sulfa drug

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1. use recreational drugs (同)do drugs
2. administer a drug to; "They drugged the kidnapped tourist" (同)dose
3. a substance that is used as a medicine or narcotic

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/14 20:21:21」(JST)

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Sulfonamide functional group

Hydrochlorothiazide is a sulfonamide and a thiazide.

Furosemide is a sulfonamide, but not a thiazide.

Sulfamethoxazole is an antibacterial sulfonamide

Sulfonamide (also called sulphonamide, sulfa drugs or sulpha drugs) 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. According to data the overall incidence of adverse drug reactions to sulfa antibiotics is approximately 3%, close to penicillin; 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 (brain damage due to excess bilirubin) is an important potential side effect of sulfonamide use.

Function

Antimicrobial

Main article: 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.

Structural similarity between sulfonamide (left) and PABA (center) is the basis for the inhibitory activity of sulfa drugs on dihydrofolate (right) biosynthesis

Other uses

Sulfonamides are used to treat allergies and cough, as well as 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.

History

Sulfonamide drugs were the first antibiotics 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 (working under the general direction of 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. 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 (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.

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. (son of US President Franklin Delano Roosevelt) 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 pK_a 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 pK_a, 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 (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.

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, Republic of Ireland is the largest exporter worldwide of Sulfonamides, accounting for approximately 32% of total exports.

List of sulfonamides

Children's antibacterial drugs

• Sulfafurazole (in Pediazole)

Antimicrobials

Short-acting

• Sulfacetamide
• Sulfadiazine
• Sulfadimidine
• Sulfafurazole (= Sulfisoxazole)
• Sulfisomidine (= sulfaisodimidine)
• Sulfanilamide

Intermediate-acting

• Sulfadoxine
• Sulfamethoxazole
• Sulfamoxole
• Sulfanitran

Long-acting

• Sulfadimethoxine
• Sulfamethoxypyridazine
• Sulfametoxydiazine

Ultra long-acting

• Sulfadoxine
• Sulfametopyrazine

Sulfonylureas (anti-diabetic agents)

• Acetohexamide
• Carbutamide
• Chlorpropamide
• Glibenclamide (also known as glyburide)
• Glibornuride
• Gliclazide
• Glyclopyramide
• Glimepiride
• Glipizide
• Gliquidone
• Glisoxepide
• Tolazamide
• Tolbutamide

Diuretics

• Acetazolamide
• Bumetanide
• Chlorthalidone
• Clopamide
• Dorzolamide
• Furosemide
• Hydrochlorothiazide (HCT, HCTZ, HZT)
• Indapamide
• Mefruside
• Metolazone
• Xipamide

Anticonvulsants

• Ethoxzolamide
• Sultiame
• Topiramate (a sulfamate, not a true sulfonamide)
• Zonisamide

Dermatologicals

• Mafenide

Antiretrovirals

• Amprenavir (protease inhibitor)
• Darunavir (protease inhibitor)
• Delavirdine (non-nucleoside reverse transcriptase inhibitor)
• Fosamprenavir (protease inhibitor)
• Simeprevir (protease inhibitor)
• Tipranavir (protease inhibitor)

Other

• Apricoxib (COX-2 inhibitor)
• Bosentan (endothelin receptor antagonist)
• Brinzolamide (carbonic anhydrase inhibitor for glaucoma)
• Celecoxib (COX-2 inhibitor)
• Dofetilide (class III antiarrhythmic)
• Dronedarone (class III antiarrhythmic)
• Ibutilide (class III antiarrhythmic)
• Parecoxib (COX-2 inhibitor)
• Probenecid (PBN)
• Sotalol (beta blocker)
• Sulfasalazine (SSZ)
• Sumatriptan (SMT)
• Tamsulosin (alpha blocker)
• Udenafil (PDE5 inhibitor)
• Azabon (Stimulant)
• Disufene (Muscle relaxant)

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).

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 (e.g. 'cotrimoxazole allergy').

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 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
• Dihydropteroate synthase
• PABA

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 (Chemotherapy)
• 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.edu/classroom/bsci424/Chemotherapy/AntibioticsHistory.htm - A history of antibiotics

UpToDate Contents

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• 1. Sulfonamide allergy in HIV-uninfected patients
• 2. トリメトプリムスルファメトキサゾール：概要 trimethoprim sulfamethoxazole an overview
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English Journal

• Capillary electrochromatography using knitted aromatic polymer as the stationary phase for the separation of small biomolecules and drugs.

• Tang P1, Chen Z2.
• Talanta.Talanta.2018 Feb 1;178:650-655. doi: 10.1016/j.talanta.2017.10.004. Epub 2017 Oct 3.
• PMID 29136876

• Synthesis, characterization and biological studies of a cobalt(III) complex of sulfathiazole.

• Pontoriero A1, Mosconi N1, Monti L1, Bellú S1, Williams PAM2, Raimondi M3, Lima B4, Feresin GE4, Nerli B1, Rizzotto M5.
• Chemico-biological interactions.Chem Biol Interact.2017 Dec 25;278:152-161. doi: 10.1016/j.cbi.2017.10.004. Epub 2017 Oct 5.
• PMID 28987326

• 8-Mercaptoguanine derivatives as inhibitors of dihydropteroate synthase.

• Swarbrick J1, Dennis M2, Lee M2, Harjani J2, Ahmed M3, Debono A2, Pitcher N2, Wang ZC2, Chhabra S4, Barlow N2, Rahmani R2, Cleary B2, Dolezal O2, Hattarki M2, Aurelio L2, Shonberg J2, Graham B2, Peat T2, Baell J2.
• Chemistry (Weinheim an der Bergstrasse, Germany).Chemistry.2017 Nov 24. doi: 10.1002/chem.201704730. [Epub ahead of print]
• PMID 29171692

Japanese Journal

• Characterization of Eimeria brunetti Isolated from a Poultry Farm in Japan

• KAWAHARA Fumiya,ZHANG Guohong,SUZUKI Takayuki,IWATA Akira,NAGAMUNE Kisaburo,NUNOYA Tetsuo
• Journal of Veterinary Medical Science 76(1), 25-29, 2014
• … Sulfa drugs and lasalocid were so effective that the E. …
• NAID 130003362284

• 牛コクシジウム症におけるトリトラズリルの治療効果

• 立川 文雄
• 家畜診療 58(7), 419-423, 2011-07
• NAID 40018911066

• Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

• Yoneyama Hiroshi,Katsumata Ryoichi
• Bioscience, biotechnology, and biochemistry 70(5), 1060-1075, 2006-05-23
• … Since the first introduction of the sulfa drugs and penicillin into clinical use, large numbers of antibiotics have been developed and hence contributed to human health. … But extensive use of antibiotics has raised a serious public health problem due to multiantibiotic resistant bacterial pathogens that inevitably develop resistance to every new drug launched in the clinic. …
• NAID 10018530732

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