
486-681: A myocardial infarction is suspected, various cardiac markers may be used. Blood tests routinely performed include electrolytes ( sodium , potassium ), measures of kidney function , liver function tests , thyroid function tests , a complete blood count , and often C-reactive protein if infection is suspected. Hyponatremia (low serum sodium concentration) is common in heart failure. Vasopressin levels are usually increased, along with renin, angiotensin II, and catecholamines to compensate for reduced circulating volume due to inadequate cardiac output. This leads to increased fluid and sodium retention in
567-590: A normal ECG virtually excludes left ventricular systolic dysfunction. N-terminal pro-BNP (NT-proBNP) is the favored biomarker for the diagnosis of heart failure, according to guidelines published 2018 by NICE in the UK . Brain natriuretic peptide 32 (BNP) is another biomarker commonly tested for heart failure. An elevated NT-proBNP or BNP is a specific test indicative of heart failure. Additionally, NT-proBNP or BNP can be used to differentiate between causes of dyspnea due to heart failure from other causes of dyspnea. If
648-419: A person with a failure of one ventricle lives long enough, it will tend to progress to failure of both ventricles. For example, left ventricular failure allows pulmonary edema and pulmonary hypertension to occur, which increases stress on the right ventricle. Though still harmful, right ventricular failure is not as deleterious to the left side. Since heart failure is a syndrome and not a disease, establishing
729-485: A person with heart failure may have a reduced force of contraction due to overloading of the ventricle . In a normal heart, increased filling of the ventricle results in increased contraction force by the Frank–Starling law of the heart , and thus a rise in cardiac output . In heart failure, this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This
810-423: A result of a blocked coronary artery . Cardiomyopathy refers specifically to problems within the heart muscle, and these problems can result in heart failure. Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease. Dilated cardiomyopathy implies that the muscle damage has resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves enlargement and thickening of
891-512: A result, coronary catheterization may be used to identify possibilities for revascularisation through percutaneous coronary intervention or bypass surgery . Heart failure is commonly stratified by the degree of functional impairment conferred by the severity of the heart failure, as reflected in the New York Heart Association (NYHA) functional classification . The NYHA functional classes (I–IV) begin with class I, which
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#1732780316411972-476: A serious condition in which the body produces high levels of blood acids called ketones). By reducing glucose blood circulation, gliflozins cause less stimulation of endogenous insulin secretion or lower dose of exogenous insulin that results in diabetic ketoacidosis. They can specifically cause euglycemic DKA (euDKA, DKA where the blood sugar is not elevated) because of the renal tubular absorption of ketone bodies. A particularly high risk period for ketoacidosis
1053-487: Is a halogen and it has a high electronegativity . This electronegativity withdraws electrons off the bonds and therefore it reduces the metabolism. The Cl atom also reduces the IC50 value of the medication so the medication has better activity. The carbon-fluorine bond (C-F) has also has a very low electron density . For example, in the chemical structure of canagliflozin a fluorine atom is connected to an aromatic ring then
1134-429: Is a pathophysiological condition in which the heart's output is insufficient to meet the needs of the body and lungs. The term "congestive heart failure" is often used because one of the most common symptoms is congestion or fluid accumulation in the tissues and veins of the lungs or other parts of a person's body. Congestion manifests itself particularly in the form of fluid accumulation and swelling (edema) , in
1215-812: Is a syndrome caused by an impairment in the heart 's ability to fill with and pump blood . Although symptoms vary based on which side of the heart is affected, HF typically presents with shortness of breath , excessive fatigue , and bilateral leg swelling . The severity of the heart failure is mainly decided based on ejection fraction and also measured by the severity of symptoms. Other conditions that have symptoms similar to heart failure include obesity , kidney failure , liver disease , anemia , and thyroid disease . Common causes of heart failure include coronary artery disease , heart attack , high blood pressure , atrial fibrillation , valvular heart disease , excessive alcohol consumption , infection , and cardiomyopathy . These cause heart failure by altering
1296-420: Is a common, costly, and potentially fatal condition, and is the leading cause of hospitalization and readmission in older adults. Heart failure often leads to more drastic health impairments than the failure of other, similarly complex organs such as the kidneys or liver. In 2015, it affected about 40 million people worldwide. Overall, heart failure affects about 2% of adults, and more than 10% of those over
1377-702: Is a worsening of chronic heart failure symptoms, which can result in acute respiratory distress . High-output heart failure can occur when there is increased cardiac demand that results in increased left ventricular diastolic pressure which can develop into pulmonary congestion (pulmonary edema). Several terms are closely related to heart failure and may be the cause of heart failure, but should not be confused with it. Cardiac arrest and asystole refer to situations in which no cardiac output occurs at all. Without urgent treatment, these events result in sudden death. Myocardial infarction ("Heart attack") refers to heart muscle damage due to insufficient blood supply, usually as
1458-466: Is associated with a decrease in body weight which is statistically superior compared to placebo or other active comparators. It is primarily associated with caloric rather than fluid loss. In contrast with other anti-hyperglycemic diabetes medications , SGLT2 inhibitors enhance, rather than suppress, gluconeogenesis and ketogenesis . Because SGLT2 inhibitors activate sirtuin 1 (and thus PGC-1α and FGF21 ), they are more cardioprotective than
1539-517: Is associated with canagliflozin but further data is needed to confirm this risk associated with different gliflozins. A European Medicines Agency review concluded that there is a potential increased risk of lower limb amputation (mostly affecting the toes) in people taking canagliflozin, dapagliflozin and empagliflozin. In August 2018, the FDA issued a warning of an increased risk of Fournier gangrene in patients using SGLT2 inhibitors. The absolute risk
1620-463: Is based on each patient's underlying blood sugar control and kidney function . The results are decreased kidney reabsorption of glucose, glucosuria effect increases with higher level of glucose in the blood circulation. Therefore, dapagliflozin reduces the blood glucose concentration with a mechanism that is independent of insulin secretion and sensitivity, unlike many other antidiabetic medications . Functional pancreatic β-cells are not necessary for
1701-471: Is by the side of the heart involved (left heart failure versus right heart failure). Right heart failure was thought to compromise blood flow to the lungs compared to left heart failure compromising blood flow to the aorta and consequently to the brain and the remainder of the body's systemic circulation. However, mixed presentations are common, and left heart failure is a common cause of right heart failure. A more accurate classification of heart failure type
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#17327803164111782-421: Is caused by any condition that reduces the efficiency of the heart muscle, through damage or overloading . Over time, these increases in workload, which are mediated by long-term activation of neurohormonal systems such as the renin–angiotensin system and the sympathoadrenal system, lead to fibrosis , dilation, and structural changes in the shape of the left ventricle from elliptical to spherical. The heart of
1863-512: Is considered very low. In the FDA Adverse Event Reporting System an increase was reported in events of acute kidney injury associated with SGLT2 inhibitors, though data from clinical trials actually showed a reduction in such events with SGLT-2 treatment. Interactions are important for SGLT2 inhibitors because most people with type 2 diabetes are taking many other medications. Gliflozins appear to increase
1944-410: Is consistent with an international 2021 report termed "Universal Definition of Heart Failure". Score-based algorithms have been developed to help in the diagnosis of HFpEF , which can be challenging for physicians to diagnose. The AHA / ACC / HFSA defines heart failure as symptoms and signs consistent with heart failure in combination with shown "structural and functional alterations of the heart as
2025-432: Is defined as a person who experiences no limitation in any activities and has no symptoms from ordinary activities. People with NYHA class II heart failure have slight, mild limitations with everyday activities; the person is comfortable at rest or with mild exertion. With NYHA class III heart failure, a marked limitation occurs with any activity; the person is comfortable only at rest. A person with NYHA class IV heart failure
2106-491: Is due to the reduced ability to cross-link actin and myosin myofilaments in over-stretched heart muscle. No diagnostic criteria have been agreed on as the gold standard for heart failure, especially heart failure with preserved ejection fraction (HFpEF). In the UK , the National Institute for Health and Care Excellence recommends measuring N-terminal pro-BNP (NT-proBNP) followed by an ultrasound of
2187-605: Is exposure to certain toxins such as lead and cobalt . Additionally, infiltrative disorders such as amyloidosis and connective tissue diseases such as systemic lupus erythematosus have similar consequences. Obstructive sleep apnea (a condition of sleep wherein disordered breathing overlaps with obesity, hypertension, and/or diabetes) is regarded as an independent cause of heart failure. Recent reports from clinical trials have also linked variation in blood pressure to heart failure and cardiac changes that may give rise to heart failure. High-output heart failure happens when
2268-448: Is later reabsorbed by passive transfer of endothelial cells into the interstitial glucose transporter protein. Ratios of activity between SGLT1 and SGLT2 may be helpful in defining expression. The elimination half-life , bioavailability , protein binding , the blood concentration Cmax at time tmax, and other pharmacokinetic parameters of various medications of this class are present in table 2. These medications are excreted in
2349-422: Is made by measuring ejection fraction , or the proportion of blood pumped out of the heart during a single contraction. Ejection fraction is given as a percentage with the normal range being between 50 and 75%. The types are: Heart failure may also be classified as acute or chronic. Chronic heart failure is a long-term condition, usually kept stable by the treatment of symptoms. Acute decompensated heart failure
2430-506: Is mentioned in the Ebers Papyrus around 1550 BCE. When the heart functions poorly as a pump and does not circulate blood adequately via the circulatory system to meet the demands of the body the term cardiovascular insufficiency is sometimes used. This generally leads to the syndrome of heart failure, a combination of signs and symptoms It develops when the heart fails to properly fill with blood during diastole , resulting in
2511-437: Is not specific for it. It is also indicated by congestion of the pulmonary circulation. SGLT2 inhibitor SGLT2 inhibitors (also called gliflozins or flozins ) are a class of medications that inhibit sodium-glucose transport proteins in the nephron (the functional units of the kidney ), unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa . The foremost metabolic effect of this
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2592-883: Is not the same as cardiac arrest , in which blood flow stops completely due to the failure of the heart to pump. Diagnosis is based on symptoms, physical findings, and echocardiography . Blood tests , and a chest x-ray may be useful to determine the underlying cause. Treatment depends on severity and case. For people with chronic, stable, or mild heart failure, treatment usually consists of lifestyle changes, such as not smoking , physical exercise , and dietary changes, as well as medications. In heart failure due to left ventricular dysfunction, angiotensin-converting-enzyme inhibitors , angiotensin II receptor blockers (ARBs), or angiotensin receptor-neprilysin inhibitors , along with beta blockers , mineralocorticoid receptor antagonists and SGLT2 inhibitors are recommended. Diuretics may also be prescribed to prevent fluid retention and
2673-625: Is symptomatic at rest and becomes quite uncomfortable with any physical activity. This score documents the severity of symptoms and can be used to assess response to treatment. While its use is widespread, the NYHA score is not very reproducible and does not reliably predict walking distance or exercise tolerance on formal testing. In its 2001 guidelines, the American College of Cardiology / American Heart Association working group introduced four stages of heart failure: The ACC staging system
2754-475: Is the X-ray imaging of blood vessels , which is done by injecting contrast agents into the bloodstream through a thin plastic tube ( catheter ), which is placed directly in the blood vessel. X-ray images are called angiograms. Heart failure may be the result of coronary artery disease, and its prognosis depends in part on the ability of the coronary arteries to supply blood to the myocardium (heart muscle). As
2835-735: Is the perioperative period. SGLT2 inhibitors may need to be discontinued before surgery, and only recommended when someone is not unwell, is adequately hydrated and able to consume a regular diet. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing. To lessen the risk of developing ketoacidosis after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin , dapagliflozin , and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery. In September 2015,
2916-494: Is the precipitating cause, and may manifest as regional wall motion abnormalities on echo. Chest X-rays are frequently used to aid in the diagnosis of CHF. In a person who is compensated, this may show cardiomegaly (visible enlargement of the heart), quantified as the cardiothoracic ratio (proportion of the heart size to the chest). In left ventricular failure, evidence may exist of vascular redistribution (upper lobe blood diversion or cephalization), Kerley lines , cuffing of
2997-484: Is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar . They act by inhibiting sodium/glucose cotransporter 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes . Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes . As of 2014 , several medications of this class had been approved or were under development. In studies on canagliflozin ,
3078-491: Is useful since stage A encompasses "pre-heart failure" – a stage where intervention with treatment can presumably prevent progression to overt symptoms. ACC stage A does not have a corresponding NYHA class. ACC stage B would correspond to NYHA class I. ACC stage C corresponds to NYHA class II and III, while ACC stage D overlaps with NYHA class IV. Histopathology can diagnose heart failure in autopsies . The presence of siderophages indicates chronic left-sided heart failure, but
3159-616: The shortening fraction is the preferred measure of systolic function. Normally, the EF should be between 50 and 70%; in systolic heart failure, it drops below 40%. Echocardiography can also identify valvular heart disease and assess the state of the pericardium (the connective tissue sac surrounding the heart). Echocardiography may also aid in deciding specific treatments, such as medication, insertion of an implantable cardioverter-defibrillator , or cardiac resynchronization therapy . Echocardiography can also help determine if acute myocardial ischemia
3240-402: The FDA issued a warning related to canagliflozin (Invokana) and canagliflozin/metformin (Invokamet) due to decreased bone mineral density and therefore increased risk of bone fractures. Using gliflozins in combination therapy with metformin can lower the risk of hypoglycemia compared to other type 2 diabetes treatments such as sulfonylureas and insulin. Increased risk of lower limb amputation
3321-465: The activity of the medication so it is convenient for patients with diminished β-cell function. Sodium and glucose are co-transported by the SGLT-2 protein into the tubular epithelial cells across the brush-border membrane of the proximal convoluted tubule . This happens because of the sodium gradient between the tubule and the cell and therefore provides a secondary active transport of glucose. Glucose
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3402-530: The age of 70. Rates are predicted to increase. The risk of death in the first year after diagnosis is about 35%, while the risk of death in the second year is less than 10% in those still alive. The risk of death is comparable to that of some cancers. In the United Kingdom, the disease is the reason for 5% of emergency hospital admissions. Heart failure has been known since ancient times in Egypt ; it
3483-453: The amount of blood pumped out is more than typical and the heart cannot keep up. This can occur in overload situations such as blood or serum infusions, kidney diseases, chronic severe anemia , beriberi (vitamin B 1 / thiamine deficiency), hyperthyroidism , cirrhosis , Paget's disease , multiple myeloma , arteriovenous fistulae , or arteriovenous malformations . Chronic stable heart failure may easily decompensate (fail to meet
3564-418: The areas around the bronchi , and interstitial edema. Ultrasound of the lung may also detect Kerley lines. An electrocardiogram (ECG or EKG) may be used to identify arrhythmias , ischemic heart disease , right and left ventricular hypertrophy , and presence of conduction delay or abnormalities (e.g. left bundle branch block ). Although these findings are not specific to the diagnosis of heart failure,
3645-496: The arylated anomeric center of the sugar. Phlorizin was the first type of gliflozin and it was non-selective against SGLT2/SGLT1. It is a natural O-aryl glycoside composed of a d-glucose and an aromatic ketone. However phlorizin is very unstable, it is rapidly degraded by glucosidases in the small intestines, so it can not be used as an oral administration medication to treat diabetes. Structural modifications have been made to overcome this instability problem. The most efficient way
3726-407: The blood , is a late sign of extremely severe pulmonary edema. Other signs of left ventricular failure include a laterally displaced apex beat (which occurs when the heart is enlarged) and a gallop rhythm (additional heart sounds), which may be heard as a sign of increased blood flow or increased intracardiac pressure. Heart murmurs may indicate the presence of valvular heart disease, either as
3807-604: The body first, causing foot and ankle swelling in people who are standing up and sacral edema in people who are predominantly lying down. Nocturia (frequent night-time urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and liver enlargement may develop. Significant liver congestion may result in impaired liver function ( congestive hepatopathy ), jaundice, and coagulopathy (problems of decreased or increased blood clotting). Dullness of
3888-457: The body's metabolic needs). This most commonly results from a concurrent illness (such as myocardial infarction (a heart attack) or pneumonia ), abnormal heart rhythms , uncontrolled hypertension , or a person's failure to maintain a fluid restriction, diet, or medication. Other factors that may worsen CHF include: anemia, hyperthyroidism, excessive fluid or salt intake, and medication such as NSAIDs and thiazolidinediones . NSAIDs increase
3969-412: The body; the rate of fluid retention is higher than the rate of sodium retention in the body, this phenomenon causes hypervolemic hyponatremia (low sodium concentration due to high body fluid retention). This phenomenon is more common in older women with low body mass. Severe hyponatremia can result in accumulation of fluid in the brain, causing cerebral edema and intracranial hemorrhage . Angiography
4050-478: The brain. Right-sided heart failure is often caused by pulmonary heart disease (cor pulmonale), which is typically caused by issues with pulmonary circulation such as pulmonary hypertension or pulmonic stenosis . Physical examination may reveal pitting peripheral edema, ascites, liver enlargement , and spleen enlargement . Jugular venous pressure is frequently assessed as a marker of fluid status, which can be accentuated by testing hepatojugular reflux . If
4131-456: The composite of myocardial infarction , stroke , or cardiovascular death. Genital infections seem to be the most common adverse effect of gliflozins. In clinical trials fungal infections , urinary tract infections and osmotic diuresis were higher in patients treated with gliflozins. In May 2015, the FDA issued a warning that gliflozins can increase risk of diabetic ketoacidosis (DKA,
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#17327803164114212-519: The compound is more stable and the metabolism of the compound is reduced. Empagliflozin contains a tetrahydrofuran ring but not canagliflozin nor dapagliflozin. In the development of gliflozins the distal ring contains a thiophene ring instead of an aromatic ring. However the final chemical structures of the marketing gliflozins does not contain this thiophene ring. SGLT2 inhibitors increase circulating ketone body concentrations. The cardioprotective effects of SGLT2 inhibitors have been attributed to
4293-489: The diuretic effect of thiazides , loop diuretics and related diuretics and may increase the risk of dehydration and hypotension . It is important to adjust the dose of antidiabetics if the treatment is combination therapy to avoid hypoglycemia. For example, interactions with sulfonylureas have led to severe hypoglycemia presumably due to cytochrome P450 . Some members of the gliflozin class: Sodium glucose cotransporters (SGLTs) are proteins that occur primarily in
4374-606: The effects of diuretic medications. Gossypol can increase the effects of diuretics, leading to toxicity. Gynura can cause low blood pressure. Licorice can worsen heart failure by increasing blood pressure and promoting fluid retention. Lily of the Valley can cause abnormally slow heart rates with mechanisms similar to those of digoxin. Tetrandrine can lower blood pressure by inhibiting L-type calcium channels . Yohimbine can exacerbate heart failure by increasing blood pressure through alpha-2 adrenergic receptor antagonism. Heart failure
4455-488: The first segment of the proximal convoluted tubule. By inhibiting SGLT2, gliflozins prevent the kidneys' reuptake of glucose from the glomerular filtrate and subsequently lower the glucose level in the blood and promote the excretion of glucose in the urine ( glucosuria ). The mechanism of action on a cellular level is not well understood. Work is underway to define this mechanism as a prodiuretic with great promise. However, it has been shown that binding of different sugars to
4536-523: The force with which the heart ejects blood , thus are not recommended in people with heart failure with a reduced ejection fraction. Breast cancer patients are at high risk of heart failure due to several factors. After analyzing data from 26 studies (836,301 patients), the recent meta-analysis found that breast cancer survivors demonstrated a higher risk heart failure within first ten years after diagnosis (hazard ratio = 1.21; 95% CI: 1.1, 1.33). The pooled incidence of heart failure in breast cancer survivors
4617-509: The form of peripheral edema (causing swollen limbs and feet) and pulmonary edema (causing difficulty breathing) and ascites (swollen abdomen). Pulse pressure , which is the difference between the systolic ("top number") and diastolic ("bottom number") blood pressures, is often low/narrow (i.e. 25% or less of the level of the systolic) in people with heart failure, and this can be an early warning sign. Symptoms of heart failure are traditionally divided into left-sided and right-sided because
4698-678: The formation of prostaglandins , NSAIDs may exacerbate heart failure through several mechanisms, including promotion of fluid retention, increasing blood pressure , and decreasing a person's response to diuretic medications. Similarly, the ACC/AHA recommends against using COX-2 inhibitor medications in people with heart failure. Thiazolidinediones have been strongly linked to new cases of heart failure and worsening of pre-existing congestive heart failure due to their association with weight gain and fluid retention. Certain calcium channel blockers, such as diltiazem and verapamil , are known to decrease
4779-516: The glucose site affects the orientation of the aglycone in the access vestibule. So when the aglycone binds it affects the entire inhibitor. Together these mechanisms lead to a synergistic interaction. Therefore, variations in the structure of both the sugar and the aglycone are crucial for the pharmacophore of SGLT inhibitors. Dapagliflozin is an example of an SGLT-2 inhibitor, it is a competitive, highly selective inhibitor of SGLT. It acts via selective and potent inhibition of SGLT-2, and its activity
4860-402: The glucose sugar moiety and the β-isomeric aryl substituent the aryl group is composed of a diarylmethylene structure. The synthesis of gliflozins involves three general steps. The first one is the construction of the aryl substituent, the next one is the introduction of the aryl moiety onto the sugar or glucosylation of the aryl substituent and the last one the deprotection and modification of
4941-739: The heart if positive. In Europe , the European Society of Cardiology , and in the United States, the AHA / ACC / HFSA , recommend measuring NT-proBNP or BNP followed by an ultrasound of the heart if positive. This is recommended in those with symptoms consistent with heart failure such as shortness of breath . The European Society of Cardiology defines the diagnosis of heart failure as symptoms and signs consistent with heart failure in combination with "objective evidence of cardiac structural or functional abnormalities". This definition
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#17327803164115022-535: The heart muscle. An echocardiogram ( ultrasound of the heart) is commonly used to support a clinical diagnosis of heart failure. This can determine the stroke volume (SV, the amount of blood in the heart that exits the ventricles with each beat), the end-diastolic volume (EDV, the total amount of blood at the end of diastole), and the SV in proportion to the EDV, a value known as the ejection fraction (EF). In pediatrics,
5103-599: The heart's myocardial tissue (termed myocarditis ) can similarly contribute to the development of heart failure. Genetic predisposition plays an important role. If more than one cause is present, progression is more likely and prognosis is worse. Heart damage can predispose a person to develop heart failure later in life and has many causes including systemic viral infections (e.g., HIV ), chemotherapeutic agents such as daunorubicin , cyclophosphamide , trastuzumab and substance use disorders of substances such as alcohol , cocaine , and methamphetamine . An uncommon cause
5184-427: The kidneys and play an important role in maintaining glucose balance in the blood. SGLT1 and SGLT2 are the two most known SGLTs of this family. SGLT2 is the major transport protein and promotes reabsorption from the glomerular filtration glucose back into circulation and is responsible for approximately 90% of the kidney's glucose reabsorption. SGLT2 is mainly expressed in the kidneys on the epithelial cells lining
5265-430: The left and right ventricles supply different parts of the circulation. In biventricular heart failure, both sides of the heart are affected. Left-sided heart failure is the more common. The left side of the heart takes oxygen-rich blood from the lungs and pumps it to the rest of the circulatory system in the body (except for the pulmonary circulation ). Failure of the left side of the heart causes blood to back up into
5346-441: The lung fields when percussed and reduced breath sounds at the base of the lungs may suggest the development of a pleural effusion (fluid collection between the lung and the chest wall ). Though it can occur in isolated left- or right-sided heart failure, it is more common in biventricular failure because pleural veins drain into both the systemic and pulmonary venous systems. When unilateral, effusions are often right-sided. If
5427-446: The lungs, causing breathing difficulties and fatigue due to an insufficient supply of oxygenated blood. Common respiratory signs include increased respiratory rate and labored breathing (nonspecific signs of shortness of breath). Rales or crackles are heard initially in the lung bases and when severe in all lung fields indicate the development of pulmonary edema (fluid in the alveoli ). Cyanosis , indicates deficiency of oxygen in
5508-520: The medication has a rapid absorption and minimal excretion by the kidney . Dapagliflozin disposition is not evidently affected by body mass index (BMI) or body weight , therefore the pharmacokinetic findings are expected to be applicable to patients with a higher BMI. Dapagliflozin resulted in dose-dependent increases excretions in urinary glucose, up to 47g/d following single-dose administration, which can be expected from its mechanism of action , dapagliflozin. Some studies found that dapagliflozin
5589-575: The number of pillows required to lie comfortably, with extreme cases of orthopnea forcing the patient to sleep sitting up. Another symptom of heart failure is paroxysmal nocturnal dyspnea : a sudden nocturnal attack of severe shortness of breath, usually occurring several hours after falling asleep. There may be " cardiac asthma " or wheezing . Impaired left ventricular forward function can lead to symptoms of poor systemic perfusion such as dizziness , confusion , and cool extremities at rest. Loss of consciousness may also occur due to loss of blood supply to
5670-400: The other medications used to treat diabetes . The structure-activity relationship (SAR) of gliflozins is not fully understood. The most common gliflozins are dapagliflozin, empagliflozin and canagliflozin. The differences in the structures is relatively small. The general structure includes a glucose sugar with an aromatic group in the β-position at the anomeric carbon. In addition to
5751-503: The resulting shortness of breath. Depending on the case, an implanted device such as a pacemaker or implantable cardiac defibrillator may sometimes be recommended. In some moderate or more severe cases, cardiac resynchronization therapy (CRT) or cardiac contractility modulation may be beneficial. In severe disease that persists despite all other measures, a cardiac assist device ventricular assist device , or, occasionally, heart transplantation may be recommended. Heart failure
5832-403: The right ventricular pressure is increased, a parasternal heave which causes the compensatory increase in contraction strength may be present. Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin ( peripheral edema or anasarca ) and usually affects the dependent parts of
5913-520: The risk reduction due to SGLT-2 inhibitors was larger in populations with a higher proportion of albuminuria , but this relationship was not observed for GLP-1 receptor agonists. This suggests a differential use of the two substance classes in patients with preserved and reduced renal function or with and without diabetic nephropathy , respectively. Two reviews have concluded that SGLT2 inhibitors benefit patients with atherosclerotic major adverse cardiovascular events. One of those studies defined MACE as
5994-626: The risk twofold. A number of medications may cause or worsen the disease. This includes NSAIDs , COX-2 inhibitors , a number of anesthetic agents such as ketamine , thiazolidinediones, some cancer medications , several antiarrhythmic medications , pregabalin , alpha-2 adrenergic receptor agonists , minoxidil , itraconazole , cilostazol , anagrelide , stimulants (e.g., methylphenidate ), tricyclic antidepressants , lithium , antipsychotics , dopamine agonists , TNF inhibitors , calcium channel blockers (especially verapamil and diltiazem ), salbutamol , and tamsulosin . By inhibiting
6075-436: The structure or the function of the heart or in some cases both. There are different types of heart failure: right-sided heart failure , which affects the right heart , left-sided heart failure , which affects the left heart , and biventricular heart failure, which affects both sides of the heart. Left-sided heart failure may be present with a reduced ejection fraction or with a preserved ejection fraction . Heart failure
6156-541: The underlying cause for the clinical presentation", for HFmrEF and HFpEF specifically requiring "evidence of spontaneous or provokable increased left ventricle filling pressures". The European Society of Cardiology has developed a diagnostic algorithm for HFpEF , named HFA-PEFF. HFA-PEFF considers symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes, elderly, atrial fibrillation), and diagnostic laboratory tests, ECG, and echocardiography. One historical method of categorizing heart failure
6237-565: The underlying cause is vital to diagnosis and treatment. In heart failure, the structure or the function of the heart or in some cases both are altered. Heart failure is the potential end stage of all heart diseases. Common causes of heart failure include coronary artery disease , including a previous myocardial infarction (heart attack), high blood pressure , atrial fibrillation , valvular heart disease , excess alcohol use , infection , and cardiomyopathy of an unknown cause. In addition, viral infection and subsequent inflammation of
6318-408: The urine as inactive metabolites. In studies that were made on healthy people and people with type 2 diabetes, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a pharmacokinetic profile of the medication. With dose-dependent concentrations the half-life is about 12–13 hours, Tmax 1–2 hours and it is protein-bound, so
6399-488: Was 4.44 (95% CI 3.33-5.92) per 1000 person-years of follow-up. Certain alternative medicines carry a risk of exacerbating existing heart failure, and are not recommended. This includes aconite , ginseng , gossypol , gynura , licorice , lily of the valley , tetrandrine , and yohimbine . Aconite can cause abnormally slow heart rates and abnormal heart rhythms such as ventricular tachycardia. Ginseng can cause abnormally low or high blood pressure and may interfere with
6480-632: Was associated with a 20% reduction in death compared with placebo or no treatment. Another systematic review discussed the mechanisms by which SGLT-2 inhibitors improve cardio-renal function in patients with type 2 diabetes, emphasizing the impacts in improving neural tone. A meta-analysis including 13 cardiovascular outcome trials found that SGLT-2 inhibitors reduce the risk for three-point major adverse cardiovascular events (MACE), especially in subjects with an estimated glomerular filtration rate (eGFR) below 60 ml/min, whereas GLP-1 receptor agonists were more beneficial in persons with higher eGFR. Likewise,
6561-444: Was to conjugate aryl moiety with glucose moiety since C-glucosides are more stable in the small intestines than O-glucoside derivatives (C-C bond instead of C-O-C bond). In the sugar analogues of dapagliflozin, the β-C series are more active than α-C series so it is critical that the β-configuration is at C-1 for the inhibitory activity. Both dapagliflozin and empagliflozin contain a chlorine (Cl) atom in their chemical structure. Cl
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