Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial
sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides
are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas
and thiazide diuretics are newer drug groups based on the antibacterial sulfonamides.
Allergies to sulfonamide are common, 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. Because sulfonamides displace bilirubin from
albumin, kernicterus is an important potential side effect of sulfonamide use.
Function Antimicrobial
In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate
synthetase, an enzyme involved in folate synthesis. Sulfonamides are therefore bacteriostatic
and inhibit growth and multiplication of bacteria, but do not kill them. Humans, in contrast
to bacteria, acquire folate through the diet.
Other uses The sulfonamide chemical moiety is also present
in other medications that are not antimicrobials, including thiazide diuretics, loop diuretics,
acetazolamide, sulfonylureas, and some COX-2 inhibitors.
Sulfasalazine, in addition to its use as an antibiotic, is also used in the treatment
of inflammatory bowel disease. 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 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 which
are able to bind preferentially to bacteria and parasites might be used to attack 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 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. 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 discovered by Bovet, Federico
Nitti and J. and Th. Jacques Tréfouël, 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
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.
The result was a sulfa craze. 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 in the United States. 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. They are credited with saving the lives of tens of thousands
of patients, including Franklin Delano Roosevelt, Jr. 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.
The sulfanilamide compound is more active in the protonated form. The drug has very
low solubility 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 analogous compounds prevent this complication because
they have a lower pKa, around 5–6, making them more likely to remain in a soluble form.
Many thousands of molecules containing the sulfanilamide structure have been created
since its discovery, 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. Preparation
Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an
amine. Certain sulfonamides are sometimes mixed with the drug trimethoprim, which acts
against dihydrofolate reductase. As of 2013, Republic of Ireland is the largest exporter
worldwide of Sulfonamides, accounting for approximately 32% of total exports.
List of sulfonamides Child antibacterial drugs
Pediazole Antimicrobials
Sulfonylureas
Diuretics
Anticonvulsants Ethoxzolamide
Sultiame Topiramate
Zonisamide Dermatologicals
Mafenide Antiretrovirals
Amprenavir Darunavir
Delavirdine Fosamprenavir
Tipranavir Other
Stimulant Azabon
Side effects
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. 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%.
Hypersensitivity reactions are less common in nonantibiotic 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 nonantibiotic
agents. A key component to the allergic response to sulfonamide antibiotics is the arylamine
group at N4, found in sulfamethoxazole, sulfasalazine, sulfadiazine, and the anti-retrovirals amprenavir
and fosamprenavir. Other sulfonamide drugs do not contain this arylamine group; available
evidence suggests that patients who are allergic to arylamine sulfonamides do not cross-react
to sulfonamides that lack the arylamine group, and may therefore safely take non-arylamine
sulfonamides. It has therefore been argued that the terms 'sulfonamide allergy' or 'sulfa
allergy' are misleading, and should be replaced by a reference to a specific drug.
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 nonantibiotic sulfonamides lack both of
these structures. 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, fulminant
hepatic necrosis, and acute pancreatitis, among others.
See also Antibiotic
Timeline of antibiotics Elixir sulfanilamide
References
External links List of sulfonamides
Author of "The Demon under the Microscope," a history of the discovery of the sulfa drugs
A History of the Fight Against Tuberculosis in Canada
Presentation speech, Nobel Prize in Physiology and Medicine, 1939
The History of WW II Medicine "Five Medical Miracles of the Sulfa Drugs."
Popular Science, June 1942, pp. 73–78. http:www.life.umd.edubsci424AntibioticsHistory.htm
- A history of antibiotics