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Problem Set 1: the Sulfonamides

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Problem Set 1: the Sulfonamides PROBLEM SET 1: THE SULFONAMIDES 1. Several bacteria are uneffected by the sulfonamides even though the drugs are capable of penetrating their cell walls and membranes and they do not contain a resistant dihydropteroate synthetase or increased levels of PABA. Also, these bacteria require folates like sulfonamide-sensitive bacteria. Postulate an explanation for these observations. SEVERAL ANSWERS ARE ACCEPTABLE. Most commonly bacteria that fit this description are those that can take up folic acid (like human cells) and reduce it directly to dihydro- and then tetrahydrofolate. These bacteria don't have dihydropteroate synthetase, much less a resistant form of the enzyme, and therefore are not affected by the sulfonamides. OTHER POSSIBLE ANSWERS: · It would be possible for bacteria that require the dihydropteroate synthetase pathway to synthesize large quantities of this enzyme to competitively overcome sulfonamide inhibition. Thus while the sulfonamides can inhibit the enzyme, it is produced in such large quantities that the sulfonamides cannot effectively shut down the pathway. · Bacteria may produce enzymes (like acetylases) that inactivate the drug. This pathway of resistance has not been detected in resistant bacteria, but is possible. · It is at least theoretically possible that bacteri may not require the folates for DNA, protein, etc. biosynthesis, although very unlikely. 2. The American Academy of Pediatrics has stated that "breast feeding and sulfonamide use are compatible in healthy, full-term neonates, but not premature infants or those with hyperbilirubinemia or glucose-6-phosphate deficiency". Explain the chemical/biochemical rationale for this precaution. This clearly relates to fact that the sulfonamides distribute to breast milk, although in low concentrations, and can be effectively transferred to (absorbed by) breast-fed offspring. The key to this precaution involves the inability of newborn to effectively clear the drug by conjugative metabolism. Healthy, full-term neonates typically have sufficient metabolic capacity to conjugate (acetylate, glucuronidate) the small quantity of drug transferred in the breast milk. Premature infants cannot. As a result, even these low sulfonamide concentrations may displace bilirubin (see the answer to question 6 elow) and interfer with glucose-6-phosphate dehydrogenase mediated formation of NADPH and GSH (see answer to question 3 below). ALSO, the N-acetyl conjugates of the sulfonamides are more efficiently transferred in breast milk than the parent sulfonamides, and this may contribute to greater "apparent sulfonamide sensit- ivity" (toxicity) in premature breast-fed neonates. 3. Patients with sulfonamide-associated hemolytic anemia have reduced erythrocyte levels of glutathione (reduced form) compared to "normals" who do not display drug-induced anemia. Explain the chemical/biochemical reason for this and its significance relative to hemolytic anemia. See class notes on sulfonamides and GSH levels in RBCs. Glutathione (GSH) is a key "protective" peptide for red blood cells (and other cells). It detoxifies electrophilic toxins by sulfhydryl atttack (as you learned in PY 419) and quenches free radicals (formed largely under the oxidative conditions in which the red blood cell exists). When glutatione levels are below those required for red blood cell protection, lysis of the cell occurs more readily (hemolytic anemia). Glutathione is formed from oxidized glutathione (GS-SG) by glutathone reductase, an reaction that requires the cofactor NADPH. NADPH is generated by the phosphate shunt which is initiated by glucose-6-phosphate. Individuals with a genetic deficiency of this enzyme have minimal capacity to generate NADPH. Thus they also have minimal NADPH reserve to sustain adequate levels of GSH. The sulfonamides, or more likely "aniline radicals" (see below) or electrophilic oxidation products (see class notes) formed from the sulfonamides, may either directly inhibit the already impaired dehydrogenase system, or directly place an excess oxidative stress on cells with minimal free GSH (the radicals themselves cause cellular injury and death). Thus individuals with a deficiency of the dehydrogenase will not produce "normal" NADPH levels, and this will lead to a decline in GSH levels. 4. Facts and Comparisons states that "aniline radicals" are responsible for the effects of sulfonamides on the blood and the hematopoietic system. What is meant by this, what are these radicals and how are they formed? (THE ANSWER IS NOT IN FACTS AND COMPARISONS). Drugs compounds possessing an aniline moiety (acetaminophen, aminoquinoline antimalarials, and SULFONAMIDES) or a nitro group that can be reduced to an aniline-type moiety (chloramphenicol, nitrofurantoin) are notorious "blood toxins". The precise mechanism of the effects of anilines on blood cells or the hematopoietic system are not clearly understood, but it appears to involve OXIDATION of the aniline nitrogen to a hydroxylamine and then nitroso metabolite. These species may may give rise to the free radicals by redox cycles that produce oxidative damage to blood cell enzymes and structures. See class notes on sulfonamides and GSH. 5. A prominent pharmacology text states that the "volume of distribution of most sulfonamides approaches that of total body water and the drugs penetrate cells. One exception to this is sulfisoxazole which distributes only in extracellular water". What is meant by this statement and what is the chemical basis for this? Sulfisoxazole is one of the most polar sulfonamides employed as a systemic antibacterial. It is relatively acidic, but even it's unionized form is relatively water soluble; it contains an isoxazole "R" group with two polar atoms and polarized double bonds. Thus this compound distributes preferentially to aqueous environments. Of course this polarity does not limit kidney distribution since capillary membranes of these tissues are relatively porous. Naturally the acidic sulfonamides also tend to be more extensively bound by plasma proteins and this may contribute as well. 6. Some sulfonamides are reported to “cause fatal kernicterus when administered to neonates”. What is "kernicterus" and what is the chemical/biochemical rationale for this reaction with sulfonamides? The plasma concentration of the bile pigment bilirubin is maintained (kept low) by metabolic conjugation (glucuronidation) and plasma protein (albumin) binding; plasma proteins bind the unconjugated form of bilirubin. In neonates conjugative metabolism is not completely developed, thus protein binding represents the principle mechanism of control of free bilirubin levels. This is important because free bilirubin can penetrate the CNS of neonates and impair brain development, a condition known as KERNICTERUS. When sulfonamides are administered they, as a result of their acidic nature, displace bilirubin from albumin, thereby elevating plasma levels of free bilirubin and penetration into the CNS. Also, there are some reports that sulfonamides can inhibit the glucuronidation of bilirubin. This would also contribute to the development of fatal kernicterus. 7. Why is sulfasalazine used to treat inflammatory bowel disease and NOT phthalylsulfacetamide or phthalylsulfathiazole? The principle difference between these three sulfonamide prodrugs is that sulfasalazine releases a sulfonamide and 5-AMINOSALICYLIC ACID upon metabolic activation (reduction), while the other two release phthalic acid and a sulfonamide. In inflammatory bowel disease 5-aminosalicylic acid is proposed to be the ACTIVE moiety. 5-Aminosalicylic acid inhibits prostaglandin synthesis, reduces leukotriene production, inhibits leukocyte mobility and inhibits mast cell degranulation (and other anti-inflammatory actions). Phthalic acid (released by the other two sulfonamide prodrugs) does not produce these anti-inflammatory effects. The sulfonamide moiety of sulfasalazine (sulfapyridine) may contribute to the overall activity of this compound as a result of its antibacterial actions. 8. The sulfonamides are reported to increase the bone marrow depressant effects of methotrexate (A DHFR inhibitor). Provide the biochemical/chemical rationale for this observation This may result from pharmacokinetic or pharmacologic drug interactions or both. Of the two type of interactions, the pharmacokinetic appear more likely to result in the observed increased in bone marrow toxicity. Pharmacokinetic interactions may involve: a. The sulfonamides are capable of displacing methotrexate and it's 17-hydroxy metabolite from plasma proteins. This would increase free levels of these compounds and could contribute to increased toxicity via inhibition of mammalian DHFR. b. A small fraction of methotrexate is metabolized by oxidation to the 17-hydroxy metabolite. Some evidence suggests the sulfonamides may inhibit this reaction and thereby block this contribution to clearance c. Competition for tubular secretion. A significant fraction of methotrexate is eliminated renally by tubular secretion. Secretion may play (although probably lesser) a role in sulfonamide elimination. Thus any ability of sulfonamides to competitively inhibit secretion of methotrexate would delay it's clearance, elevate plasma levels and thereby enhance toxicity. A pharmacologic contribution to this interaction may result from the ability of both drugs to depress folate biosynthesis. Methotrexate is an effective inhibitor of DHFR and thereby reduces tetrahydrofolate levels. The sulfonamides themselves or sulfonamide-dihydropteridine conjugates may also inhibit tetrahydrofolate formation (possible inhibition of DHFR) and this would result in an apparent increase in methotrexate activity, particularly versus blood cell lines. .
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