SULFANAMIDE DRUGS — chemotherapeutic broad-spectrum agents from group of derivatives of amide sulphanilic to - you (streptocide) with the general formula:
Amide sulphanilic to - you are synthesized by P. Gelmo in 1908. However use of this substance in medical practice was begun only in 1935. In 1932 — 1935 G. Domagk's researches established high activity of prontosil (sulfanylamidoorthochrisoidine) at an experimental streptococcal infection. Prontosil was synthesized as azoic dye in 1932 Mr. Mitch and Klarer (F. Mietzsch, J. Klarer). In the USSR similar connection was synthesized in 1935 by O. Yu. Magidson and M. V. Rubtsov and received the name «red streptocide». In 1935 spouses Trefuel (J. Tgyo-fouel, J. Trefouel), to F. Nit-ti and D. Bowe it was shown that as a result of biotransformation of prontosil in an organism its active metabolite — amide sulphanilic to - you is formed, to-ry defines antimicrobic activity of prontosil. In this regard it was offered to apply in medical practice instead of prontosil amide sulphanilic to - you, to - ry in the USSR received the name «white streptocide» (see. Streptocide ).
More than 10 thousand various derivatives of streptocide, from to-rykh St. 130, since 1935 are synthesized, were applied in medical practice. In modern medicine it is used apprx. 40 chemotherapeutic drugs of this row. Synthesis of derivatives of streptocide was carried out through receiving the connections replaced on hydrogen of sulphamide group (R1, derivatives on N1) or on hydrogen of an amino group (R2, derivatives on N4). It is established that manifestation of antimicrobic action of S. of the item requires existence at them not replaced amino group in para-situation to sulphamide, to t. e. at N4. Introduction of nek-ry heterocycles (a pyrimidine, pyridazinum, pyrazine, etc.) instead of hydrogen of sulphamide group, i.e. in situation at N1 (R1), significantly raises a degree of activity of S. of the item. Substitution of hydrogen of an amino group at N4 (R2) is followed by considerable decrease and even full loss of antimicrobic activity of connections. Such connections show antimicrobic activity in an organism only if in the course of biotransformation they are exposed to hydrolytic or recovery decomposition with formation of a free amino group in situation N4. This pattern is used for receiving special drugs for treatment of intestinal infections. Items are among such S., e.g., Ftalazolum (see), Phthazinum (see) and other N4 — the items replaced with S., to-rye are characterized by absence or extremely low antibacterial activity of in vitro, bad solubility and insignificant extent of absorption from went. - kish. path. However such drugs in intestines are hydrolyzed and turn into active metabolites with a free amino group in situation N4, than their efficiency at intestinal infections is caused.
Pages of the item — white or inodorous yellow-white crystal powders, nek-ry of them have bitterish taste. S. of the item from among derivatives are painted, among to-rykh practical value have so-called salazosulfanila-mida, e.g., Salazopyridazinum (see) and Salazodimethoxinum (see). Page of the item in the form of the bases badly rastvorima in water. Well rastvorima in water their sodium and methylglucamine salts, to-rye use for preparation of solutions C. of the item and including injection.
Pages of the item have a wide range of antimicrobic action. Gram-positive and gram-negative bacteria, nek-ry protozoa (plasmodiums of malaria, toxoplasma), chlamydias, actinomycetes, mycobacteria of a leprosy are sensitive to them. Affect sensitive microorganisms of S. of the item bacteriostatically. They can render bactericidal effect only in high concentration, in to-rykh they do not collect in an organism at use in therapeutic doses.
Mechanism of antimicrobic action Page of the item it is caused by the fact that they block synthesis dihydrofolic to - you on a mode of formation digidro-pterinovy to - you since thanks to structural looking alike the PUB To — the paraben (see) participating in synthesis digidrop-terinovy to - you, S. items force out the PUB To from the corresponding fermental system and at the same time inhibit enzyme, to-ry catalyzes this stage of synthesis. Dihydrofolic to - you under the influence of S. the item leads oppression of education to disturbance of biosynthesis of nucleotides that is followed by an arrest of development and reproduction of microorganisms. At surplus among the PUB To and its derivatives, e.g., of novocaine, anaesthesin, etc., and also methionine, folic to - you, the purine and pirimidinovy bases antimicrobic activity of S. of the item decreases. Reduction of activity of S. of the item in the presence of pus and is connected wound separated with high content in these PUBS substrates K and other antagonists of S. of the item.
According to features of pharmacokinetics and use among S. items distinguish the relevant subgroups. E.g., allocate S.'s subgroup of the item which are well soaking up from went. - kish. path. Items use such S. for system treatment of infections and for this purpose appoint inside and parenterally. Depending on the speed of their allocation among S. the item of this group is distinguished:
1) drugs of short action (time of semi-removal less than 10 hours) — streptocide (see), Norsulfazolum (see), a sulfacetamide (see), Etazolum (see), Sulfadimezinum (see), Urosulfanum (see Sulfanilmochevin), etc.;
2) drugs of average duration of action (time of semi-removal of 10 — 24 hours) — Sulfazinum (see), sulfamethoxazole, sulfafe-nazol, Methlsulfazinum, etc.;
3) drugs of long action (time of semi-removal from 24 to 48 hours) — Sulfapyridazinum (see), sulfadimethoxine (see), suljfamono-Methoxynum (see), sulfaperin, etc.;
4) drugs of superlong action (time of semi-removal more than 48 hours) — sulfalene, sulphadoxine, sulfaklomid.
The page of the item of the prolonged action differ from S. in the item of short action by higher lipophilicity and in this regard in significant amounts (to 50 — 90%) re-are absorbed in renal tubules owing to what they are more slowly brought from an organism.
To subgroup badly soaking up from went. - kish. S.'s path of the item belong sulfaguanidine (see), Ftalazolum and Phthazinum. These drugs use for treatment of intestinal infections.
Usually include soluble salts in S.'s subgroup of the item intended for topical administration (e.g., sodium) the drugs which are well soaking up from went. - kish. path, e.g., Norsulfazolum sodium, Etazolum sodium, Streptocidum solubile, etc. Drugs of this subgroup are used locally for treatment of purulent infections of skin and mucous membranes, contaminated wounds, etc.
Besides, items distinguish from S. so-called Sal azostreptocides — the azoic dyes synthesized on the basis of nek-ry S. by the item of systemic action and salicylic acid (see). Treat their number: Salazopyridazinum (see), Salazodimethoxinum (see) and Sulfasalazinum, to-rye are applied to treatment of nonspecific ulcer colitis.
In modern a wedge, practice also combined drugs containing streptocides and nek-ry derivatives of a diaminopyrimidine are widely used (e.g., Trimethoprimum), to-rye exponentiate S.'s action the item by disturbance of synthesis tetrahydrofolic to - you at the expense of inhibition of enzyme the diguide-rofolatreduktazy. Biseptolum is among such combined drugs (a synonym: Bactrimum, co-trimoxazole, Septrinum, etc.), the containing sulfamethoxazole and Trimethoprimum (concerning 5:1). Unlike S. Biseptolum works with the item bakteritsidno, has wider range of antimicrobic activity and is effective concerning the strains steady against S. of the item.
Also other combinations of S. of the item to derivatives of a diaminopyrimidine are in practice used. E.g., to treatment of drug resistant forms of malaria apply combinations of sulfalene or sulphadoxine with Chloridinum (see), and to treatment of a toxoplasmosis — a combination of Sulfazinum with Chloridinum.
Pages of the item apply to treatment of the infections caused by microorganisms, sensitive to these drugs. The choice of drugs is made taking into account features of their pharmacokinetics. So, at system infections (bacterial respiratory infections, easy, zhelche-and urinary tract etc.) S. use the items which are well soaking up from went. - kish. path. For treatment of intestinal infections appoint S. the items which are badly soaking up from went. - kish. a path (sometimes in a combination with well soaking up S. of the item).
Single and course doses of S. of the item, and also scheme of their appointment establish according to duration of effect of drugs. So, S. items of short action apply 4 — 6 g in daily doses, appointing them in 4 — 6 receptions (course doses of 20 — 30 g); Page of the item of average duration of action — in daily doses of 1 — 3 g, appointing them in 2 receptions (course doses of 10 — 15 g); Pages of the item of long action appoint in one step in a daily dose 0,5 — 2 g (course doses to 8 g). The page of the item of superlong action is appointed according to two schemes: 1) daily in an initial dose (in the first day) 0,8 — 1 g and further in maintenance doses on 0,2 g of 1 times a day; 2) on 1 time a week in a dose of 1,5 — 2 g. To children of a dose reduce according to age.
Side effect The page of the item is shown by dispeptic frustration, allergic reactions, neuritis, disturbances from c. N of page (headache, dizziness, etc.), leukopenia, methemoglobinemia, etc. It is also necessary to mean that owing to bad water solubility of S. the item and products of their acetylation in an organism can drop out in kidneys in the form of crystals and cause a crystalluria (especially at acidulation of urine). For prevention of this complication at S.'s reception plentiful alkaline drink is reasonable to recommend the item.
Pages of the item are contraindicated in the presence in the anamnesis of data on toksiko-allergic reactions to any drugs of this group.
Bibliography: Kivman G. Ya., Rudzit E. A. and Yakovlev V. P. Pharmacokinetics of chemotherapeutic drugs, M., 1982; M and sh to about fi-of a ska y M. D. Pharmaceuticals, p. 2, page 217, M., 1977; P ady with to and I am E. N and P about l at x and N of a JI. M. New sulfanamide drugs of long action for treatment of infectious diseases, M., 1974; Experimental chemotherapy, ed. by R. J. Schnitzer a. F. Hawking, v. 2, pt 1, p. 169, 249, N. Y. — L., 1964; Kli-nische Pharmakologie und Pharmakothera-pie, hrsg. v. H. P. Kuemmerle u. a., Miin-chen, 1976; The pharmacological basis of therapeutics, ed. by A. G. Gilman a. o., N. Y., 1980.
E. H. Padeyskaya.