(Antimetabolites) Sulfonamides

Classes of Sulfonamides Systemic Sulfonamides Short-acting Sulfonamides Intermediate-acting sulfonamides Long-acting sulfonamides Intestinal sulfonamides Ophthalmic sulfonamides Sulfonamides for burn therapy

I. Systemic Sulfonamides According to their duration of action they are divided to: Short-acting Sulfonamides Intermediate-acting sulfonamides Long-acting sulfonamides

A) Short-acting Sulfonamides They are rapidly absorbed and rapidly excreted. Their half lives from 4-7 hours and they are administered every 4 to 8 hours.

B) Intermediate-acting sulfonamides They are absorbed and excreted more slowly than short-acting. Their half lives range from 10 to 12 hours so they are given twice daily.

C) Long-acting sulfonamides They are rapidly absorbed but slowly excreted their half lives are 35 to 40 hours.

II. Intestinal sulfonamides Water soluble latent forms which are poorly absorbed from the GIT (5%) and thus reach a high concentration in the colon lumen, By means of either bacterial or enzymatic hydrolysis releases the parent sulfonamide. Examples: sulfasalazine, phthalylsulfathiazole and succinylsulfathiazole (Prodrugs).

Intestinal sulfonamides (cont.) Sulfasalazine is mainly used for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is also effective in several types of arthritis, particularly rheumatoid arthritis Reductive metabolism by means of azoreductase enzyme converts the drug to sulfapyridine and 5-aminosalicylic acid (anti-inflammatory) both components are active

Ophthalmic sulfonamides They are used in treatment of conjunctivitis and other superficial ocular infections.

IV. Sulfonamides for burn therapy Mafenide is not a true sulfonilamide, it is not effective systemically, but is particularly effective topically in the treatment of burns or for healing infected wounds.

Sulfonamides for burn therapy (cont.) Silver sulfadiazine is used as effective topical antimicrobial agents, especially against Pseudomonas s. in burn therapy, where treatment failure with other drugs may occur.

Mixtures of sulfonamides Sulfonamides alone The main purpose is to reduce the risk of crystalluria Trisulfapyrimidine Each drug is administered in one third of the total dose, they behave independently concerning solubility but their therapeutic effects are additive.

b. Multiple (or Triple) sulfas They are a 1:1:1 combination of sulfabenzamide, sulfacetamide, and sulfathiazole. The combination is primarily used as topical cream for Gardnerella vaginalis in vaginal infections

2) Mixtures of sulfonamides with other drugs Sulfamethoxazole and Trimethoprim There is a synergistic effect obtained from such combination. It is usually given orally and I.V. administration. When taken orally the tablet has a standard ratio of 5 : 1 40 mg of the sulfa and 8 mg trimethoprim. Both drugs are excreted in urine their half lives are about 8-10 hours

This approach has been described as Trimethoprim is often given in conjunction with the sulfonamide sulfamethoxazole. The latter inhibits the incorporation of PABA into folic acid, while the former inhibits dihydrofolate reductase. Therefore, two enzymes in the one biosynthetic route are inhibited. This is a very effective method of inhibiting a biosynthetic route and has the advantage that the doses of both drugs can be kept down to safe levels. To get the same level of inhibition using a single drug, the dose level of that drug would have to be much higher, leading to possible side-effects. This approach has been described as 'sequential blocking'.

Pharmacokinetic factors of the combination Pairing these two particular antibacterial agents was based upon pharmacokinetic factors and convenient availability. For such a combination to be useful in vivo the two agents must arrive at the necessary infected tissues at the correct time and in the right ratio. It is used for oral treatment of urinary tract infections, shigellosis, otitis media, traveler's diarrhea and bronchitis.

Selectivity of Trimethoprim There is a significant differences between the bacterial and the mammalian dihydrofolate reductases away from the active site. The bacterial enzyme is sensitive to inhibition by trimethoprim by up to 100,000 times lower concentrations than is the mouse enzyme. This difference explains the useful selective toxicity of trimethoprim.

Advantages of this combination The combination of sulfamethoxazole-trimethoprim is not only synergistic in vitro but is less likely to induce bacterial resistance than either agent alone. Thus, these agents block sequentially at two different steps in the same essential pathway, and this combination is extremely difficult for a naive microorganism to survive. It is also comparatively uncommon that a microorganism will successfully mutate to resistance at both enzymes during the course of therapy. It is useful and comparatively nontoxic for AIDS patients who are infected with the pneumonia causing opportunistic pathogen Pneumotystis carinii.

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