Sulpha-Drugs

Increased bilirubin levels are caused due to the intake of large doses of such drugs as chloroquine, vitamin K, sulpha-drugs, tetracyclines, paracetamol, nicotinic acid and monoamine oxidase inhibitors (e.g., iproniazid RP 1.0 nialamide RP 1.8 isocarboxazid RP 3.1 phenelzine RP 18 pheniprazine RP31 and tranylcypromine RP 45), where RP designates the Relative Potency based on the tiyptamine potentiation test. The elevated levels are due to hepatic injury, and... 

There are a few medicinals that cause increased bilirubin levels which ultimately enhances AP-levels unless and until a corrective measure is taken in the respective procedure one may be left with false AP-level enhancement. Some typical examples are, namely amitriptyline, chloropropamide, erythromycin, phenylbutazone, sulpha-drugs and tetracyclines. 

Much information on the mechanism of action and cross-resistance of purine analogues has been obtained in bacteria, some of which are quite sensitive to certain of these compounds in vitro. There is a great deal of variation in response of the various bacteria to a particular agent and of a particular bacterium to the various cytotoxic purine analogues. Some, if not most, of these differences are probably due to differences in the anabolism of the various compounds. Despite the fact that certain purine analogues have quite a spectrum of antibacterial activity in vitro, none has been useful in the treatment of bacterial infections in vivo because their toxicity is not selective—the metabolic events whose blockade is responsible for their antibacterial activity are also blocked in mammalian cells and thus inhibition of bacterial growth can only be attained at the cost of prohibitive host toxicity. In contrast, the sulpha drugs and antibiotics such as penicillin act on metabolic events peculiar to bacteria. 

Figure 1.1. Opposite) Sulpha drugs and their mode of action. The first sulpha drug to be used medically was the red dye prontosil rubrum (a). In the early 1930s, experiments illustrated that the administration of this dye to mice infected with haemolytic streptococci prevented the death of the mice. This drug, while effective in vivo, was devoid of in vitro antibacterial activity. It was first used clinically in 1935 under the name Streptozon. It was subsequently shown that prontosil rubrum was enzymatically reduced by the liver, forming sulphanilamide, the actual active antimicrobial agent (b). Sulphanilamide induces its effect by acting as an anti-metabolite with respect to /iflra-aminobenzoic acid (PABA) (c). PABA is an essential component of tetrahydrofolic acid (THF) (d). THF serves as an essential co-factor for several cellular enzymes. Sulphanilamide (at sufficiently high concentrations) inhibits manufacture of THF by competing with PABA. This effectively inhibits essential THF-dependent enzyme reactions within the cell. Unlike humans, who can derive folates from their diets, most bacteria must synthesize it de novo, as they cannot absorb it intact from their surroundings...

Antimicrobial sulpha drugs, e.g. sulphanilamide, are the amide of sulpha-nilic acid, and certain related substituted amides. Sulphanilamide, the first of the sulpha drugs, acts by inhibiting the bacterial enzyme that incorporates para-aminobenzoic acid into folic acid. Sulphanilamide is a bacteriostatic drug, i.e. inhibits the further growth of the bacteria. 

Multistep synthesis, starting from aniline, as depicted in the following scheme, can achieve the product, sulpha drug. 

To date, over 10 000 structural analogues of sulphanilamide, the parent of all sulpha drugs, have been synthesized and used in the SAR studies. However, only about 40 of them have ever been used as prescribed drugs. Sulpha drugs are bactereostatic, i.e. they inhibit bacterial growth but do not actively kill bacteria. These drugs act on the biosynthetic pathway of tetrahydrofolic acid, inhibit dihydropteroate synthetase and mimic the shape of PABA (para-aminobenzoic acid). 

From numerous studies, it has now been established that the amino functional groups (—NH2) is essential for the activity. In addition, the following structural features have to be present in sulpha drugs for the optimum antibacterial activity. 

Mammals must obtain their tetrahydrofolate requirements from their diet, but microorganisms are able to synthesize this material. This offers scope for selective action and led to the use of sulphanilamide and other antibacterial sulpha drugs, compounds which competitively inhibit dihydropteroate synthase, the biosynthetic enzyme incorporating p-aminobenzoic acid into the structure. These sulpha drugs thus act as antimetabolites of p-aminobenzoate. Specific dihydrofolate reductase inhibitors have also become especially useful as antibacterials,... 

Sulpha drugs (sulphaquinoxaline, sul-phadimethoxine, sulphaguanidine, sulphamethazine etc.), pyrimethamine, ormetoprim, etho-pabate, amoprolium, arprinocid, clopidol, decoquinate. 

A number of the sulphonamides have been evaluated against human malaria including chloroquin-resistant P. falciparum. Of these sulfadoxine (8) and sulphalene (9) were found to possess better antimalarial activity than the other sulpha drugs. Although sulphonamides have been found to be of value in the chemotherapy of... 

During World War II there was a great demand for an effective antimalarial, which could be used to protect the Allied troops. Consequently a large variety of synthetic compounds were tested against avian malaria. Those found effectives were tested in human subjects in federal prisons and military hospitals [5]. This effort resulted in the discovery of sulpha drugs with marked antimalarial activity. The most... 

The chemistry of sulphonamides has been dealt exhaustively by Lednicer and Mitscher [64] and by Korger [65]. Generally the sulpha drugs are prepared by two alternative routes (Scheme 1). The first method uses acetanilide (39) as the starting material, which is chlorosulphonated to get 4-acetamidobenzenesulphonyl chloride (40). Reaction of the latter with the appropriate arylamine affords the intermediate 41, which is hydrolysed with an acid or base to form the sulphonamides. Alternatively 4-nitrobenzenesulphonyl chloride (43) may be used to synthesize the sulpha drugs (as shown in Scheme 1). One can also use benzenesulphenyl chloride (45) as the starting material to synthesize the desired sulphonamides [65]. 

Sulphadoxine, the most commonly used sulpha drug is a structural analogue of pABA and acts as a competitive inhibitor of plasmodial DHPS. Resistance to sulphadoxine in P. falciparum involves amino acid substitutions in DHPS that alter enzyme function. Resistance to... 

This species is to be recognized as the archetype of the sulpha drugs, sulphanilamide. 

Polycyclic hydrocarbons, pesticides (dieldrin, ODD, DDT) and sulpha drugs were investigated. No detection limits and sensitivities were stated. 

It is now used very rarely beeause of its high toxicity and hence now being replaeed by comparatively less toxic sulpha drugs and antibiotics. It is still used in veterinary medieine. 

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