Bipedal edema

abdominal distension & osmotic diarrhea

edema of the feet

palpable liver

uriennormal

Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial

sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that
contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g.,
theanticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based on the
antibacterial sulfonamides.[1]

Sulfa allergies are common,[2] hence medications containing sulfonamides are prescribed carefully. It is
important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such
as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the
same hypersensitivity reactions seen in the sulfonamides.

Contents
 [hide]

1 Function

o 1.1 Anti

microbial

o 1.2 Other

uses

2 History

3 Preparation

4 List of
sulfonamides

o 4.1 Antib

iotics

o 4.2 Diure

tics

o 4.3 Antic

onvulsants

o 4.4 Derm

atologicals

o 4.5 Other

5 Side effects

6 See also

7 References

8 External links

[edit]Function

[edit]Antimicrobial
Main article:  Dihydropteroate synthetase inhibitor

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate

synthetase (DHPS), an enzyme involved in folate synthesis.

[edit]Other uses
The sulfonamide chemical moiety is also present in other medications that are not antimicrobials,
including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among others),
loop diuretics
(including furosemide, bumetanide and torsemide) sulfonylureas (including glipizide, glyburide, among
others), some COX-2 inhibitors (e.g. celecoxib) and acetazolamide.

Sulfasalazine, in addition to its use as an antibiotic, is also utilized in the treatment of inflammatory bowel
disease.

[edit]History

Sulfonamide drugs were the first antimicrobial drugs, and paved the way for the antibiotic revolution in
medicine. The first sulfonamide, trade named Prontosil, was actually a prodrug. Experiments with
Prontosil began in 1932 in the laboratories of Bayer AG, at that time a component of the huge German
chemical trust IG Farben. The Bayer team believed that coal-tar dyes able to preferentially bind to
bacteria and parasites might be used to target harmful organisms in the body. After years of fruitless trial-
and-error work on hundreds of dyes, a team led by physician/researcher Gerhard Domagk(working under
the general direction of Farben executive Heinrich Hoerlein) finally found one that worked: a red dye
synthesized by Bayer chemist Josef Klarer that had remarkable effects on stopping some bacterial
infections in mice.[3] The first official communication about the breakthrough discovery was not published
until 1935, more than two years after the drug was patented by Klarer and his research partner Fritz
Mietzsch. Prontosil, as Bayer named the new drug, was the first medicine ever discovered that could
effectively treat a range of bacterial infections inside the body. It had a strong protective action against
infections caused by streptococci, including blood infections, childbed fever, and erysipelas, and a lesser
effect on infections caused by other cocci. However, it had no effect at all in the test tube, exerting its
antibacterial action only in live animals. Later it was accidentally discovered by a French research team,
led by Ernest Fourneau, at the Pasteur Institute that the drug was metabolized into two pieces inside the
body, releasing from the inactive dye portion a smaller, colorless, active compound called sulfanilamide.
The discovery helped establish the concept of "bioactivation" and dashed the German corporation's
dreams of enormous profit; the active molecule sulfanilamide (or sulfa) had first been synthesized in 1906
and was widely used in the dye-making industry; its patent had since expired and the drug was available
to anyone.[4]

The result was a sulfa craze.[5] For several years in the late 1930s, hundreds of manufacturers produced
tens of thousands of tons of myriad forms of sulfa. This and nonexistent testing requirements led to
the Elixir Sulfanilamide disaster in the fall of 1937, during which at least 100 people were poisoned
with diethylene glycol. This led to the passage of the Federal Food, Drug, and Cosmetic Act in 1938. As
the first and only effective antibiotic available in the years before penicillin, sulfa drugs continued to thrive
through the early years of World War II.[6] They are credited with saving the lives of tens of thousands of
patients including Franklin Delano Roosevelt, Jr. (son of President Franklin Delano Roosevelt) (in 1936)
and Winston Churchill. Sulfa had a central role in preventing wound infections during the war. American
soldiers were issued a first-aid kit containing sulfa pills and powder and were told to sprinkle it on any
open wound.

During the years 1942 to 1943, Nazi doctors conducted sulfanilamide experiments on prisoners in
concentration camps.[7][8]

The sulfanilamide compound is more active in the protonated form, which in case of the acid works better
in a basic environment. The solubility of the drug is very low and sometimes can crystallize in the kidneys,
due to its first pKa of around 10. This is a very painful experience so patients are told to take the
medication with copious amounts of water. Newer compounds have a pKa of around 5–6 so the problem
is avoided.
Many thousands of molecules containing the sulfanilamide structure have been created since its
discovery (by one account, over 5,400 permutations by 1945), yielding improved formulations with greater
effectiveness and less toxicity. Sulfa drugs are still widely used for conditions such as acne and urinary
tract infections, and are receiving renewed interest for the treatment of infections caused by bacteria
resistant to other antibiotics.

[edit]Preparation

Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an amine. Certain
sulfonamides (sulfadiazine or sulfamethoxazole) are sometimes mixed with the drug trimethoprim, which
acts against dihydrofolate reductase.

[edit]List of sulfonamides
[edit]Antibiotics
Short-acting

 Sulfamethoxazole
 Sulfisomidine (also known as sulfaisodimidine)
Intermediate-acting

 Sulfacetamide[9]
 Sulfadoxine
Ophthalmologicals

 Dichlorphenamide (DCP)
 Dorzolamide
[edit]Diuretics

 Acetazolamide
 Bumetanide
 Chlorthalidone
 Clopamide
 Furosemide
 Hydrochlorothiazide (HCT, HCTZ, HZT)
 Indapamide
 Mefruside
 Metolazone
 Xipamide
[edit]Anticonvulsants

 Acetazolamide
 Ethoxzolamide
 Sultiame
 Zonisamide
[edit]Dermatologicals

 Mafenide
[edit]Other

 Celecoxib (COX-2 inhibitor)
 Darunavir (Protease Inhibitor)
 Probenecid (PBN)
 Sulfasalazine (SSZ)
 Sumatriptan (SMT)
[edit]Side effects

Patient Suffering from Stevens–Johnson syndrome

Sulfonamides have the potential to cause a variety of untoward reactions, including urinary tract
disorders, haemopoietic disorders, porphyria and hypersensitivity reactions. When used in large doses,
they may cause a strong allergic reaction. Two of the most serious are Stevens Johnson
syndrome and toxic epidermal necrolysis(also known as Lyell syndrome).[2]

Approximately 3% of the general population have adverse reactions when treated with sulfonamide
antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about
60%.[10] People who have a hypersensitivity reaction to one member of the sulfonamide class are likely to
have a similar reaction to others.

Hypersensitivity reactions are less common in non-antibiotic sulfonamides, and, though controversial, the
available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an
increased risk of hypersensitivity reaction to the non-antibiotic agents.[11]

Allergic urticaria on the skin induced by an antibiotic

Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity
reactions associated with the class.

 The first is the N1 heterocyclic ring, which causes a type I hypersensitivity reaction.

 The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites
that cause either direct cytotoxicity or immunologic response.

The non-antibiotic sulfonamides lack both of these structures.[12]

The most common manifestations of a hypersensitivity reaction to sulfa drugs are rash and hives.
However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs,
including Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic
anemia, thrombocytopenia, and fulminant hepatic necrosis, among others.[13]

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)[1] are two forms of a life-

threatening condition affecting the skin in which cell death causes the epidermis to separate from
the dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous
membranes. Although the majority of cases are idiopathic, the main class of known causes is
medications, followed by infections and (rarely) cancers.

Contents
 [hide]

1 Classification

2 Signs and

symptoms

3 Causes

o 3.1 Infecti

ons

o 3.2 Medic

ation/drugs

o 3.3 Geneti

cs

4 Treatment

5 Prognosis

6 Epidemiology

7 History

8 Notable cases

9 See also

10 External links

11 References

[edit]Classification

There is agreement in the medical literature that Stevens–Johnson syndrome (SJS) can be considered a
milder form of toxic epidermal necrolysis (TEN). These conditions were first recognised in 1922.[2]

Both diseases can be mistaken for erythema multiforme. Erythema multiforme is sometimes caused by a
reaction to a medication but is more often a type III hypersensitivity reaction to an infection (caused most
often by Herpes simplex) and is relatively benign. Although both SJS and TEN can also be caused by
infections, they are most often adverse effects of medications. Their consequences are potentially more
dangerous than those of erythema multiforme.

[edit]Signs and symptoms

Conjunctivitis (inflammation of eye and eyelid) in SJS

SJS usually begins with fever, sore throat, and fatigue, which is misdiagnosed and usually treated with
antibiotics. Ulcers and other lesions begin to appear in the mucous membranes, almost always in the
mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful
and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children
who develop SJS. A rash of round lesions about an inch across arises on the face, trunk, arms and legs,
and soles of the feet, but usually not the scalp.[3]

[edit]Causes

SJS is thought to arise from a disorder of the immune system.[3]

[edit]Infections

It can be caused by infections (usually following infections such as herpes simplex

virus, influenza, mumps, cat-scratch fever, histoplasmosis, Epstein-Barr virus, mycoplasma
pneumoniae or similar).

[edit]Medication/drugs
See also:  List of SJS inducing substances

It can be caused by adverse effects of drugs (allopurinol, diclofenac, etravirine, Isotretinoin,

aka Accutane, fluconazole,[4] valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamide
s,phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil,[5] lamotrigine, nevirapine, pyrimethamin
e, ibuprofen,[6] ethosuximide, carbamazepine, nystatin, and gout medications).[7][8]

Although Stevens–Johnson Syndrome can be caused by viral infections, malignancies or severe allergic
reactions to medication, the leading cause appears to be the use of antibiotics and sulfa drugs.

Medications that have traditionally been known to lead to SJS, erythema multiforme and toxic epidermal
necrolysis
include sulfonamides (antibiotics), penicillins (antibiotics), barbiturates (sedatives),lamotrigine and phenyt
oin (e.g. Dilantin) (anticonvulsants). Combining lamotrigine with sodium valproate increases the risk of
SJS.

Non-steroidal anti-inflammatory drugs are a rare cause of SJS in adults; the risk is higher for older
patients, women and those initiating treatment.[2] Typically, the symptoms of drug-induced SJS arise
within a week of starting the medication. People with systemic lupus erythematosus or HIV infections are
more susceptible to drug-induced SJS.[3]

SJS has also been consistently reported as an uncommon side effect of herbal supplements
containing ginseng. SJS may also be caused by cocaine usage.[9]

[edit]Genetics

In some East Asian populations studied (Han Chinese and Thai), carbamazepine- and phenytoin-induced

SJS is strongly associated with HLA-B*1502 (HLA-B75), an HLA-B serotype of the broader serotype HLA-
B15.[10][11][12] A study in Europe suggested that the gene marker is only relevant for East Asians.[13][14] Based
on the Asian findings, similar studies were performed in Europe which showed 61% of allopurinol-induced
SJS/TEN patients carried the HLA-B58 (B*5801 allele - phenotype frequency in Europeans is typically
3%). One study concluded "even when HLA-B alleles behave as strong risk factors, as for allopurinol,
they are neither sufficient nor necessary to explain the disease."[15]

[edit]Treatment

SJS constitutes a dermatological emergency. All medications should be discontinued, particularly those
known to cause SJS reactions. Patients with documented mycoplasma infections can be treated with
oral macrolide or oral doxycycline.[3]

Initially, treatment is similar to that for patients with thermal burns, and continued care can only be
supportive (e.g. intravenous fluids and nasogastric or parenteral feeding) and symptomatic
(e.g.analgesic mouth rinse for mouth ulcer). Dermatologists and surgeons tend to disagree about whether
the skin should be debrided.[3]

Beyond this kind of supportive care, there is no accepted treatment for SJS. Treatment
with corticosteroids is controversial. Early retrospective studies suggested that corticosteroids increased
hospital stays and complication rates. There are no randomized trials of corticosteroids for SJS, and it can
be managed successfully without them.[3]

Other agents have been used, including cyclophosphamide and cyclosporine, but none has exhibited
much therapeutic success. Intravenous immunoglobulin (IVIG) treatment has shown some promise in
reducing the length of the reaction and improving symptoms. Other common supportive measures include
the use of topical pain anesthetics and antiseptics, maintaining a warm environment, and intravenous
analgesics. An ophthalmologist should be consulted immediately, as SJS frequently causes the formation
of scar tissue inside the eyelids, leading to corneal vascularization, impaired vision and a host of other
ocular problems. Now, a treatment appears to not only help bring a halt to the ocular reaction, but could
prevent all or most of these sequelae from developing. This treatment involves the application of amniotic
membrane to all eye and inner lid surfaces as soon as possible during the acute phase. Ideally, the
amniotic membrane should be applied to the eyes within the first several days of the reaction. But, due to
its anti-inflammatory and growth factors, amniotic membrane transplantation can still be of value within
the first 7-10 days (<14 days) of the onset of SJS. Also, an extensive physical therapy program ensues
after the patient is discharged from the hospital.

Diarrhea (from the Greek διάρροια meaning "flowing through"[2]), also spelled diarrhoea, is the condition

of having three or more loose or liquid bowel movements per day.[3] It is a common cause of death
in developing countries and the second most common cause of infant deaths worldwide. The loss
offluids through diarrhea can cause dehydration and electrolyte imbalances. In 2009 diarrhea was
estimated to have caused 1.1 million deaths in people aged 5 and over[4] and 1.5 million deaths in children
under the age of 5.[1] Oral rehydration salts and zinc tablets are the treatment of choice and have been
estimated to have saved 50 million children in the past 25 years.[1]

Contents
 [hide]

1 Definition

o 1.1 Secretory

o 1.2 Osmotic

o 1.3 Exudative

o 1.4 Motility-related

o 1.5 Inflammatory

o 1.6 Dysentery

2 Differential diagnosis

o 2.1 Infections

o 2.2 Malabsorption

o 2.3 Inflammatory bowel

disease

o 2.4 Irritable bowel syndrome

o 2.5 Other causes

3 Pathophysiology

o 3.1 Evolution

4 Diagnostic approach

5 Prevention

6 Management

o 6.1 Medications

 6.1.1 Antibiotics

 6.1.2 Anti motility

agents

 6.1.3 Bismuth

compounds

 6.1.4 Codeine

phosphate

 6.1.5 Zinc

o 6.2 Alternative therapies

7 Epidemiology

8 See also

9 References

10 External links

Definition
Type 7 on the Bristol Stool Chart indicates diarrhea

Diarrhea is defined by the World Health Organization as having 3 or more loose or liquid stools per day,
or as having more stools than is normal for that person.[3]

Secretory
Secretory diarrhea means that there is an increase in the active secretion, or there is an inhibition of
absorption. There is little to no structural damage. The most common cause of this type of diarrhea is
a cholera toxin that stimulates the secretion of anions, especially chloride ions. Therefore, to maintain a
charge balance in the lumen, sodium is carried with it, along with water. In this type of diarrhea intestinal
fluid secretion is isotonic with plasma even during fasting.[5] It continues even when there is no oral food
intake.

Osmotic
Osmotic diarrhea occurs when too much water is drawn into the bowels. This can be the result of
maldigestion (e.g., pancreatic disease or celiac disease), in which the nutrients are left in the lumen to pull
in water. Osmotic diarrhea can also be caused by osmotic laxatives (which work to
alleviate constipation by drawing water into the bowels). In healthy individuals, too
much magnesium or vitamin C or undigested lactose can produce osmotic diarrhea and distention of the
bowel. A person who has lactose intolerance can have difficulty absorbing lactose after an extraordinarily
high intake of dairy products. In persons who have fructose malabsorption, excess fructose intake can
also cause diarrhea. High-fructose foods that also have a high glucose content are more absorbable and
less likely to cause diarrhea. Sugar alcohols such as sorbitol (often found in sugar-free foods) are difficult
for the body to absorb and, in large amounts, may lead to osmotic diarrhea.[5] Osmotic diarrhea stops
when offending agent (e.g. milk, sorbitol) is stopped.

Exudative
Exudative diarrhea occurs with the presence of blood and pus in the stool. This occurs with inflammatory
bowel diseases, such as Crohn's disease or ulcerative colitis, and other severe infections such as E.
coli or other forms of food poisoning.[5]

Motility-related
Motility-related diarrhea is caused by the rapid movement of food through the intestines (hypermotility). If
the food moves too quickly through the gastrointestinal tract, there is not enough time for sufficient
nutrients and water to be absorbed. This can be due to a vagotomy or diabetic neuropathy, or a
complication of menstruation[citation needed]. Hyperthyroidism can produce hypermotility and lead
to pseudodiarrhea and occasionally real diarrhea. Diarrhea can be treated with antimotility agents (such
as loperamide). Hypermotility can be observed in people who have had portions of their bowel removed,
allowing less total time for absorption of nutrients.

Inflammatory
Inflammatory diarrhea occurs when there is damage to the mucosal lining or brush border, which leads to
a passive loss of protein-rich fluids, and a decreased ability to absorb these lost fluids. Features of all
three of the other types of diarrhea can be found in this type of diarrhea. It can be caused by bacterial
infections, viral infections, parasitic infections, or autoimmune problems such as inflammatory bowel
diseases. It can also be caused by tuberculosis, colon cancer, and enteritis.[citation needed]

Dysentery
Generally, if there is blood visible in the stools, it is not diarrhea, but dysentery. The blood is trace of an
invasion of bowel tissue. Dysentery is a symptom of, among others, Shigella, Entamoeba histolytica,
and Salmonella.

Differential diagnosis

Diagram of the human gastrointestinal tract.

Diarrhea is most commonly due to viral gastroenteritis with rotavirus, which accounts for 40% of cases in
children under five.[1](p. 17) In travelers howeverbacterial infections predominate.[6]

It can also be the part of the presentations of a number of medical conditions such as: Crohn's
disease or mushroom poisoning.

Infections
Main article:  Infectious diarrhea

There are many causes of infectious diarrhea, which include viruses, bacteria and parasites.

[7]
 Norovirus is the most common cause of viral diarrhea in adults,[8] but rotavirus is the most common
cause in children under five years old.[9] Adenovirus types 40 and 41,[10] and astroviruses cause a
significant number of infections.[11]

The bacterium campylobacter is a common cause of bacterial diarrhea, but infections

by salmonellae, shigellae and some strains of Escherichia coli (E.coli) are frequent.[12] In the elderly,
particularly those who have been treated with antibiotics for unrelated infections, a toxin produced
by Clostridium difficile often causes severe diarrhea.[13]

Parasites do not often cause diarrhea except for the protozoan Giardia, which can cause chronic
infections if these are not diagnosed and treated with drugs such as metronidazole,[14] and Entamoeba
histolytica.[15][16]

Other infectious agents such as parasites and bacterial toxins also occur.[6] In sanitary living conditions
where there is ample food and a supply of clean water, an otherwise healthy person usually recovers from
viral infections in a few days. However, for ill or malnourished individuals, diarrhea can lead to
severe dehydration and can become life-threatening.[17]

Malabsorption
Main article:  Malabsorption

Malabsorption is the inability to absorb food, mostly in the small bowel but also due to the pancreas.

Causes include:

 enzyme deficiencies or mucosal abnormality, as in food allergy and food intolerance, (e.g. celiac

disease (gluten intolerance), lactose intolerance (intolerance to milk sugar, common in non-
Europeans), fructose malabsorption)
 pernicious anemia (impaired bowel function due to the inability to absorb vitamin B12),
 loss of pancreatic secretions (may be due to cystic fibrosis or pancreatitis),
 structural defects, like short bowel syndrome (surgically removed bowel) and radiation fibrosis
(usually following cancer treatment and other drugs, including agents used in chemotherapy),
 certain drugs (like orlistat, which inhibits the absorption of fat).
Inflammatory bowel disease
Main article:  Inflammatory bowel disease

The two overlapping types here are of unknown origin:

 Ulcerative colitis is marked by chronic bloody diarrhea and inflammation mostly affects the
distal colon near the rectum.
 Crohn's disease typically affects fairly well demarcated segments of bowel in the colon and often
affects the end of the small bowel.
Irritable bowel syndrome
Main article:  Irritable bowel syndrome

Another possible cause of diarrhea is irritable bowel syndrome (IBS) which usually presents with
abdominal discomfort relieved by defecation and unusual stool (diarrhea or constipation) for at least 3
days a week over the previous 3 months.[18] There is no direct treatment for IBS, however symptoms can
be managed through a combination of dietary changes, soluble fiber supplements, and/or medications.

Other causes

 Diarrhea can be caused by chronic ethanol ingestion.[19]

 Ischemic bowel disease. This usually affects older people and can be due to blocked arteries.
 Hormone-secreting tumors: some hormones (e.g., serotonin) can cause diarrhea if excreted in
excess (usually from a tumor).
 Chronic mild diarrhea in infants and toddlers may occur with no obvious cause and with no other
ill effects; this condition is called toddler's diarrhea.
Pathophysiology
Evolution
According to two researchers, Nesse and Williams, diarrhea may function as an evolved expulsion
defense mechanism. As a result, if it is stopped, there might be a delay in recovery.[20] They cite in support
of this argument research published in 1973 which found that treating Shigella with the anti-diarrhea drug
(Co-phenotrope, Lomotil) caused people to stay feverish twice as long as those not so treated. The
researchers indeed themselves observed that: "Lomotil may be contraindicated in shigellosis. Diarrhea
may represent a defense mechanism".[21]

Diagnostic approach
The following types of diarrhea may indicate further investigation is needed:

 In infants
 Moderate or severe diarrhea in young children
 Associated with blood
 Continues for more than two days
 Associated non-cramping abdominal pain, fever, weight loss, etc.
 In travelers
 In food handlers, because of the potential to infect others;
 In institutions such as hospitals, child care centers, or geriatric and convalescent homes.
A severity score is used to aid diagnosis in children.[22]

Prevention
A rotavirus vaccine has the potential to decrease rates of diarrhea.[1] There are currently two licensed
vaccines against rotavirus. New vaccines against rotavirus, Shigella, ETEC, and cholera are under
development, as well as other causes of infectious diarrhea.

A Cochrane Review of studies found that in institutions and in communities, interventions that promote
hand washing lead to significant reductions in the incidence of diarrhea.[23]

Management
In many cases of diarrhea, replacing lost fluid and salts is the only treatment needed. This is usually by
mouth – oral rehydration therapy – or, in severe cases, intravenously.[1] Diet restrictions such as
the BRAT diet are no longer recommended.[24] Research does not support the limiting of milk to children
as doing so has no effect on duration of diarrhea.[25]

Medications such as loperamide (Imodium), bismuth subsalicylate may be beneficial, however they may

be contraindicated in certain situations.[26