Sulfonamide is afunctional group (a part of amolecule) that is the basis of several groups ofdrugs, which are calledsulphonamides,sulfa drugs orsulpha drugs. The original antibacterial sulfonamides are syntheticantimicrobial agents that contain thesulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., theanticonvulsantsultiame. Thesulfonylureas andthiazide diuretics are newer drug groups based upon the antibacterial sulfonamides.[1][2]
Allergies to sulfonamides are common. The overall incidence ofadverse drug reactions to sulfa antibiotics is approximately 3%, close topenicillin;[3] hence medications containing sulfonamides are prescribed carefully.
Sulfonamide drugs were the first broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine.
In bacteria, antibacterial sulfonamides act ascompetitive inhibitors of the enzymedihydropteroate synthase (DHPS), an enzyme involved infolate synthesis. Sulfonamides are therefore bacteriostatic and inhibit growth and multiplication of bacteria, but do not kill them. Humans, in contrast to bacteria, acquirefolate (vitamin B9) through the diet.[4]
Sulfonamides are used to treat allergies and coughs, as well as having antifungal and antimalarial functions. The moiety is also present in other medications that are not antimicrobials, includingthiazidediuretics (includinghydrochlorothiazide,metolazone, andindapamide, among others), loop diuretics (includingfurosemide,bumetanide, andtorsemide),acetazolamide,sulfonylureas (includingglipizide,glyburide, among others), and someCOX-2 inhibitors (e.g.,celecoxib).
Sulfasalazine, in addition to its use as an antibiotic, is also used in the treatment ofinflammatory bowel disease.[5]
Sulfonamide drugs were the first broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine. The first sulfonamide, trade-namedProntosil, was aprodrug. Experiments with Prontosil began in 1932 in the laboratories ofBayer AG, at that time a component of the huge German chemical trustIG Farben. The Bayer team believed thatcoal-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/researcherGerhard Domagk[6] (working under the general direction of IG Farben executiveHeinrich Hörlein) finally found one that worked: a red dye synthesized by Bayer chemistJosef Klarer that had remarkable effects on stopping some bacterial infections in mice.[7] 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.[citation needed]
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. The root word "pronto" was meant to imply "fast acting."[8] It had a strong protective action against infections caused bystreptococci, including blood infections,childbed fever, anderysipelas, 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 byDaniel Bovet,[9] Federico Nitti, andJacques andThérèse Tréfouël, a French research team led byErnest Fourneau at thePasteur Institute, that the drug was metabolized into two parts inside the body, releasing from the inactive dye portion a smaller, colorless, active compound calledsulfanilamide.[10] 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.[11]
The result was a sulfa craze.[12] For several years in the late 1930s, hundreds of manufacturers produced myriad forms of sulfa. This and the lack of testing requirements led to theelixir sulfanilamide disaster in the fall of 1937, during which at least 100 people were poisoned withdiethylene glycol. This led to the passage of theFederal Food, Drug, and Cosmetic Act in 1938 in the United States, giving authority to the U.S.Food and Drug Administration (FDA) to oversee the safety of food, drugs, medical devices, and cosmetics. As the first and only effective broad-spectrum antibiotic available in the years beforepenicillin, heavy use of sulfa drugs continued into the early years ofWorld War II.[13] They are credited with saving the lives of tens of thousands of patients, includingFranklin Delano Roosevelt Jr. (son of US PresidentFranklin Delano Roosevelt) andWinston Churchill.[14][15] Sulfa had a central role in preventing wound infections during the war. American soldiers were issued afirst-aid kit containing sulfa pills and powder and were told to sprinkle it on any open wound.[16]
The sulfanilamide compound is more active in theprotonated form. The drug has very low solubility and sometimes can crystallize in the kidneys, due to its pKa of 10.6[17] and pKb of 11.6.[18] 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, for example:sulfamethoxazole with a pKa1 1.6 and pKa2 5.7,[19] making them more likely to remain in a soluble form.
Sulfa drugs were shown to improve life expectancy in the years following their wide adoption. Because sulfa drugs were not effective against tuberculosis (TB), researchers could track the differences in mortality rates between conditions sulfa could treat and those it could not. A study of sulfa drugs—a major medical breakthrough in the 1930s—found they significantly reduced U.S. mortality rates for several infectious diseases. Between 1937 and 1943, sulfa drugs lowered maternal mortality by 25–40%, pneumonia mortality by 17–36%, and scarlet fever mortality by 52–67%. Overall, they reduced mortality by 2–4% and increased life expectancy by 0.4 to 0.8 years.[20]
Many thousands of molecules containing the sulfanilamide structure have been created since its discovery (by one account, over 5,400 permutations by 1945),[21] 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 molecules with a sulfonamide subunit are receiving growing interest with substances having antibacterial, antifungal, antiparasitic, antioxidant, and antitumour properties.[22]
Sulfonamides are prepared by the reaction of asulfonyl chloride with ammonia or an amine. Certain sulfonamides (sulfadiazine orsulfamethoxazole) are sometimes mixed with the drugtrimethoprim, which acts againstdihydrofolate reductase. As of 2013[update]Ireland is the largest exporter worldwide of sulfonamides, accounting for approximately 32% of total exports.[23]
Sulfonamides have the potential to cause a variety ofadverse effects, including urinary tract disorders,haemopoietic disorders,porphyria and hypersensitivity reactions. When used in large doses, they may cause a strong allergic reaction. The most serious of these are classified assevere cutaneous adverse reactions (i.e. SCARs) and include theStevens–Johnson syndrome,toxic epidermal necrolysis (also known as Lyell syndrome), theDRESS syndrome, and a not quite as serious SCARs reaction,acute generalized exanthematous pustulosis. Any one of these SCARs may be triggered by certain sulfonamides.[3]
The most common manifestations of a hypersensitivity reaction to sulfa drugs arerash andhives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, includingStevens–Johnson syndrome,toxic epidermal necrolysis,agranulocytosis,hemolytic anemia,thrombocytopenia, fulminant hepatic necrosis, andacute pancreatitis, among others.[24]
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%.[25]
Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class.
The nonantibiotic sulfonamides lack both of these structures.[26] The available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the nonantibiotic agents.[27]
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.[28] 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 (e.g., "cotrimoxazole allergy").[29]
