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on Jul 17, 2012 Says :
nice ppt on sulphonamides
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INTRODUCTION First chemotherapeutic agents used systemically. Discovered by –Domagk, 1935. Prontosil, an azo dye- Release of an active metabolite– Sulphanilamide. Sulphonamide or sulpha drug- generic name for all derivatives of sulphanilamide.
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Description One of the oldest antibacterial agents used to combat infection Used for coccal infection in 1935 They are bacteriostatic because it inhibits bacterial synthesis of folic acid Clinical usefulness has decreased because of the effectiveness of other antibiotics and penicillin
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Alternative drug for clients allergic to penicillin Not effective against viruses and fungi
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Intermediate acting sulfonamides
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Prontosil - red dye Antibacterial activity in vivo (1935) Inactive in vitro Metabolised to active sulfonamide Acts as a prodrug Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections Lead Compound
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Possess a common chemical nucleus, closely related to PABA, an essential member of vit.B complex. INTRODUCTION ( Cont…)
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Structure-activity relationship The sulphanamide nucleus possesses two amine groups- N4 and N1. The presence of para-amino group (N4) is essential for the antibacterial activity. Substitution at N1 by heterocyclic aromatic nuclei yields highly potent compounds such as sulphamerazine, sulphadiazine and sulphadimidine.
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Any substitution on the benzene ring results in loss of antibacterial activity. Acetylation at N1 may not alter the chemotherapeutic activity (or may decrease), but such compounds become water soluble and are less toxic. These compounds may be used for renal or eye infections – sulphacetamide.
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With the exception of some sulphonamides (pyrimidine sulphonamides like sulphamerazine and sulphadiazine), acetylation at N4 decreases the water solubility and enhances chances of renal toxicity. The antibacterial activity may be abolished by N4 acetylation.
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The molecular modifications of “Sulfanilamide” have been resulted into about 15,000 compounds and only less than three-dozen of them have attained therapeutic significance. The nitrogen of “Sulfanilamide” is designated as N1 and that of aniline as N4. (A) ISOMERIC FORMS OF SULFANILAMIDE: The ortho and meta isomers i.e. orthonilamide and metanilamide, as well as the corresponding isomers of N1-heterocyclic derivatives are antibacterially inactive both in vivo and in vitro. Some metanilamides have been proved effective as antimalarials e.g. 2-metanilamide-5-chloropyrimide is 16-times more active against plasmodium gallinaceum than quinine or Sulfadiazine. SAR
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(B) SUBSTITUTION OF BENZENE RING: In general, any substitution of the nucleus of the sulfanilamides leads to loss of activity. This effect is related to mechanism of action, which requires a basic amino group that should be free to conjugate with sulfamoyl group. For example, 3-carboxyhydrazide is active only against staphylococcus and pneumococcus in vitro. (C) REPLACEMENT OF THE BENZENE RING: The benzene nucleus can’t be replaced by 5 or 6-membered heterocyclics because the arylakylation with PTERIDYLMETHYL moiety, in the PABA utilization process, would occur at the ring nitrogen and not at the amino group if it is nest to a heterocyclic ring nitrogen e.g. 3-aza analog is inactive. (D) DERIVATION OR REPLACEMENT OF –SO2 The antibacterial activity lies in –SO2 group and any addition or removal at –SO2 group or even –SO3 will result in total loss of antibacterial activity.
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(E) DERIVATION OR REPLACEMENT OF 4-AMINO GROUP: Amino group at position-4 is responsible for the anti-microbial activity of sulphonamides. Any permanent substitution at N4 results in loss of anti-microbial activity. If alkyl or any other functional group is placed at N4 removing hydrogen, activity is lost. Pro-drugs can be formed by attaching a functional group at N4, which, can be hydrolyzed in the body to resume free NH2 state again, necessary for anti-bacterial activity. N4 acetylation with dicarboxylic acids such as succinic acid or phthalic acid yields sulphonamides, which are not absorbed in small intestine but are hydrolyzed in large intestine to yield free active form of drug allowed to act locally.
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Chemical properties Sulphonamides are weak organic compounds. Most of these are relatively insoluble in water, but their sodium salts are water soluble. The sodium salts have an alkaline pH (except sulphacetamide) and sulphonamides are about twice or more soluble in alkaline pH as compared with the acidic or neutral pH.
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In acid urine, sulphonamides may form crystals because of their decreased solubility. The N4 acetylated sulphonamides derivatives are relatively insoluble in acidic urine and some may even precipitate in the renal tubules of species having acid urine (e.g., carnivores) leading to crystalluria and renal failure.
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Solubility of sulphonamides is affected (increased) by presence of another sulphonamide in the solution because they follow law of independent solubility (i.e., in a mixture of sulphonamides, each sulphonamide exhibits its own solubility in solution). Therefore combination of 2 or more sulphonamides is occasionally used to increase solubility and efficacy (additive effect) and to decrease toxicity (less crystallization in urine).
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para-Amino group is essential (R1=H) para-Amido groups (R1=acyl) are allowed inactive in vitro, but active in vivo act as prodrugs Aromatic ring is essential para-Substitution is essential Sulfonamide group is essential Sulfonamide nitrogen must be primary or secondary R2 can be varied para-Amino group Sulfonamide Aromatic
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Amide group lowers the polarity of the sulfonamide Amide cannot ionise Alkyl group increases the hydrophobic character Crosses the gut wall more easily Metabolised by enzymes (e.g. peptidases) in vivo Metabolism generates the primary amine Primary amine ionizes and can form ionic interactions Ionised primary amine also acts as a strong HBD Prodrugs of sulfonamides
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R2 is variable Different aromatic and heteroaromatic rings are allowed Affects plasma protein binding Determines blood levels and lifetime of the drug Affects solubility Affects pharmacokinetics rather than pharmacodynamices Sulfanilamide analogues
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Sulfonamides with reduced toxicity Thiazole ring is replaced with a pyrimidine ring Pyrimidine ring is more electron-withdrawing Sulfonamide NH proton is more acidic and ionizable Sulfadiazine and its metabolite are more water soluble Reduced toxicity Silver sulfadiazine is used topically to prevent infection of burns
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CLASSIFICATION Short acting ( < 12 hrs ) : Sulphadiazine , sulphisoxaxole, sulphamerazine, sulphachlorpyridazine,sulphathiazole,sulphanilamide, sulphapyridazine and sulphasomidine. Intermediate acting ( 12-24 hrs ) : Sulphadimidine, sulphamethaxazole, sulphamaxole and sulphaphenazole.
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Long-acting ( 24- 48 hrs ): Sulphadimethoxine, sulphaethoxypyridazine , sulphamethoxypyridazine, sulphabromomethazine. Ultra-long acting ( > 48 hrs ) : Sulphadoxine and sulphamethopyrazine. CLASSIFICATION ( Cont…)
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Gut acting : Succinylsulphathiazole, phthalylsulphathiazole, phthalylsulphacetamide, sulphaguinidine and sulphasalazine. Topically acting : Sulphacetamide , mafenide and silver sulphadiazine
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Short acting sulfonamides
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Short acting sulfonamides
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Intermediate acting sulfonamides
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Intermediate acting sulfonamides
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CLASSIFICATION ( Cont…)
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MECHANISM OF ACTION
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MECHANISM OF ACTION ( Cont …)
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Pathway of tetrahydro-folate cofactor synthesis and role in DNA, RNA, and protein synthesis
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Target enzyme Dihydropteroate synthetase - bacterial enzyme Not present in human cells Important in the biosynthesis of the tetrahydrofolate cofactor Cofactor is crucial to pyrimidine and DNA biosynthesis Crucial to cell growth and division Sulfonamides Competitive enzyme inhibitors Bacteriostatic agents Not ideal for patients with weakened immune systems Mimic the enzyme substrate - para-aminobenzoic acid (PABA) Bind to the active site and block access to PABA Reversible inhibition Resistant strains produce more PABA
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Binding interactions Mechanism of action
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Mechanism of action Metabolic differences between bacterial and mammalian cells Dihydropteroate synthetase is present only in bacterial cells Transport protein for folic acid is only present in mammalian cells
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SULPHONAMIDE ANTAGONISM The antibacterial action of sulphonamides is antagonised by the supply of metabolites whose synthesis is inhibited by them. These include: Presence of PABA or drugs whose metabolism yields PABA e.g., procaine (local anaesthetic) and procaine penicillin. Supply of vitamin B complex such as niacin, folic acid and choline and amino acids like glutamic acid and methionine.
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Some proteins such as gelatine, albumin, and peptone that bind with sulphonamides and reduce their availability. Products of cell and tissue death, especially pus- supply products that neutralise sulphonamides or act as non-vascular barriers and reduce diffusion of drugs.
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SYNERGISTS OF SULPHONAMIDES Sulphonamides show synergistic action with diaminopyrimidines such as trimethoprim. Trimethoprim is a potent and selective competitive inhibitor of dihydrofolate reductase enzyme in susceptible microorganisms, the enzyme required to reduce dihydrofolate to tetrahydrofolate . Combination of sulphonamide and trimethoprim produces sequential blocks in the synthesis of tetrahydrofolate, the reduced form of folic acid that is required for one carbon transfer reactions.
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Synergistic combinations of Trimethoprim & Sulfamethoxazole (Bactrim®, Septra®) Staph sensitivity Sulfamethoxazole MIC = 3 ug/ml Trimethoprim MIC = 1 ug/ml combo MIC = 0.3 Sulf & 0.015 Trim 20:1 ratio most effective Advantages more likely to be cidal broader spectrum decreased resistance lower doses = lower toxicity
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A new combination of trimethoprim with a sulphonamide, named Kelfiprim, differs from cotrimoxazole in that: sulpha drug is sulphamethopyrazine instead of sulphamethoxazole; trimethoprim to sulpha ratio is 5:4 instead of 1:5; presence of a long-acting sulphonamide allows the administration of a daily dose of one capsule, following an initial loading dose of two capsules; d) reduced amount of trimethoprim is given, as compared to cotrimoxazole, without any decrease of efficacy.
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Pharmacokinetics Well absorbed in the GI tract Well distributed to body tissues and brain Liver metabolizes and kidney excrete it
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Pharmacodynamics For oral administration Highly protein bound 2 categories of sulfonamide according to their duration of action: 1. Short acting sulfonamides (Rapid absorption and excretion rate) 2. Intermediate acting sulfonamides (Moderate to slow absorption and slow excretion rate)
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PHARMACOKINETICS Systemically acting sulphonamides are usually well absorbed (70-100%) following oral administration mainly from the small intestine. The absorption rate is affected by the solubility of sulphonamides and presence of ingesta in the GI tract. In general dogs, cats and birds absorb sulphonamides rapidly, pigs take some time and cattle require much longer time.
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After absorption, sulphonamides diffuse well into body tissues and fluids. The extent of distribution depends on ionisation state, vascularity of tissue and presence of any barrier to their diffusion. All sulphonamides bind to plasma proteins particularly albumin to variable extent. PHARMACOKINETICS (Cont…)
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The acetylated form is protein bound to a greater extent than the free form. The rate of excretions and thereby dosage to some extent is determined by the plasma protein binding. The sulphonamides are primarily metabolised by acetylation at N4 by non-microsomal enzymes in liver or some other tissues. PHARMACOKINETICS (Cont…)
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Acetylation of sulphonamides reduces their solubility thus promoting crystallization. In cattle, sulphonamides are more toxic due to extensive acetylation. Dogs lack in the ability to acetylate sulphonamides, therefore, toxicity of sulphonamides is comparatively less in dogs. PHARMACOKINETICS (Cont…)
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Sulphonamides or their metabolites are excreted mainly by kidney through glomerular filtration, although renal tubular secretion and reabsorption also occur. The tubular reabsorption determines the duration of action of sulphonamides because more lipid soluble and unionised members are highly reabsorbed in tubule and therefore they are longer acting. PHARMACOKINETICS (Cont…)
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Alkalinisation of urine favours ionisation of sulphonamides and its rapid elimination. Sulphonamides are excreted also in the tears, faeces, bile and sweat. Gut-acting sulphonamides are poorly absorbed from the GI tract and are primarily eliminated in the faeces. PHARMACOKINETICS (Cont…)
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SIDE EFFECTS / ADVERSE EFFECTS ACUTE TOXICITY : Renal toxicity Blood dyscrasias Hypersensitivity reactions CHRONIC TOXICITY : Keratoconjunctivitis sicca (KCS ) Hepatic necrosis Aplastic anaemia and thrombocytopenia
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Renal toxicity occurs due to precipitation of the sulphonamide in the glomerular filtrate leading to crystallization, haematuria and obstruction of renal tubules, ureter and even bladder. Chances of crystalluria are more in dehydrated animals as the urine may contain drug concentrations above solubility limits resulting in crystal formation. Renal toxicity
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In general, carnivores and omnivores (acid urine) are more prone to renal toxicity than herbivores. Crystalluria can be minimised or prevented by keeping the patient well hydrated (adequate water supply) and by administration of sulphonamides mixture (e.g., triple sulpha = sulphapyridine + sulphamerazine + sulphadiazine). Urine can also be made alkaline by giving sodium bicarbonate, especially in dogs or cats. Renal toxicity (Cont…)
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Sulphonamides induced blood dyscrasias are rare but potentially fatal toxic effect. Haemolytic anaemia may occur either due to sensitisation or in individuals with glucose-6-phosphate dehydrogenase deficiency. This may occur within first 2-7 days of therapy. Neutropenia and other blood dyscrasias are rare. Blood dyscrasias
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Allergic skin rashes are frequent complication of sulpha therapy. Exfoliative dermatitis or cutaneous eruption may occur and are more common with long acting sulphonamides. Sulphadiazine containing preparations may promote a reversible immune-mediated sterile polyarthritis in Doberman breed. Hypersensitivity reactions
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Prolonged treatment with certain sulphonamides (e.g., sulphasalazine, sulphadiazine and sulphamethoxazole) may cause keratoconjunctivitis sicca (dry eyes) in dogs. This occurs probably due to hypersensitivity reaction or direct lachrymotoxic effect of nitrogen-containing pyridine ring on the lachrymal acinar cells. Dogs with less weight are more susceptible. The recovery from KCS depends on the exposure time and age of dog. Keratoconjunctivitis sicca (KCS )
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Complete suppression of bone-marrow activity with anaemia, granulocytopenia and thrombocytopenia occur rarely with sulphonamide therapy. It may occur from a direct myelotoxic effect or due to an immune-mediated component. Reduction in serum folate concentration presumably by inhibition of folate production by intestinal bacteria may also induce anaemia. Aplastic anaemia and thrombocytopenia
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Potentiated sulphonamide therapy has been associated with development of hepatic necrosis in dogs. The exact mechanism responsible for this adverse effect is not known but is thought to occur from altered metabolism resulting in accumulation of hepatotoxic metabolites. The slow acetylation often results in increased sulphadehydroxyl -amine metabolite, which is hepatotoxic. Since dogs are slow acetylators, they are more susceptible to hepatic injury. Hepatic necrosis
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Copyright © 2007 by The McGraw-Hill Companies, Inc. All rights reserved.
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The following hematologic changes may occur during sulfonamide therapy Agranulocytosis—decrease in or lack of granulocytes, a type of white blood cell Thrombocytopenia—decrease in the number of platelets Aplastic anemia—anemia due to deficient red blood cell production in the bone marrow Leukopenia—decrease in the number of white blood cells
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RESISTANCE The bacterial resistance may develop due to one or more of the following causes : An alteration in the bacterial enzyme that utilise PABA i.e. the dihydropteroate synthase enzyme may have low affinity for sulphonamides. An increased capacity of bacteria to destroy or inactivate sulphonamides.
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An increased production of PABA or essential metabolites by bacterial. Adoption of alternate pathway for synthesis of essential macromolecules by bacteria. Decreased drug permeability into the bacterial cell or active efflux of drug from the target bacteria. Bacterial resistance to one sulphonamide generally provides resistance to all sulphonamides. RESISTANCE ( Cont…)
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Steps to reduce bacterial resistance : Sulphonamide therapy should be initiated in acute stage of disease. Sulphonamide therapy should be continued till complete recovery from infection occurs. Sulphonamide therapy should not be discontinued before 3 days of start of therapy. RESISTANCE ( Cont…)
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Initial doses of sulphonamide may be kept high to establish therapeutic blood concentration. This may be followed by smaller maintenance doses. Sulphonamides should be used only when the infection is from sulphonamide sensitive microorganisms. Indiscriminate use of sulphonamides should be avoided. RESISTANCE ( Cont…)
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Diagnosis: Risk for infection, risk for impaired integrity, impaired urinary elimination Planning: client’s infection will be controlled Nursing interventions: 1. Administer with full glass of water. 2. Record client’s I&O 3. Monitor VS 4. Observe for hematologic reactions 5. Observe for signs and symptoms of super infection 6. Client teaching: a. Instruct client to drink several glass of water b. Advise pregnant women to avoid sulfonamides during the last 3 months of pregnancy
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c. Inform client not to take antacids d. Warn client who has an allergy e. Take 1 hour before or 2 hours after meal with full glass of water f. Report bruising or bleeding g. CBC monitoring h. Avoid direct sunlight, use sun block and protective clothing
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Examples of Sulfonamides Sulfadoxine Pyrimethamine
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pharmacology and toxicity of Sulphanamide antimetabolites
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