Sulphonamides

 

Sulphonamides

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Sulphonamides are antimicrobial drugs of synthetic origin which are extensively used to treat human and veterinary infections. In 1935, a scientist named, Domagk found that Prontosil dye inhibited the growth of streptococcal bacteria in mice. Later on it was found that Prontosil contained Sulphanilamide and Domagk was awarded with Noble prize for his discovery. The basic structure of Sulphonamides resembles that of Para amino benzoic acid (PABA) that is used by certain micro-organisms to synthesize Folic acid (an integral component of vitamin B complex). Utilization of Sulphonamide (instead of PABA) depletes the micro-organisms of Folic acid (hence Sulphonamides are said to inhibit the metabolic pathway of micro-organisms especially bacteria). Metabolism of Sulphonamides occurs predominantly through acetylation and glucoronide conjugation and to some extent through sulphate conjugation and hydro-oxylation. The acetylation prolongs their half life as their solubility is diminished (and they get precipitated in tissues). Therefore Sulpha drugs are comparatively safe in slow acetylators (such as dogs and other non-ruminants, in which glucoronide conjugation is the principal mechanism for Sulphonamide metabolism) and carry a high risk of toxicity in fast acetylator species (like ruminants).

  

Classification of Sulphonamides

 

1. Locally acting Sulphonamides: These are further classified into two categories.

(a) Topically acting Sulphonamides (e.g. Sulphacetamide is used for eye infections): These are topically administered to treat dermal infections caused by susceptible micro-organisms.

 

(b) Gut active Sulphonamides (e.g. Sulphaguinidine, Sulphasalazine etc.): They are poorly absorbed from GIT and thus they are effective for the treatment of enteritis and diarrhea associated with bacterial or protozoal infection (like coccidiosis, colibacilosis etc.).

 

2. Systemically acting Sulphonamides: They are meant for systemic action and are classified on the basis of their duration of action.

 

Category	Duration of action	Example
Short acting Sulphonamides	< 12 hours	Sulphanilamide Sulphadiazine
Intermediate acting Sulphonamides	12-24 hours	Sulphadimidine Sulphamethoxazole
Long acting Sulphonamides	24-48 hours	Sulphaethoxypyridazine Sulphamethoxypyridazine
Ultra long acting Sulphonamides	> 48 hours	Sulphadoxine

 

3. Potentiated Sulpha drugs: Di-aminopyrimidines and Sulphonamides block consecutive steps that are crucial for the metabolism of bacteria and if used in combination they show potentiated action.

 

Brand names of commonly used Potentiated Sulphonamides
Combination	Trade name (s)
Trimethoprim + Sulphamethoxazole = (Co-trimoxazole)	Septran
Trimethoprim + Sulphadiazine = (Co-trimazine)	Tribrissin, Triben
Pyrimethamine + Sulphadoxine	Fansidar (Anti-malarial)

 

Clinical uses:

Sulphonamides have been widely used to treat microbial (bacterial and protozoal) infections in human as well as in animals. Topical preparation of (such as cream) Silver Sulphadiazine (available with the trade name of “Quench”) is quite effective to inhibit microbial invasion of burn wounds. The combination of Pyrimethamine and Sulphadoxine (Fansidar) is used to treat malaria in human patients. In case of ruminants (cattle, sheep and goats), coccidiosis, toxoplasmosis, mastitis, metritis and interdigital necrobacillosis respond very well to Sulphonamide therapy. Sulphaquinoxaline is commonly used (either alone or potentiated with Diverdine, which is a Diaminopyrimidine) to treat coccidiosis in poultry while colitis in dogs can be treated with Sulphasalazine. Sulphadiazine is combined with Minocycline (a Tetracycline antibiotic) to treat nocardiasis in dogs and cats.

 

 

Antimicrobial spectrum of Sulpha drugs: All Sulphonamides are bacteriostatic with broad spectrum antimicrobial activity (only against rapidly multiplying bacteria, those in lag phase are comparatively resistant to Sulphonamides).

 

Micro-organisms susceptible to Sulphonamides
Gram positive bacteria	Streptococcus, Hemophilus, Bacillus, Actinobacillus
Gram negative bacteria	Enterobacteracae family
Protozoa	Toxoplasma, Eimeria, Plasmodium
Micro-organisms resistant to Sulphonamides
Mycoplasma, Acid fast bacteria (e.g., Mycobacterium), Pseudomonas, Rickettsiae (e.g., Ehrlichia and Anaplasma) and Spirocheates (such as Leptospira, Borrelia etc.)

 

Antagonists of Sulpha drugs: Availability of PABA, Folic acid, thymine, purine or glycine will inhibit the utilization of Sulphonamides by bacteria therefore their concomitant administration should be avoided. Pus and tissue debris also contains these substances (especially PABA) thus Sulpha drugs may prove ineffective if used topically for pus containing lesions, like abscesses. Co-administration of Procaine (precursor of PABA that is used as a local anesthetic) with Sulpha drugs is also contraindicated.

Adverse effects: The toxicity profile of Sulphonamides is manifested in terms of acute or chronic toxicity.

1. Acute toxicity:

(a) Crystalluria: Acidic urine causes the precipitation of Sulphonamides in renal tubules of glomerulus (resulting in obstruction of renal tubules) leading to crystalluria that is characterized by hematuria. Carnivores (having acidic P_H of urine) are more vulnerable than omnivores and herbivores. Administration of urinary alkalizer (like sodium bi carbonate), improving the hydration status of patient or using a combination of two or more Sulpha drugs (in this case each Sulphonamide will provide its individual solubility and the overall solubility of the mixture will be enhanced, chances of precipitation will be abolished) can help to avoid this problem.

 

(b) Idiosyncratic hemolytic anemia: Individuals with congenital deficiency of glucose-6 phosphate dehydrogenase are unable to produce sufficient level of glutathion (anti-oxidant in RBC_S) therefore they are subjected to hemolytic anemia caused by reactive oxygen species (generated by oxidizing drugs like Sulphonamides, Paracetamol and Primaquin etc.). This may occur within 2-7 days of therapy.

 

(c) Hypersensitivity reactions: Allergic skin reactions (such as expoliative dermatitis or cutaneous eruption) are frequent complications of Sulpha therapy. Sulphadiazine containing preparations may promote a reversible immune-mediated polyarthritis in Doberman breed of dogs.

 

2. Chronic toxicity:

(a) Hypoprothrombinemia: Prolonged administration of certain Sulphonamides (like Sulphaquinoxaline) may lead to vitamin K deficiency due to inhibition of vitamin K epoxide reductase enzyme (this commonly occurs in poultry). This results in hypoprothrombinemia and deficiency of vitamin K dependent clotting factors leading to prolongation of bleeding and clotting times.

 

(b) Keratoconjuctivitis sicca (KCS):  Some Sulpha drugs possess nitrogen-containing pyridine ring (instead of benzene ring) that is responsible for lacrymotoxic effect (which causes hypolacrimation/dryness of eyes) on lachrymal acinar cells of eyes.