Sulfonamide (medicine)

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Sulfonamide functional group Sulfonamide.png
Sulfonamide functional group
Hydrochlorothiazide is a sulfonamide and a thiazide. Hydrochlorothiazide-2D-skeletal.png
Hydrochlorothiazide is a sulfonamide and a thiazide.
Furosemide is a sulfonamide, but not a thiazide. Furosemide.svg
Furosemide is a sulfonamide, but not a thiazide.
Sulfamethoxazole is an antibacterial sulfonamide Sulfamethoxazole-skeletal.svg
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 (nonantibiotic) 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. [1] [2]

Contents

Allergies to sulfonamides are common. The overall incidence of adverse drug reactions to sulfa antibiotics is approximately 3%, close to penicillin; [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.

Function

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. [4]

Structural similarity between sulfanilamide (left) and PABA (center) is the basis for the inhibitory activity of sulfa drugs on tetrahydrofolate (right) biosynthesis. Sulfa folate.svg
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. [5]

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 [6] (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. [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. 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, [8] 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. [9] 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. [10]

The result was a sulfa craze. [11] 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. 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. [12] 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. [13] [14] 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. [15]

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[ clarification needed ]. 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,[ citation needed ] 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.[ citation needed ]

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, the Republic of Ireland is the largest exporter worldwide of sulfonamides, accounting for approximately 32% of total exports. [16]

Varieties

Side effects

Urticaria 2.jpg
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. [3]

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%. [17]

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. [18] 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. [19] 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"). [20]

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. [21]

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. [22]

See also

Related Research Articles

Antibiotic Antimicrobial substance active against bacteria

An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the common cold or influenza; drugs which inhibit viruses are termed antiviral drugs or antivirals rather than antibiotics.

Gerhard Domagk

Gerhard Johannes Paul Domagk was a German pathologist and bacteriologist. He is credited with the discovery of Sulfonamidochrysoidine (KI-730), the first commercially available antibiotic and marketed under the brand name Prontosil, for which he received the 1939 Nobel Prize in Physiology or Medicine.

Hydrochlorothiazide Diuretic medication

Hydrochlorothiazide is a diuretic medication often used to treat high blood pressure and swelling due to fluid build up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is less effective than chlortalidone for prevention of heart attack or stroke. HCTZ is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness.

Dapsone Antibiotic medication

Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment and prevention of pneumocystis pneumonia and for the prevention of toxoplasmosis in those who have poor immune function. Additionally, it has been used for acne, dermatitis herpetiformis, and various other skin conditions. Dapsone is available both topically and by mouth.

Aztreonam

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa. This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis. It is given by intravenous or intramuscular injection or by inhalation.

Bacitracin Polypeptide Antibiotic (Gram Positive Bacteriacide)

Bacitracin is a polypeptide antibiotic. It is a mixture of related cyclic peptides produced by Bacillus licheniformis bacteria, that was first isolated from the variety "Tracy I" in 1945. These peptides disrupt Gram-positive bacteria by interfering with cell wall and peptidoglycan synthesis.

Bumetanide A loop diuretic

Bumetanide, sold under the brand name Bumex among others, is a medication used to treat swelling and high blood pressure. This includes swelling as a result of heart failure, liver failure, or kidney problems. It may work for swelling when other medications have not. For high blood pressure it is not a preferred treatment. It is taken by mouth, or by injection into a vein or muscle. Effects generally begin within an hour and lasts for about six hours.

Sulfamethoxazole Chemical compound

Sulfamethoxazole is an antibiotic. It is used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is effective against both gram negative and positive bacteria such as Listeria monocytogenes and E. coli.

Cefalexin Beta-lactam antibiotic

Cefalexin, also spelled cephalexin, is an antibiotic that can treat a number of bacterial infections. It kills gram-positive and some gram-negative bacteria by disrupting the growth of the bacterial cell wall. Cefalexin is a beta-lactam antibiotic within the class of first-generation cephalosporins. It works similarly to other agents within this class, including intravenous cefazolin, but can be taken by mouth.

Meropenem Broad-spectrum antibiotic

Meropenem, sold under the brand name Merrem among others, is an intravenous β-lactam antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.

Silver sulfadiazine Topical antibiotic

Silver sulfadiazine, sold under the brand Silvadene among others, is a topical antibiotic used in partial thickness and full thickness burns to prevent infection. Tentative evidence has found other antibiotics to be more effective and therefore it is no longer generally recommended for second-degree (partial-thickness) burns, but is still widely used to protect third-degree (full-thickness) burns.

Cefaclor

Cefaclor, sold under the trade name Ceclor among others, is a second-generation cephalosporin antibiotic used to treat certain bacterial infections such as pneumonia and infections of the ear, lung, skin, throat, and urinary tract. It is also available from other manufacturers as a generic.

Prontosil An early antimicrobial drug of nonantibiotic type

Prontosil is an antibacterial drug of the sulfonamide group. It has a relatively broad effect against gram-positive cocci but not against enterobacteria. One of the earliest antimicrobial drugs, it was widely used in the mid-20th century but is little used today because better options now exist. The discovery and development of this first sulfonamide drug opened a new era in medicine, because it greatly widened the success of antimicrobial chemotherapy in an era when many physicians doubted its still largely untapped potential. At the time, disinfectant cleaners and topical antiseptic wound care were widely used but there were very few antimicrobial drugs to use safely inside living bodies. Antibiotic drugs derived from microbes, which we rely on heavily today, did not yet exist. Prontosil was discovered in 1932 by a research team at the Bayer Laboratories of the IG Farben conglomerate in Germany.

Imipenem

Imipenem is an intravenous β-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s. Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria, thus play a key role in the treatment of infections not readily treated with other antibiotics.

Dicloxacillin Chemical compound

Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).

Sulfanilamide

Sulfanilamide is a sulfonamide antibacterial drug. Chemically, it is an organic compound consisting of an aniline derivatized with a sulfonamide group. Powdered sulfanilamide was used by the Allies in World War II to reduce infection rates and contributed to a dramatic reduction in mortality rates compared to previous wars. Sulfanilamide is rarely if ever used systemically due to toxicity and because more effective sulfonamides are available for this purpose. Modern antibiotics have supplanted sulfanilamide on the battlefield; however, sulfanilamide remains in use today in the form of topical preparations, primarily for treatment of vaginal yeast infections mainly vulvovaginitis which is caused by Candida albicans.

Sulfacetamide

Sulfacetamide is a sulfonamide antibiotic.

Drug eruption Medical condition

In medicine, a drug eruption is an adverse drug reaction of the skin. Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn. These are called "simple" drug eruptions. However, more serious drug eruptions may be associated with organ injury such as liver or kidney damage and are categorized as "complex". Drugs can also cause hair and nail changes, affect the mucous membranes, or cause itching without outward skin changes.

Ceftaroline fosamil

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

There are many circumstances during dental treatment where antibiotics are prescribed by dentists to prevent further infection. The most common antibiotic prescribed by dental practitioners is penicillin in the form of amoxicillin, however many patients are hypersensitive to this particular antibiotic. Therefore, in the cases of allergies, erythromycin is used instead.

References

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  19. Knowles S, Shapiro L, Shear NH (2001). "Should Celecoxib Be Contraindicated in Patients Who Are Allergic to Sulfonamides?". Drug Safety. 24 (4): 239–247. doi:10.2165/00002018-200124040-00001. PMID   11330653. S2CID   20386434.
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