Bronchitis

From Wikipedia, the free encyclopedia

Bronchitis
Figure A shows the location of the lungs and bronchial tubes. Figure B is an enlarged view of a normal bronchial tube. Figure C is an enlarged view of a bronchial tube with bronchitis.
Pronunciation	bron-kye-tis
Specialty	Infectious disease, pulmonology
Symptoms	Coughing up mucus, wheezing, shortness of breath, chest discomfort
Types	Acute, chronic
Frequency	Acute: ~5% of people a year Chronic: ~5% of people

Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Symptoms include coughing up sputum, wheezing, shortness of breath, and chest pain. Bronchitis can be acute or chronic.

Acute bronchitis usually has a cough that lasts around three weeks, and is also known as a chest cold. In more than 90% of cases the cause is a viral infection. These viruses may be spread through the air when people cough or by direct contact. A small number of cases are caused by a bacterial infection such as Mycoplasma pneumoniae or Bordetella pertussis. Risk factors include exposure to tobacco smoke, dust, and other air pollution. Treatment of acute bronchitis typically involves rest, paracetamol (acetaminophen), and nonsteroidal anti-inflammatory drugs (NSAIDs) to help with the fever.

Chronic bronchitis is defined as a productive cough – one that produces sputum – that lasts for three months or more per year for at least two years. Most people with chronic bronchitis have chronic obstructive pulmonary disease (COPD). Tobacco smoking is the most common cause, with a number of other factors such as air pollution and genetics playing a smaller role. Treatments include quitting smoking, vaccinations, rehabilitation, and often inhaled bronchodilators and steroids. Some people may benefit from long-term oxygen therapy.

Acute bronchitis is one of the most common diseases. About 5% of adults are affected and about 6% of children have at least one episode a year. Acute bronchitis is the most common type of bronchitis. In the United States, in 2016, 8.6 million people were diagnosed with chronic bronchitis.

Acute bronchitis

Bronchitis

Acute bronchitis, also known as a chest cold, is short term inflammation of the bronchi of the lungs. The most common symptom is a cough, that may or may not produce sputum. Other symptoms include coughing up mucus, wheezing, shortness of breath, fever, and chest discomfort. The infection may last from a few to ten days. The cough may persist for several weeks afterwards, with the total duration of symptoms usually around three weeks. Symptoms may last for up to six weeks.

Cause

In more than 90% of cases, the cause is a viral infection. These viruses may spread through the air when people cough or by direct contact. Risk factors include exposure to tobacco smoke, dust, and other air pollutants. A small number of cases are due to high levels of air pollution or to bacteria such as Mycoplasma pneumoniae or Bordetella pertussis.

Diagnosis

Diagnosis is typically based on a person's signs and symptoms. The color of the sputum does not indicate if the infection is viral or bacterial. Determining the underlying organism is usually not required. Other causes of similar symptoms include asthma, pneumonia, bronchiolitis, bronchiectasis, and COPD. A chest X-ray may be useful to detect pneumonia.

Another common sign of bronchitis is a cough which lasts ten days to three weeks. If the cough lasts a month or a year, it may become chronic bronchitis. In addition, a fever may be present. Acute bronchitis is normally caused by a viral infection. Typically, these infections are rhinovirus, parainfluenza, or influenza. No specific testing is normally needed in order to diagnose acute bronchitis.

Treatment

Prevention is by not smoking and avoiding other lung irritants. Frequent hand washing may also be protective. Treatment for acute bronchitis usually involves rest, paracetamol (acetaminophen), and NSAIDs to help with the fever. Cough medicine has little support for its use, and is not recommended in children under the age of six. There is tentative evidence that salbutamol may be useful in treating wheezing; however, it may result in nervousness and tremors. Antibiotics should generally not be used. An exception is when acute bronchitis is due to pertussis. Tentative evidence supports honey and pelargonium to help with symptoms. Getting plenty of rest and drinking enough fluids are often recommended as well.

Epidemiology

Acute bronchitis is one of the most-common diseases. About 5% of adults are affected, and about 6% of children have at least one episode a year. It occurs more often in the winter. More than 10 million people in the US visit a doctor each year for this condition, with about 70% receiving antibiotics which are mostly not needed. There are efforts to decrease the use of antibiotics in acute bronchitis. Acute bronchitis is the most common type of bronchitis.

Chronic bronchitis

When bronchitis, marked by a productive cough, occurs for longer than three months, in two consecutive years, it is classed as chronic bronchitis. When this occurs together with decreased airflow it is known as chronic obstructive pulmonary disease (COPD) or chronic obstructive bronchitis. Most people with chronic bronchitis have COPD however most people with COPD do not have chronic bronchitis. Previously the term "chronic bronchitis" was also used for a type of COPD. Chronic bronchitis is a respiratory tract disease marked by mucus hypersecretion. The cough is often worse soon after awakening, and the sputum produced may have a yellow or green color and may be streaked with specks of blood. The ICD-11 lists chronic bronchitis with emphysema (emphysematous bronchitis) as a "certain specified COPD".

Cause

Most cases of chronic bronchitis are caused by tobacco smoking. Chronic bronchitis in young adults who smoke is associated with a greater chance of developing COPD. In addition, chronic inhalation of air pollution or irritating fumes or dust from hazardous exposures in occupations such as coal mining, grain handling, textile manufacturing, livestock farming, and metal moulding may also be a risk factor for the development of chronic bronchitis. Bronchitis caused in this way is often referred to as industrial bronchitis. Rarely genetic factors also play a role.

Treatment

Decline in lung function in chronic bronchitis may be slowed by stopping smoking. Chronic bronchitis is treated symptomatically and may be treated with or without medications. Nonpharmacologic approaches may include pulmonary rehabilitation, and oxygen therapy.

A distinction has been made between exacerbations (sudden worsenings) of chronic bronchitis, and otherwise stable chronic bronchitis. A Cochrane review found that mucolytics in chronic bronchitis may slightly decrease the chance of the developing an acute exacerbation. The mucolytic guaifenesin is a safe and effective treatment for stable chronic bronchitis. This has an advantage in that it is available as an extended use tablet which lasts for twelve hours. Erdosteine has been found to be effective in promoting the discharge of mucus and improving lung function in the elderly. Another mucolytic Fudosteine works by inhibiting MUC5AC expression, reducing the secretion of mucin.

In those with chronic bronchitis and severe COPD, the phosphodiesterase-4 inhibitor roflumilast may decrease significant exacerbations.

Epidemiology

Chronic bronchitis affects about 3.4% to 22% of the general population. Individuals over age 45 years of age, smokers, those that live or work in areas with high air pollution, and anybody with asthma all have a higher risk of developing chronic bronchitis. This wide range is due to the different definitions of chronic bronchitis that can be diagnosed based on signs and symptoms or the clinical diagnosis of the disorder. Chronic bronchitis tends to affect men more often than women. While the primary risk factor for chronic bronchitis is smoking, there is still a 4%-22% chance that never smokers can get chronic bronchitis. This might suggest other risk factors such as the inhalation of fuels, dusts, fumes and genetic factor. In the United States, in 2016, 8.6 million people were diagnosed with chronic bronchitis, and there were 518 reported deaths. Per 100,000 of population the death rate of chronic bronchitis was 0.2.

Bilirubin

From Wikipedia, the free encyclopedia

Bilirubin

Identifiers
CAS Number	635-65-4
3D model (JSmol)	Interactive image Interactive image
ChEBI	CHEBI:16990
ChEMBL	ChEMBL501680
ChemSpider	4444055
ECHA InfoCard	100.010.218
IUPHAR/BPS	4577
PubChem CID	5280352
UNII	RFM9X3LJ49
CompTox Dashboard (EPA)	DTXSID90239827
InChI[show]
SMILES[show]
Properties
Chemical formula	C33H36N4O6
Molar mass	584.673 g·mol−1
Supplementary data page
Structure and properties	Refractive index (n), Dielectric constant (εr), etc.
Thermodynamic data	Phase behaviour solid–liquid–gas
Spectral data	UV, IR, NMR, MS

Bilirubin is a yellow compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the destruction of aged or abnormal red blood cells. First the hemoglobin gets stripped of the heme molecule which thereafter passes through various processes of porphyrin catabolism, depending on the part of the body in which the breakdown occurs. For example, the molecules excreted in the urine differ from those in the feces. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin.

Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is responsible for the yellow color of bruises and the yellow discoloration in jaundice. Its subsequent breakdown products, such as stercobilin, cause the brown color of faeces. A different breakdown product, urobilin, is the main component of the straw-yellow color in urine.

It has also been found in plants.

Structure and function

Bilirubin consists of an open chain tetrapyrrole. It is formed by oxidative cleavage of a porphyrin in heme, which affords biliverdin. Biliverdin is reduced to bilirubin. After conjugatation with glucuronic acid, bilirubin is excreted. 

Bilirubin is structurally similar to the pigment phycobilin used by certain algae to capture light energy, and to the pigment phytochrome used by plants to sense light. All of these contain an open chain of four pyrrolic rings. 

Like these other pigments, some of the double-bonds in bilirubin isomerize when exposed to light. This isomerization is relevant to the phototherapy of jaundiced newborns: the E,Z-isomers of bilirubin formed upon light exposure are more soluble than the unilluminated Z,Z-isomer, as the possibility of intramolecular hydrogen bonding is removed. Increased solubility allows the excretion of unconjugated bilirubin in bile. 

Some textbooks and research articles show the incorrect geometric isomer of bilirubin. The naturally occurring isomer is the Z,Z-isomer.

Function

Bilirubin is created by the activity of biliverdin reductase on biliverdin, a green tetrapyrrolic bile pigment that is also a product of heme catabolism. Bilirubin, when oxidized, reverts to become biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant activity of bilirubin, has led to the hypothesis that bilirubin's main physiologic role is as a cellular antioxidant.

Metabolism

Heme metabolism

Unconjugated

The measurement of unconjugated bilirubin is underestimated by measurement of indirect bilirubin, as unconjugated bilirubin (without glucuronidation) reacts with diazosulfanilic acid to create azobilirubin which is measured as direct bilirubin.

Conjugated

In the liver, bilirubin is conjugated with glucuronic acid by the enzyme glucuronyltransferase, making it soluble in water: the conjugated version is the main form of bilirubin present in the "direct" bilirubin fraction. Much of it goes into the bile and thus out into the small intestine. Though most bile acid is reabsorbed in the terminal ileum to participate in enterohepatic circulation, conjugated bilirubin is not absorbed and instead passes into the colon.

There, colonic bacteria deconjugate and metabolize the bilirubin into colorless urobilinogen, which can be oxidized to form urobilin and stercobilin. Urobilin is excreted by the kidneys to give urine its yellow color and stercobilin is excreted in the faeces giving stool its characteristic brown color. A trace (~1%) of the urobilinogen is reabsorbed into the enterohepatic circulation to be re-excreted in the bile.

Although the terms direct and indirect bilirubin are used equivalently with conjugated and unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both conjugated bilirubin and δ bilirubin (bilirubin covalently bound to albumin, which appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease). Furthermore, direct bilirubin tends to overestimate conjugated bilirubin levels due to unconjugated bilirubin that has reacted with diazosulfanilic acid, leading to increased azobilirubin levels (and increased direct bilirubin).

Urine

Under normal circumstances, only a very small amount, if any, of urobilinogen, is excreted in the urine. If the liver's function is impaired or when biliary drainage is blocked, some of the conjugated bilirubin leaks out of the hepatocytes and appears in the urine, turning it dark amber. However, in disorders involving hemolytic anemia, an increased number of red blood cells are broken down, causing an increase in the amount of unconjugated bilirubin in the blood. Because the unconjugated bilirubin is not water soluble, one will not see an increase in bilirubin in the urine. Because there is no problem with the liver or bile systems, this excess unconjugated bilirubin will go through all of the normal processing mechanisms that occur (e.g., conjugation, excretion in bile, metabolism to urobilinogen, reabsorption) and will show up as an increase in urine urobilinogen. This difference between increased urine bilirubin and increased urine urobilinogen helps to distinguish between various disorders in those systems.

Toxicity

Unconjugated hyperbilirubinaemia in a newborn can lead to accumulation of bilirubin in certain brain regions (particularly the basal nuclei) with consequent irreversible damage to these areas manifesting as various neurological deficits, seizures, abnormal reflexes and eye movements. This type of neurological injury is known as kernicterus. The spectrum of clinical effect is called bilirubin encephalopathy. The neurotoxicity of neonatal hyperbilirubinemia manifests because the blood–brain barrier has yet to develop fully, and bilirubin can freely pass into the brain interstitium, whereas more developed individuals with increased bilirubin in the blood are protected. Aside from specific chronic medical conditions that may lead to hyperbilirubinaemia, neonates in general are at increased risk since they lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the faeces (this is largely why the faeces of a neonate are paler than those of an adult). Instead the conjugated bilirubin is converted back into the unconjugated form by the enzyme β-glucuronidase (in the gut, this enzyme is located in the brush border of the lining intestinal cells) and a large proportion is reabsorbed through the enterohepatic circulation.

Health benefits

In the absence of liver disease, high levels of total bilirubin confers various health benefits. Studies have also revealed that levels of serum bilirubin are inversely related to risk of certain heart diseases.

Blood tests

Bilirubin is degraded by light. Blood collection tubes containing blood or (especially) serum to be used in bilirubin assays should be protected from illumination. For adults, blood is typically collected by needle from a vein in the arm. In newborns, blood is often collected from a heel stick, a technique that uses a small, sharp blade to cut the skin on the infant's heel and collect a few drops of blood into a small tube. Non-invasive technology is available in some health care facilities that will measure bilirubin by using an instrument placed on the skin (transcutaneous bilirubin meter)

Bilirubin (in blood) is in one of two forms: 

Abb.	Name(s)	Water-soluble	Reaction
"BC"	"Conjugated bilirubin"	Yes (bound to glucuronic acid)	Reacts quickly when dyes (diazo reagent) are added to the blood specimen to produce azobilirubin "Direct bilirubin"
"BU"	"Unconjugated bilirubin"	No	Reacts more slowly, still produces azobilirubin, Ethanol makes all bilirubin react promptly, then: indirect bilirubin = total bilirubin – direct bilirubin

Note: Conjugated bilirubin is often incorrectly called "direct bilirubin" and unconjugated bilirubin is incorrectly called "indirect bilirubin". Direct and indirect refer solely to how compounds are measured or detected in solution. Direct bilirubin is any form of bilirubin which is water-soluble and is available in solution to react with assay reagents; direct bilirubin is often made up largely of conjugated bilirubin, but some unconjugated bilirubin (up to 25%) can still be part of the "direct" bilirubin fraction. Likewise, not all conjugated bilirubin is readily available in solution for reaction or detection (for example, if it is hydrogen bonding with itself) and therefore would not be included in the direct bilirubin fraction. 

Total bilirubin (TBIL) measures both BU and BC. Total bilirubin assays work by using surfactants and accelerators (like caffeine) to bring all of the different bilirubin forms into solution where they can react with assay reagents. Total and direct bilirubin levels can be measured from the blood, but indirect bilirubin is calculated from the total and direct bilirubin.

Indirect bilirubin is fat-soluble and direct bilirubin is water-soluble.

Measurement methods

Originally, the Van den Bergh reaction was used for a qualitative estimate of bilirubin. 

This test is performed routinely in most medical laboratories and can be measured by a variety of methods.

Total bilirubin is now often measured by the 2,5-dichlorophenyldiazonium (DPD) method, and direct bilirubin is often measured by the method of Jendrassik and Grof.

Blood levels

The bilirubin level found in the body reflects the balance between production and excretion. Blood test results should always be interpreted using the reference range provided by the laboratory that performed the test. The SI units are umol/L. Typical ranges for adults are:

• 0-0.3 mg/dl - Direct (conjugated) bilirubin level
• 0.1-1.2 mg/dl - Total serum bilirubin level

	μmol/l = micromole/litre	mg/dl = milligram/ decilitre
total bilirubin	<21 nbsp="" span="">	<1 .23="" span="">
direct bilirubin	1.0–5.1	0–0.3 0.1–0.3 0.1–0.4

 

Reference ranges for blood tests, comparing blood content of bilirubin (shown in blue near horizontal center at around 3 mg/L and 3 μmol/L, scroll to the right to view) with other constituents.

Hyperbilirubinemia

Hyperbilirubinemia is a higher-than-normal level of bilirubin in the blood. For adults, this is any level above 170 μmol/l and for newborns 340 µmol/l and critical hyperbilirubinemia 425 µmol/l. 

Mild rises in bilirubin may be caused by:

• Hemolysis or increased breakdown of red blood cells
• Gilbert's syndrome – a genetic disorder of bilirubin metabolism that can result in mild jaundice, found in about 5% of the population
• Rotor syndrome: non-itching jaundice, with rise of bilirubin in the patient's serum, mainly of the conjugated type

Moderate rise in bilirubin may be caused by:

• Pharmaceutical drugs (especially antipsychotic, some sex hormones, and a wide range of other drugs)
  • Sulfonamides are contraindicated in infants less than 2 months old (exception when used with pyrimethamine in treating toxoplasmosis) as they increase unconjugated bilirubin leading to kernicterus.
  • Drugs such as protease inhibitors like Indinavir can also cause disorders of bilirubin metabolism by competitively inhibiting the UGT1A1 enzyme.
• Hepatitis (levels may be moderate or high)
• Chemotherapy
• Biliary stricture (benign or malignant)

Very high levels of bilirubin may be caused by:

• Neonatal hyperbilirubinaemia, where the newborn's liver is not able to properly process the bilirubin causing jaundice
• Unusually large bile duct obstruction, e.g. stone in common bile duct, tumour obstructing common bile duct etc.
• Severe liver failure with cirrhosis (e.g. primary biliary cirrhosis)
• Crigler–Najjar syndrome
• Dubin–Johnson syndrome
• Choledocholithiasis (chronic or acute).

Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis. 

To further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., hepatitis A, B, C, delta, E, etc.).

Jaundice

Jaundice may be noticeable in the sclera of the eyes at levels of about 2 to 3 mg/dl (34 to 51 μmol/l), and in the skin at higher levels. For conversion, 1 mg/dl = 17.1 µmol/l.

Jaundice is classified, depending upon whether the bilirubin is free or conjugated to glucuronic acid, into conjugated jaundice or unconjugated jaundice.

Urine tests

Urine bilirubin may also be clinically significant. Bilirubin is not normally detectable in the urine of healthy people. If the blood level of conjugated bilirubin becomes elevated, e.g. due to liver disease, excess conjugated bilirubin is excreted in the urine, indicating a pathological process. Unconjugated bilirubin is not water-soluble and so is not excreted in the urine. Testing urine for both bilirubin and urobilinogen can help differentiate obstructive liver disease from other causes of jaundice.

History

Bilirubin was discovered by Rudolf Virchow in 1847.) It is not always distinguished from hematoidin, which one modern dictionary defines as synonymous with it but another defines as "apparently chemically identical with bilirubin but with a different site of origin, formed locally in the tissues from hemoglobin, particularly under conditions of reduced oxygen tension."

Duloxetine

From Wikipedia, the free encyclopedia

Duloxetine

Clinical data
Trade names	Cymbalta, others
AHFS/Drugs.com	Monograph
MedlinePlus	a604030
License data	EU EMA: by INN US FDA: duloxetine
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	By mouth
Drug class	Serotonin–norepinephrine reuptake inhibitor
ATC code	N06AX21 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	~ 50% (32% to 80%)
Protein binding	~ 95%
Metabolism	Liver, two P450 isozymes, CYP2D6 and CYP1A2
Elimination half-life	12 hours
Excretion	70% in urine, 20% in feces
Identifiers
IUPAC name[show]
CAS Number	116539-59-4  as HCl: 136434-34-9
PubChem CID	60835
IUPHAR/BPS	202
DrugBank	DB00476
ChemSpider	54822
UNII	O5TNM5N07U as HCl: 9044SC542W
KEGG	D07880
ChEBI	CHEBI:36795
ChEMBL	ChEMBL1175
PDB ligand	29E (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID6048385
ECHA InfoCard	100.116.825
Chemical and physical data
Formula	C18H19NOS
Molar mass	297.41456 g/mol g·mol−1
3D model (JSmol)	Interactive image

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, and neuropathic pain. It is taken by mouth.

Common side effects include dry mouth, nausea, feeling tired, dizziness, agitation, sexual problems, and increased sweating. Severe side effects include an increased risk of suicide, serotonin syndrome, mania, and liver problems. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. It is a serotonin–norepinephrine reuptake inhibitor. How it works is not entirely clear.

Duloxetine was approved for medical use in the United States in 2004. It is available as a generic medication. In the United States the wholesale cost per dose is about 0.20 USD as of 2018. In 2016 it was the 48th most prescribed medication in the United States with more than 15 million prescriptions.

Medical uses

The main uses of duloxetine are in major depressive disorder, generalized anxiety disorder, neuropathic pain, chronic musculoskeletal pain, and fibromyalgia.

Duloxetine is recommended as a first-line agent for the treatment of chemotherapy-induced neuropathy by the American Society of Clinical Oncology, as a first-line therapy for fibromyalgia in the presence of mood disorders by the German Interdisciplinary Association for Pain Therapy, as a Grade B recommendation for the treatment of diabetic neuropathy by the American Association for Neurology and as a level A recommendation in certain neuropathic states by the European Federation of Neurological Societies.

A 2014 Cochrane review concluded that duloxetine is beneficial in the treatment of diabetic neuropathy and fibromyalgia but that more comparative studies with other medicines are needed. The French medical journal Prescrire concluded that duloxetine is no better than other available agents and has a greater risk of side effects. Thus they recommend against its general use.

Major depressive disorder

Duloxetine was approved for the treatment of major depression in 2004. While duloxetine has demonstrated improvement in depression-related symptoms compared to placebo, comparisons of duloxetine to other antidepressant medications have been less successful. A 2012 Cochrane Review did not find greater efficacy of duloxetine compared to SSRIs and newer antidepressants. Additionally, the review found evidence that duloxetine has increased side effects and reduced tolerability compared to other antidepressants. It thus did not recommend duloxetine as a first line treatment for major depressive disorder, given the (then) high cost of duloxetine compared to inexpensive off-patent antidepressants and lack of increased efficacy. Duloxetine appears less tolerable than some other antidepressants. Generic duloxetine became available in 2013.

Generalized anxiety disorder

Duloxetine is more effective than placebo in the treatment of generalized anxiety disorder (GAD). Major guidelines such as Maudsley Prescribing Guidelines, and Canadian Psychiatric Association Guidelines do not list duloxetine among the recommended treatment options. A review from the Annals of Internal Medicine lists duloxetine among the first line drug treatments, however, along with citalopram, escitalopram, sertraline, paroxetine, and venlafaxine.

Diabetic neuropathy

Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN), based on the positive results of two clinical trials. The average daily pain was measured using an 11-point scale, and duloxetine treatment resulted in an additional 1–1.7 points decrease of pain as compared with placebo. At least 50% pain relief was achieved in 40–45% of the duloxetine patients vs. 20–22% of placebo patients. Pain decreased by more than 90%, in 9–14% of duloxetine patients vs. 2–4% of placebo patients. Most of the response was achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose; this effect was deemed to be of "minimal clinical significance", however.

The comparative efficacy of duloxetine and established pain-relief medications for DPN is unclear. A systematic review noted that tricyclic antidepressants (imipramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants and anticonvulsants have similar tolerability while the opioids caused more side effects. Another review in Prescrire International considered the moderate pain relief achieved with duloxetine to be clinically insignificant and the results of the clinical trials unconvincing. The reviewer saw no reason to prescribe duloxetine in practice. The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. The authors noted that the evidence in favor of duloxetine is much more solid, however. A Cochrane review concluded that the evidence in support of duloxetine's efficacy in treating painful diabetic neuropathy was adequate, and that further trials should focus on comparisons with other medications.

Fibromyalgia and chronic pain

A review of duloxetine found that it reduced pain and fatigue, and improved physical and mental performance compared to placebo.

The U.S. Food and Drug Administration (FDA) regulators approved the drug for the treatment of fibromyalgia in June 2008.

It may be useful for chronic pain from osteoarthritis.

On November 4, 2010, the U.S. Food and Drug Administration approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.

Stress urinary incontinence

Duloxetine failed to receive US approval for stress urinary incontinence amid concerns over liver toxicity and suicidal events; it was approved for this use in the UK, however, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery.

The safety and utility of duloxetine in the treatment of incontinence has been evaluated in a series of meta analyses and practice guidelines.

• A 2017 meta-analysis found that harms are at least as great if not greater than the benefits.
• A 2013 meta-analysis concluded that duloxetine decreased incontinence episodes more than placebo with people about 56% more likely than placebo to experience a 50% decrease in episodes. Adverse effects were experienced by 83% of duloxetine-treated subjects and by 45% of placebo-treated subjects.
• A 2012 review and practice guideline published by the European Association of Urology concluded that the clinical trial data provides Grade 1a evidence that duloxetine improves but does not cure urinary incontinence, and that it causes a high rate of gastrointestinal side effects (mainly nausea and vomiting) leading to a high rate of treatment discontinuation.
• The National Institute for Clinical and Health Excellence recommends (as of September 2013) that duloxetine not be routinely offered as first line treatment, and that it only be offered as second line therapy in women wishing to avoid therapy. The guideline further states that women should be counseled regarding the drug's side effects.

Contraindications

The following contraindications are listed by the manufacturer:

• Hypersensitivity: duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
• Monoamine oxidase inhibitors (MAOIs): concomitant use in patients taking MAOIs is contraindicated.
• Uncontrolled narrow-angle glaucoma: in clinical trials, Cymbalta use was associated with an increased risk of mydriasis (dilation of the pupil); therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma, in which mydriasis can cause sudden worsening.
• Central nervous system (CNS) acting drugs: given the primary CNS effects of duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.
• Duloxetine and thioridazine should not be co-administered.

In addition, the FDA has reported on life-threatening drug interactions that may be possible when co-administered with triptans and other drugs acting on serotonin pathways leading to increased risk for serotonin syndrome.

Adverse effects

Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.

In a trial for major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group. In a long-term study of fibromyalgia patients receiving duloxetine, frequency and type of adverse effects was similar to that reported in the MDD above. Side effects tended to be mild-to-moderate, and tended to decrease in intensity over time.

In 4 clinical trials of duloxetine for the treatment of MDD, sexual dysfunction occurred significantly more frequently in patients treated with duloxetine than those treated with placebo, and this difference occurred only in men. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). Loss of or decreased response to sexual stimuli and ejaculatory anhedonia are also reported. Frequency of treatment-emergent sexual dysfunction were similar for duloxetine and SSRIs when compared in a 6 month observational study in depressed patients. Rates of sexual dysfunction in MDD patients treated with duloxetine vs escitalopram did not differ significantly at 4, 8, and 12 weeks of treatment, although the trend favored duloxetine (33.3% of duloxetine patients experienced sexual side effects compared to 43.6% of those receiving escitalopram and 25% of those receiving placebo).

Discontinuation syndrome

During marketing of other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as brain zap electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. The withdrawal syndrome from duloxetine resembles the SSRI discontinuation syndrome. 

When discontinuing treatment with duloxetine, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. 

In placebo-controlled clinical trials of up to nine weeks' duration of patients with MDD, a systematic evaluation of discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.

Suicidality

The FDA requires all antidepressants, including duloxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.

To obtain statistically significant results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As suicidal ideation and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance.

In 2005 the United States FDA released a public health advisory noting that there had been 11 reports of suicide attempts and 3 reports of suicidality within the mostly middle-aged women participating in the open label extension trials of duloxetine for the treatment of stress urinary incontinence. The FDA described the potential role of confounding social stressors "unclear". The suicide attempt rate in the SUI study population (based on 9,400 patients) was calculated to be 400 per 100,000 person years. This rate is greater than the suicide attempt rate among middle-aged U.S. women that has been reported in published studies, i.e., 150 to 160 per 100,000 person years. In addition, one death from suicide was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer without SUI. No increase in suicidality was reported in controlled trials of Cymbalta for depression or diabetic neuropathic pain.

Postmarketing reports

Reported adverse events that were temporally correlated to duloxetine therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatotoxicity, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens–Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.

Pharmacology

Mechanism of action

Duloxetine inhibits the reuptake of serotonin and norepinephrine (NE) in the central nervous system. Duloxetine increases dopamine (DA) specifically in the prefrontal cortex, where there are few DA reuptake pumps, via the inhibition of NE reuptake pumps (NET), which is believed to mediate reuptake of DA and NE. Duloxetine has no significant affinity for dopaminergic, cholinergic, histaminergic, opioid, glutamate, and GABA reuptake transporters, however, and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NE transporters. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.

Major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system. Antidepressants including ones with a similar mechanism of action as duloxetine, i.e. serotonin metabolism inhibition, cause a decrease in proinflammatory cytokine activity and an increase in anti-inflammatory cytokines; this mechanism may apply to duloxetine in its effect on depression but research on cytokines specific to duloxetine therapy is lacking.

The analgesic properties of duloxetine in the treatment of diabetic neuropathy and central pain syndromes such as fibromyalgia are believed to be due to sodium ion channel blockade.

Pharmacokinetics

Absorption: Duloxetine is acid labile, and is formulated with enteric coating to prevent degradation in the stomach. Duloxetine has good oral bioavailability, averaging 50% after one 60 mg dose. There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post dose. Food does not affect the C_max of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours.

Distribution: Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Volume of distribution is 1640L.

Metabolism: Duloxetine undergoes predominately hepatic metabolism via two cytochrome P450 isozymes, CYP2D6 and CYP1A2. Circulating metabolites are pharmacologically inactive.

Elimination: Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state is usually achieved after 3 days. Only trace amounts (<1 20="" 70="" about="" and="" appears="" approx.="" are="" as="" dose="" duloxetine="" excreted="" feces.="" in="" metabolites="" most="" of="" p="" present="" the="" unchanged="" urine="" with="">

History

Cymbalta (duloxetine) 60mg

 

Duloxetine was created by Lilly researchers. David Robertson; David Wong, a co-discoverer of fluoxetine; and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990. The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988. The (+)-enantiomer of LY227942, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes to twice the degree of the (–)-enantiomer. This molecule was subsequently named duloxetine.

In 2001, Lilly filed a New Drug Application (NDA) for duloxetine with the US Food and Drug Administration. In 2003, however, the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP (current Good Manufacturing Practice) violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and QTc interval prolongation appeared as a concern. The FDA experts concluded that "duloxetine can cause hepatotoxicity in the form of transaminase elevations. It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver." The FDA also recommended "routine blood pressure monitoring" at the new highest recommended dose of 120 mg, "where 24% patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients."

After the manufacturing issues were resolved, the liver toxicity warning included in the prescribing information, and the follow-up studies showed that duloxetine does not cause QTc interval prolongation, duloxetine was approved by the FDA for depression and diabetic neuropathy in 2004. In 2007, Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.

Duloxetine was approved for use of stress urinary incontinence (SUI) in the EU in 2004. In 2005, Lilly withdrew the duloxetine application for stress urinary incontinence (SUI) in the U.S., stating that discussions with the FDA indicated "the agency is not prepared at this time to grant approval ... based on the data package submitted." A year later Lilly abandoned the pursuit of this indication in the U.S. market.

The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.

Cymbalta generated sales of nearly $5 billion in 2012 with $4 billion of that in the U.S., but its patent protection terminated January 1, 2014. Lilly received a six-month extension beyond June 30, 2013 after testing for the treatment of depression in adolescents, which may produce $1.5 billion in added sales. It was the most prescribed antidepressant in 2013–14.

The first generic duloxetine was marketed by Dr. Reddy.