Sulfonamide (medicine)

{{Short description|Molecular moiety or the drug class that uses it}} {{for|chemistry of the functional group|Sulfonamide}} {{Use dmy dates|date=April 2017}} [[File:Sulfonamide.png|thumb|Sulfonamide functional group]] [[File:Hydrochlorothiazide-2D-skeletal.png|thumb|Hydrochlorothiazide is a sulfonamide and a thiazide.]] [[File:Furosemide.svg|thumb|Furosemide is a sulfonamide, but not a thiazide.]] [[File:Sulfamethoxazole-skeletal.svg|thumb|Sulfamethoxazole is an antibacterial sulfonamide.]]

'''Sulfonamide''' is a functional group (a part of a molecule) that is the basis of several groups of drugs, which are called '''sulphonamides''', '''sulfa drugs''' or '''sulpha 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 upon the antibacterial sulfonamides.<ref name="modeofaction">{{cite journal | author = Henry RJ | title = The Mode of Action of Sulfonamides | journal = Bacteriological Reviews | volume = 7 | issue = 4 | pages = 175–262 | year = 1943 | pmid = 16350088 | pmc = 440870 | doi = 10.1128/br.7.4.175-262.1943 }}</ref> Allergies to sulfonamides are common. The overall incidence of adverse drug reactions to sulfa antibiotics is approximately 3%, close to penicillin;<ref name="allergies.about.com">{{cite web|url=http://allergies.about.com/od/medicationallergies/a/sulfa.htm|title=Sulfa Drugs Allergy -- Sulfa Bactrim Drug Allergies|publisher=allergies.about.com|access-date=17 January 2014|archive-date=14 April 2014|archive-url=https://web.archive.org/web/20140414070242/http://allergies.about.com/od/medicationallergies/a/sulfa.htm|url-status=dead}}</ref> 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.

==Function== {{Main|Dihydropteroate synthase inhibitor}}

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthase (DHPS), 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 (vitamin B9) through the diet.<ref>M. Madigan, J. Martinko, D. Stahl, D. Clark, ''Brock Biology of Microorganisms (13th ed.)'', Pearson Education, 2012, p. 797 {{ISBN|9780321735515}}</ref> [[File:Sulfa folate.svg|thumb|upright=1.6|Structural similarity between sulfanilamide (left) and PABA (center) is the basis for the inhibitory activity of sulfa drugs on tetrahydrofolate (right) biosynthesis.]]

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, including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among others), loop diuretics (including furosemide, bumetanide, and torsemide), acetazolamide, sulfonylureas (including glipizide, glyburide, among others), and some COX-2 inhibitors (e.g., celecoxib).

Sulfasalazine, in addition to its use as an antibiotic, is also used in the treatment of inflammatory bowel disease.<ref>{{cite book |last1=Lackie |first1=John |title=A Dictionary of Biomedicine |date=2010 |publisher=Oxford University Press |isbn=978-0199549351 |page=543}}</ref>

==History== 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-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<ref>{{cite journal | author = Otten H | title = Domagk and the development of the sulphonamides | journal = Journal of Antimicrobial Chemotherapy | volume = 17 | issue = 6 | pages = 689–696 | year = 1986 | pmid = 3525495 | doi = 10.1093/jac/17.6.689 | doi-access = free }}</ref> (working under the general direction of IG Farben executive Heinrich Hörlein) 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.<ref>{{Cite book | url = https://books.google.com/books?id=S32TrACJa6kC&q=demon+under+the+microscope | title = The Demon Under the Microscope: From Battlefield Hospitals to Nazi Labs, One Doctor's Heroic Search for the World's First Miracle Drug | isbn = 978-0-307-35228-6 | last1 = Hager | first1 = Thomas | date = 2006-09-01| publisher = Crown }}</ref> 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|date=November 2020}}

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."<ref>{{cite book |last1=Voiovich |first1=Jason |title=Bullfrogs, Bingo, and the Little House on the Prairie: How Innovators of the Great Depression Made the Best of the Worst of Times |date=May 13, 2025 |publisher=Jaywalker Publishing |isbn=978-1737001379 |pages=95–111}}</ref> 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 Daniel Bovet,<ref>Cf. Daniel Bovet, ''Une chimie qui guérit : Histoire de la découverte des sulfamides'', Paris, Payot, coll. « Médecine et sociétés », 1988 ({{ISBN|2-228-88108-2}}).</ref> Federico Nitti, and Jacques and Thérèse Tréfouël, a French research team led by Ernest Fourneau at the Pasteur Institute, that the drug was metabolized into two parts inside the body, releasing from the inactive dye portion a smaller, colorless, active compound called sulfanilamide.<ref>{{cite journal|first1=J.|last1=Tréfouël|first2=Th.|last2=Tréfouël|first3=F.|last3=Nitti|first4=D.|last4=Bovet|title=Activité du p. aminophénylsulfamide sur l'infection streptococcique expérimentale de la souris et du lapin|journal=C. R. Soc. Biol.|volume=120|date=23 November 1935|page=756}}</ref> 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.<ref name="britannica">{{cite encyclopedia|url=https://www.britannica.com/science/history-of-medicine/Medicine-in-the-20th-century#ref35670|title=History of medicine|encyclopedia=Encyclopædia Britannica|access-date=17 January 2014}}</ref>

The result was a sulfa craze.<ref name="wordpress">{{cite web|url=https://blogofbad.wordpress.com/2009/02/09/bad-health-elixir-sulfanilamide/|title=Bad Health—Elixir Sulfanilamide|website=The Blog of Bad|date=9 February 2009|access-date=17 January 2014}}</ref> For several years in the late 1930s, hundreds of manufacturers produced myriad forms of sulfa. This and the lack of 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, 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 before penicillin, heavy use of sulfa drugs continued into the early years of World War II.<ref name="att">{{cite web |url=http://home.att.net/~steinert/wwii.htm#The%20Use%20of%20Sulfanilamide%20in%20World%20War%20II |archive-url=https://web.archive.org/web/19991014020444/http://home.att.net/%7Esteinert/wwii.htm#The%20Use%20of%20Sulfanilamide%20in%20World%20War%20II |archive-date=14 October 1999 |url-status=dead |title=History of WWII Medicine |access-date=2014-04-04 |df=dmy-all }}</ref> They are credited with saving the lives of tens of thousands of patients, including Franklin Delano Roosevelt Jr. (son of US President Franklin Delano Roosevelt) and Winston Churchill.<ref>{{cite magazine|title=Medicine: Prontosil|url=http://content.time.com/time/magazine/article/0,9171,771900,00.html|magazine=Time|access-date=2014-03-28|date=28 December 1936|language=en|url-access=subscription|archive-date=19 August 2022|archive-url=https://web.archive.org/web/20220819144103/https://content.time.com/time/magazine/article/0,9171,771900,00.html|url-status=dead}}</ref><ref>{{cite journal|title=Adaptation and extension of sulfonamide and other antibiotics determination by solid-phase extraction followed by liquid chromatography and mass spectrometry|first1=Lajos|last1=Kadenczki|first2=Henrietta Stefánné|last2=Szopkó|url=http://www.matarka.hu/koz/ISSN_2063-6997/Vol1_No1/ISSN_2063-6997_vol_1_no_1_2012_eng_145-157.pdf|journal=Geosciences and Engineering|issue=1|year=2012|volume=1|page=147|language=en|issn=2063-6997|oclc=1066656753}}</ref> 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.<ref>[https://www.nationalww2museum.org/medical-innovations-antibiotics Medical Innovations: Antibiotics] The National WWII Museum. Accessed 29 July 2021.</ref>

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 pKa of 10.6<ref name=Serjeant>{{cite book |title=Ionisation Constants of Organic Acids in Aqueous Solution |date=1979 |publisher=Elsevier Science & Technology |isbn=0080223397}}</ref> and pKb of 11.6.<ref name=cid5333>Sulfanilamide {{PubChemLink|5333}}</ref> 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,<ref name=Boreen>{{cite journal| last1 = Boreen | first1 = Anne L. | last2 = Arnold | first2 = William A. | last3 = McNeill | first3 = Kristopher | title = Photochemical Fate of Sulfa Drugs in the Aquatic Environment: Sulfa Drugs Containing Five-Membered Heterocyclic Groups | journal = Environmental Science & Technology |pmid = 15298203| doi = 10.1021/es0353053 | date = July 2004 | volume = 38 | issue = 14 | pages = 3933–3940 }}</ref> 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.<ref>{{cite journal |last1=Jayachandran |first1=Seema |last2=Lleras-Muney |first2=Adriana |last3=Smith |first3=Kimberly |title=MODERN MEDICINE AND THE 20TH CENTURY DECLINE IN MORTALITY: EVIDENCE ON THE IMPACT OF SULFA DRUGS |journal=National Bureau of Economic Research |series=Working Paper Series |date=June 2009 |doi=10.3386/w15089 |url=http://www.nber.org/papers/w15089 |access-date=9 July 2025|doi-access=free }}</ref>

Many thousands of molecules containing the sulfanilamide structure have been created since its discovery (by one account, over 5,400 permutations by 1945),<ref>{{Cite book|title=The First Miracle Drugs: How the Sulfa Drugs Transformed Medicine|last=Lesch|first=John|date=September 2023|isbn=9780195187755|doi=10.1093/oso/9780195187755.001.0001}}</ref> 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.<ref name=Azevedo-Barbosa>{{cite journal|last1 = Azevedo-Barbosa |first1 = Helloana |last2 = Dias |first2 = Danielle Ferreira |last3 = Franco |first3 = Lucas Lopardi |last4 = Hawkes |first4 = Jamie Anthony |last5 = Carvalho |first5 = Diogo Teixeira |title = From Antibacterial to Antitumour Agents: A Brief Review on the Chemical and Medicinal Aspects of Sulfonamides |journal = Mini-Reviews in Medicinal Chemistry |date = 2020 |volume = 20 |issue = 19 |pages = 2052–2066 |doi = 10.2174/1389557520666200905125738 |pmid = 32888265 }}</ref>

== 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. {{As of|2013}} Ireland is the largest exporter worldwide of sulfonamides, accounting for approximately 32% of total exports.<ref>{{cite web | url=http://atlas.media.mit.edu/hs4/2935/ | title=Trade of Sulfonamides | publisher=Massachusetts Institute of Technology | access-date=26 October 2013}}</ref>

== Varieties == {{main|List of sulfonamides}}

== Side effects == {{multiple image|total_width=250 | image1 = Stevens-johnson-syndrome.jpg | caption1 = Person with Stevens–Johnson syndrome | image2 = Urticaria 2.jpg | caption2 = Allergic urticaria on the skin induced by an antibiotic }}

Sulfonamides have the potential to cause a variety of adverse 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 as severe cutaneous adverse reactions (i.e. SCARs) and include the Stevens–Johnson syndrome, toxic epidermal necrolysis (also known as Lyell syndrome), the DRESS syndrome, and a not quite as serious SCARs reaction, acute generalized exanthematous pustulosis. Any one of these SCARs may be triggered by certain sulfonamides.<ref name="allergies.about.com"/>

=== Hypersensitivity === 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.<ref name="Harrison's">{{ cite book | title = Harrison's Principles of Internal Medicine, 13th Ed. | publisher = McGraw-Hill Inc | year = 1994 | pages = 604 }}</ref>

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%.<ref name=SMJ>{{cite journal | author = Tilles SA | title = Practical issues in the management of hypersensitivity reactions: sulfonamides | journal = Southern Medical Journal | volume = 94 | issue = 8 | pages = 817–24 | date = August 2001 | pmid = 11549195 | doi = 10.1097/00007611-200108000-00013 | s2cid = 8493824 }}</ref>

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.<ref name=Cross>{{cite journal | vauthors=Brackett CC, Singh H, Block JH | title = Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group | journal = Pharmacotherapy | volume = 24 | issue = 7 | pages = 856–70 | date = July 2004 | pmid = 15303450 | doi = 10.1592/phco.24.9.856.36106| s2cid = 25623592 }}</ref> The available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the nonantibiotic agents.<ref name=Immun>{{cite journal |vauthors=Slatore CG, Tilles SA | title = Sulfonamide hypersensitivity | journal = Immunology and Allergy Clinics of North America | volume = 24 | issue = 3 | pages = 477–490, vii | year = 2004 | pmid = 15242722 | doi = 10.1016/j.iac.2004.03.011 }}</ref>

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.<ref name=Knowles>{{cite journal |vauthors=Knowles S, Shapiro L, Shear NH | title = Should Celecoxib Be Contraindicated in Patients Who Are Allergic to Sulfonamides? | journal = Drug Safety | volume = 24 | issue = 4 | pages = 239–247 | year = 2001 | pmid = 11330653 | doi = 10.2165/00002018-200124040-00001 | s2cid = 20386434 }}</ref> 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").<ref name=WAMSG>{{cite web | author = Veroni M | title = ALLERGIES TO SULFONAMIDE ANTIBIOTICS AND CROSS-REACTIVITIES | publisher = Western Australian Therapeutic Advisory Group | url = http://www.watag.org.au/wamsg/docs/WAMSG_alert_Sulfonamide.pdf | access-date = 2014-02-07 | archive-url = https://web.archive.org/web/20110303045623/http://www.watag.org.au/wamsg/docs/WAMSG_alert_Sulfonamide.pdf | archive-date = 3 March 2011 }}</ref>

== See also == * Dihydropteroate synthase * Elixir sulfanilamide * Hellmuth Kleinsorge (1920–2001) German medical doctor * PABA * Timeline of antibiotics

== References == {{Reflist}}

== External links == * [https://web.archive.org/web/20160303195437/http://www.nlm.nih.gov/cgi/mesh/2004/MB_cgi?field=entry&term=Sulfonamides List of sulfonamides] * [https://web.archive.org/web/20060524135032/http://www.lung.ca/tb/tbhistory/treatment/chemo.html A History of the Fight Against Tuberculosis in Canada (Chemotherapy)] * [https://www.nobelprize.org/prizes/medicine/1939/ceremony-speech/ Presentation speech], Nobel Prize in Physiology and Medicine, 1939 * [https://web.archive.org/web/20100301192707/http://home.att.net/~steinert/wwii.htm The History of WW II Medicine] * [https://books.google.com/books?id=RicDAAAAMBAJ&pg=PA73&dq=popular+science+1930#v=twopage&q=popular%20science%201930&f=true "Five Medical Miracles of the Sulfa Drugs"]. ''Popular Science'', June 1942, pp. 73–78. * [https://science.umd.edu/classroom/bsci424/Chemotherapy/AntibioticsHistory.htm A history of antibiotics]

{{SulfonamideAntiBiotics}} {{Anticonvulsants}} {{Antibiotics and chemotherapeutics for dermatological use}} {{Diuretics}}

Category:Dermatoxins Category:Disulfiram-like drugs Category:Hepatotoxins * Category:Sulfonamides