Sulfonamides & Antifolate Drugs

Since the demonstration, in 1935, of the striking antibacterial activity of sulfanilamide, the molecule has been drastically altered in many ways. More than 150 different sulfonamides have been marketed at one time or another, the modifications being designed principally to achieve greater antibacterial activity, a wider anti-bacterial spectrum, greater solubility, or more prolonged action. Because of their law cost and their relative efficacy in some common bacterial infections, sulfonamides are still used widely in many parts of the world. However, the increasing emergence of sulfonamide resistance (eg, among streptococci, meningococ-ci, and shigellae) and the higher efficacy of other anti-microbial drugs have drastically curtailed the number of specific indications for sulfonamides as drugs of choice. The present indications for the use of these drugs can be summarized as follows:

  1. First (previously untreated) infection of the urinary tract : Many coliform organisms, which are the most common causes of urinary infections, are still susceptible to sulfonamides.
  2. Chlamydial infections of the trachoma-inclusion conjunctivitis-LGV group : Sulfonamides are often as effective as tetracyclines in suppressing clinical activity, and they may be curative in acute infections. However, they often fail to eradicate chronic infection, and they are ineffective in psittacosis.
  3. Parasitic and fungal diseases : In combination with pyrimethamine, sulfonamides are used in toxo-plasmosis. In combination with trimethoprim, sulfon amides are sometimes effective in falciparum malaria. Alone or in combination with cycloserine, sulfon-amides may be active in nocardiosis.
  4. Bacterial infections : In underdeveloped parts of the world, sulfonamides, because of their availabil-ity and low cost, may still be useful for the treatment of pneumococcal or staphylococcal infections; bac-terial sinusitis, bronchitis, or otitis media; bacillary (shigella) dysentery; and meningococcal infections. In most developed countries, however, sulfonamides are not the drugs of choice for any of these conditions, and sulfonamide resistance of the respective etiologic organisms is widespread.
  5. Leprosy : Certain sulfones are the drugs of choice in leprosy.

Antimicrobial Activity

The action of sulfonamides is bacteriostatic and is reversible upon removal of the drug or in the presence of an excess of p-aminobenzoic acid (PABA). Suscepti ble microorganisms require extracellular PABA in or-der to synthesize folic acid, an essential step in the formation of purines. Sulfonamides are structural ana-logues of PABA, can enter into the reaction in place of PABA competing for the enzyme involved, and can form nonfunctional analogues of folic acid. As a result, further growth of the microorganism is inhibited. Animal cells and some sulfonamide-resistant microor-ganisms are unable to synthesize folic acid from PABA but depend on exogenous sources of preformed folic acid.

Trimethoprim can inhibit the step in bacterial purine synthesis (dihydrofolic acid reductase) which follows the step blocked by sulfonamides. Trimetho prim plus sulfonamides (co-trimoxazole) can therefore produce sequential blocking of purine synthesis. Such "synergism" has been used in bacterial urinary tract and enteric infection and in malaria. Trimethoprim-resistant coliforms and haemophilus are appearing.

Pharmacologic Properties

The soluble sulfonamides are readily absorbed from the gut, distributed widely in tissues and body fluids, and excreted primarily by glomerular filtration into the urine. Varying amounts of sulfonamides are acetylated by the liver or bound to plasma protein. A portion of the drug in the urine is acetylated, but enough active drug remains in the urine to permit effective treatment of urinary tract infections (usually 10-20 times the concentration present in the blood). In order to be therapeutically effective for systemic therapy, a sulfonamide must achieve a concentration of 8-12 mg/ml of blood. This is accomplished by full systemic doses listed below.

"Long-acting" sulfonamides (eg, sulfamethoxy-pyridazine, sulfadimethoxine, sulfameter) are readily absorbed after oral intake, but urinary excretion is very slow, resulting in prolonged blood levels. "Intermediate-acting" sulfonamides (eg, sulfamethoxazole) are also excreted relatively slowly. All of these compounds may have a convenience factor but cause a higher incidence of severe toxic reactions.

"Insoluble" sulfonamides (eg, succinylsulfathiazole) are absorbed only slightly after oral administration and are largely excreted in the feces. Their action is mainly on the intestinal flora, and their use is limited.

For parenteral (usually intravenous) administration, sodium salts of several sulfonamides are used be-cause of their greater solubility. Their distribution and excretion are similar to those of the orally administered, absorbed sulfonamides.

Dosages & Routes of Administration

A. Topical : The application of sulfonamides to skin, wounds, or mucous membranes is undesirable because of the high risk of allergic sensitization or reaction and the low antimicrobial activity. Exceptions are the application of sodium sulfacetamide solution (30%) or ointment (10%) to the conjunctivas, and mafenide acetate cream (Sulfamylon®) or silver sulfadiazine to control the flora of the burn wound.

B. Oral : For systemic disease, the soluble, rapidly excreted sulfonamides (eg, sulfadiazine, sulfisoxazole) are given in an initial dose of 2-4 gm (40 mg/kg) followed by a maintenance dose of 0.5-1 gm (20 mg/kg) every 4-6 hours. Trisulfapyrimidines USP may be given in the same total doses. Urine must be kept alkaline.

For urinary tract infections (first attack, not previously treated), trisulfapyrimidines, sulfisoxazole, or another sulfonamide with equally high solubility in urine are given in the same (or somewhat lower) doses as shown above. Following one course of sulfonamides, resistant organisms usually prevail. Simultaneous ad-ministration of sulfamethoxazole, 2 gm/day orally, and trimethoprim, 400 mg/day orally, may be more effective in urinary tract infections than sulfonamide alone.

For "intestinal surgery prophylaxis," insoluble sulfonamides (eg, succinylsulfathiazole, phthalylsulfa-thiazole), 8-15 gm/day, are given for 5-7 days before operations on the bowel. These, however, are not currently manufactured in the 'USA. Salicylazosulfapyridine, 6 gm/day, has been given in ulcerative colitis, but there is little evidence of its efficacy.

"Long-acting" and "intermediate-acting" sulfon-amides (eg, sulfamethoxypyridazine, sulfadimethoxine, sulfamethoxazole) can be used in doses of 0.5-1 gm/day (10 mg/kg) for prolonged maintenance therapy (eg, trachoma) or for the treatment of minor infec-tions. These drugs have a significantly higher rate of toxic effects than the "short-acting" sulfonamides.

C. Intravenous : Sodium sulfadiazine can be in-jected intravenously in 0.5% concentration in 5% dextrose in water or physiologic salt solution in a total dose of 6-8 gm/day (120 mg/kg/day). This is reserved for comatose individuals or those unable to take oral medication.

Adverse Effects

Sulfonamides produce a wide variety of side-effects-due partly to hypersensitivity, partly to direct toxicity-which must be considered whenever unexplained symptoms or signs occur in a patient who may have received these drugs. Except in the mildest reactions, fluids should be forced, and-if symptoms and signs progressively increase-the drugs should be discontinued. Precautions to prevent complications (below) are important.

A. Systemic Side-Effects : Fever, skin rashes, urticaria; nausea, vomiting, or diarrhea; stomatitis, conjunctivitis, arthritis, exfoliative dermatitis; hematopoietic disturbances, including thrombocytopenia, hemolytic (in G6PD deficiency) or aplastic anemia, granulo-cytopenia, leukemoid reactions; hepatitis, polyarteritis nodosa, vasculitis, Stevens-Johnson syndrome; psychosis; and many others. Mafenide application to burns may cause severe pain.

B. Urinary Tract Disturbances : Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing hematuria, crystalluria, or even obstruction. They have also been implicated in various types of nephritis and nephrosis. Sulfonamides and methenamine salts should not be given together.

Precautions in the Use of Sulfonamides

  1. There is cross-allergenicity among all sulfonamides. Obtain a history of past administration or reaction. Observe for possible allergic responses.
  2. Keep the urine volume above 1500 mg/day by forcing fluids. Check urine pH-it should be 7.5 or higher. Give alkali by mouth (sodium bicarbonate or equivalent, 5-15 gm/day). Examine fresh urine for crystals and red cells every 2-4 days.
  3. Check hemoglobin, white blood cell count, and differential count every 3-5 days to detect possible disturbances early.

Sulfones Used in The Treatment of Leprosy

A number of drugs closely related to the sulfonamides have been used effectively in the long-term treatment of leprosy. The clinical manifestations of both lepromatous and tuberculoid leprosy can often be suppressed by treatment extending over several years.

Absorption, Metabolism, & Excretion

All of the sulfones are well absorbed from the intestinal tract, are distributed widely in all tissues, and tend to be retained in skin, muscle, liver, and kidney. Skin involved by leprosy contains 10 times more drug than normal skin. Sulfones are excreted into the bile and reabsorbed by the intestine. Consequently, blood levels are prolonged. Excretion into the urine is variable and occurs mostly as a glucuronic acid conjugate. Some persons acetylate sulfones slowly and others rapidly, and this requires dosage adjustment.

Adverse Effects

The sulfones may cause any of the side-effects listed above for sulfonamides. Anorexia, nausea, and vomiting are common. Hemolysis, methemoglobinemia, or agranulocytosis may occur.

Source : NEJM.W.L. Madoff MA

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