Sulfonamides and TrimethoprimS. Parasuraman, M.Pharm., Ph.D.,Senior Lecturer, Faculty of PharmacyAIMST
SulfonamidesSulfonamide = Sulfone + amideSulfonamides derivative of p-amino-benzene sulfonamide are commonlyreferred as sulfa drugs.1932: Gerhard Domagk discovered sulfonamido-chrysoidine (Prontosil Red-dye)In 1933: First clinical case study reported presentedprontosil (pro-drug): active against streptococcal infection in 10-moth-oldinfant.In 1937: Prontosil is a pro-drug. After metabolism prontosil converted intosulfanilamide which was the active antibacterial agent (exceptscombinations).1969- CombinationsE.g.: sulfonamide + trimethoprim (cotrimoxazole) and sulfonamide +trimethoprimDiscovery of sulfonamides: a milestone event in the discovery of AMAS
Classification of sulfonamides• Short acting (4-8 h): Sulfadiazine• Intermediate acting (8-12 h): Sulfamethoxazole• Long acting ( ~ 7 days): Sulfadoxine, Sulfamethopyrazine• Special purpose sulfonamides: Sulfacetamide sodium,Mafenide, Silver sulfadiazine, Sulfasalazine
Antibacterial spectrum of sulfonamides• Primary bacteriostatic against many gram-positive and gram-negative bacteria. In higher concentration it may be act asbactericidal.• Sensitivity patterns among microbes changed time-to-timeand place-to-place. Sulfonamides are sensitive toStreptococcus pyogenes, Haemophilus influenza, Vibriocholerae.• Sulfonamides are primarily used to prevent urinary tractinfections.
NNNNPteridineH2NOHNHNOCOOHCOOHPABA Glutamic acidFolic acidMechanism of action
NNNNPteridineH2NOHNHNOCOOHCOOHPABA Glutamic acidFolic acidMechanism of action
Mechanism of action• Bacteria synthesize their own folic acid(FA) of which p-aminobenzoic acid (PABA)is a constituent, and is taken up from themedium.• Sulfonamides, are structural analogues ofPABA, inhibit bacterial folate synthaseand formation of folate get inhibited.• Sulfonamides competitively inhibit thePABA with pteridine residue to formdihydropteroic acid which conjugateswith glutamic acid to producedihydrofolic acid.• Sulfonamide altered folate an which ismetabolically injuriousPteridine +p-Aminobenzoic acid (PABA)+Glutamic acidDihydropteroic acidDihyderopteroatesynthetaseGlutamateDihydrofolic acidTetrahydrofolic acidDNASulfonamidesDihydrofolatereductase
Mechanism of actionCont.,• Sulfonamides will affect the Human folic acid synthesis? Human cells also require FA, but they utilize preformed FA suppliedin diet and are unaffected by sulfonamides. Only those microbes which synthesize their own FA and cannot takeit from the medium are susceptible to sulfonamides.
Resistance to sulfonamides• Most bacteria are capable of developing resistance tosulfonamides. E.g.: gonococci, pneumococci, Staph. aureus,meningococci, E. coli, Shigella, Strep. pyogenes, Strep. viridansand anaerobes.• Bacterial resistance to sulfonamide presumably originates bymutation or by transfer of resistance by plasmids.• The resistant mutants either:(a) produce increased amounts of PABA, or(b) Microbes folate synthase enzyme has low affinity for sulfonarnides(c) adopt an alternative pathway in folate metabolism• When an organism is resistance to one sulfonamide, it isresistance to all sulfonamide. No cross resistance. Resistancelimited to clinical case component.
Pharmacokinetics• Sulfonamides are– usually not given topically, because of the risk ofsensitization and allergic reactions– readily absorbed in the G.I.T and reach maximumconcentrations in the plasma in 4-6 h– cross the placental and blood-brain barriers and availablefree in inflammatory site– metabolised in liver by acetylation (N-acetylation)– excreted by the kidney through glomerular filtration(Metabolites are insoluble in urine, hence crystalluria can occur)
Sulfadiazine (Short acting sulfonamide)• Absorption: Rapid oral absorption. It has good penetrability inbrain and CSF-was the preferred compound for meningitis.• Metabolism: Liver by acetylation. It is 50% plasma proteinbound and 20-40% acetylated.• Excretion: Trough urine. The acetylated derivative is lesssoluble in urine, crystalluria is likely.• Dose: 0.5 g QID to 2 g TDS; oral tablets
Sulfamethoxazole (Intermediate acting)• Absorption: Slow oral absorption. It is the Preferredcompound for combining with trimethoprim because the t1/2of both is similar.• Metabolism: Liver by acetylation.• Excretion: Trough urine. Acetylated fraction ofsulfamethoxazole is relatively insoluble- crystalluria can occur• Dose: 1 g BD for 2 days, then 0.5 g BD; oral tablets
Sulfadoxine, Sulfamethopyrazine(Long acting)• These are ultralong acting compounds, action lasting > 1 weekbecause of high plasma protein binding and slow renalexcretion (t1/2 5-9 days).• They attain low plasma concentration (of free form) and arenot suitable for treatment of acute pyogenic infections. Theyare used in combination with pyrimethamine in the treatmentof malaria, (especially chloroquine resistant P. falciparum),Pneumocystis jiroveci pneumonia in AIDS patients and intoxoplasmosis. Because they have caused serious cutaneousreactions, large-scale use of the combination for prophylaxisof malaria is not recommended.
Sulfacetamide sodium(Special purpose sulfonamides)• Highly soluble compound - Mildly irritating to the eye(concentrations up to 30%).• Used topically for ocular bacterial infections and chlamydia,including ophthalmia neonatorum caused by chlamydialoculogenitalis. Incidence of sensitivity reactions with ocularuse has been low, but it must be promptly stopped when theyoccur.• Dose: 10%, 20% and 30% eye drops.
Sliver sulfadiazine(Special purpose sulfonamides)• Its act against large number of bacteria and fungi, even thoseresistance to other sulfonamides (e.g.: Pseudomonas).• Slow releases silver ions which appear to be largelyresponsible for the antimicrobial action.• Most effective drugs for preventing infection of burnt surfacesand chronic ulcers (skin). However, it is not good for treatingestablished infection.• Dose: 1% cream• Local side effect: burning sensation and itching.
Adverse effects• Adverse effects to sulfonamides are relativelycommon. Sulfonamides– produce mild-to-moderate nausea, vomiting,headache and mental depression– produce hypersensitivity reactions (rashes, fever,eosinophilia)– Rarely cause Stevens-Johnson syndrome, erythemamultiforme associated with lesions of skin andmucous membranes– Produce kenicterus (bilirubin-induced braindysfunction) in neonates because of thedisplacement of bilirubin form serum albuminbinding site– Sever adverse effects includes hepatitis, bonemarrow depression and crystalluria.– In person with glucose-6-phosphate dehydrogenasedeficiency, sulfonamide can cause hemolytic aplasticanemia.Stevens-Johnsonsyndrome
Interactions• Sulfonamides inhibit the metabolism of phenytoin,tolbutamide and warfarin.
Trimethoprim• Trimethoprim is a bacteriostatic antibiotics.• Trimethoprim is diaminopyrimidine related pyrimethamine (folateantagonist), which is selectively inhibits bacterial dihydrofolatereeducates (DHFRase).• Trimethoprim is >50,000 times more active against bacterialDHFRase than against the mammalian enzyme.• Used for treatment of urinary track and respiratory infections.• Trimethoprim is weak base and is concentrated in acidic prostatetissue and vaginal fluids via ion trapping, so it is useful for thetreatment of bacterial prostatitis and vaginitis.
Spectrum of activity• Trimethoprim is a bacteriostatic antibiotics. It is active against manyaerobic gram-negative bacilli and a few gram-positive organism.• sulfonamide and trimethoprim are bacteriostatic, but thecombination becomes bactericidal against many organisms.Pharmacokinetics• Given orally, fully absorbed in the gastrointerstinal tract and widelydistributed throughout the tissue and body fluid (t1/2=10h).• Reaches high concentration in lungs and kidneys.• Trimethoprim is partly metabolized in liver and excreted in urine.Adverse effect• Nausea, vomiting, skin rashes• Folate deficiency, results megaloblastic anemia.• Trimethoprim effect can be prevented by folinic acid.
Cotrimoxazole• The fixed dose combination of trimethoprim andsulfamethoxazole is called cotrimoxazole.• Cotrimoxazole introduced in 1969 to block the bacterialfolate metabolism (sequential)• Both the compounds are bactriostatic, but thecombination becomes cidal against many pathogens.Maximum synergism is seen when the organism issensitive to both the compound.
Cotrimoxazole• Sulfamethoxazole was selectedfor combining with trimethoprimbecause both have nearly thesame t1/2 (~10 h).• Optimal synergy in case of mostorganisms is exhibited at aconcentration ratio ofsulfamethoxazole: trimethoprim(20:1), the MIC of eachcomponent may be reduced by 3-6 times.Pteridine +p-Aminobenzoic acid (PABA)+Glutamic acidDihydropteroic acidDihyderopteroatesynthetaseGlutamateDihydrofolic acidTetrahydrofolic acidDNASulfonamidesTrimethoprimDihydrofolatereductase
Cotrimoxazole• Dose ratio of sulfamethoxazole: trimethoprim is 5:1. The 5:1 doseratio produce a 20:1 plasma concentration ratio becausetrimethoprim has a grater volume of distribution than doessulfamethoxazole.• Trimethoprim adequately crosses blood-brain barrier and placenta,while sulfamethoxazole has a poorer entry.• Trimethoprim is more rapidly absorbed than sulfamethoxazole andthe concentration ratios may vary with time. Trimethoprim is 40%plasma protein bound, while sulfamethoxazole is 65% bound.
Spectrum of activity• Exhibits bactericidal activity• Active against Salmonella typhi, Serratia, Enterobacter,Pneumocystis and many sulfonamide resistant strains of Staph.aureus, Staph. Pyogenes, shigella, E. coli, infuenzae, gonococci andmeningococci.Resistance• Bacteria are acquiring resistance to trimethoprim throughmutational or plasmid mediated acquisition of DHFRasehaving lower affinity. Combinations reduced responsivenessof over 20% originally sensitive strains.
Uses• Urinary tract infections: Used to prevent or treat urinary tractinfections or prostate infections. singe dose therapy with 4 tabletsfor acute cystitis. Courses of 3 -10 days have been advised for lowerand upper UTI.• Respiratory tract infections: Upper and lower respiratory tractinfections (chronic bronchitis and facio-maxillary infections) and H.influenzae. Drug of choice for respiratory infection caused byPneumocystis jiroveci and Nocardia asteroides.• Typhoid• Bacterial diarrheas and dysentery• Pneumonia (caused by Pneumocystis jiroveci)• Chancroid (bacterial sexually transmitted infection)
Adverse effect• All adverse effects seen with sulfonamides can be producedby cotrimoxazole.• Folate deficiency (megaloblastic anemia)• Blood dyscrasias occurs rarely.Caution• Should not given during pregnancy (Neonatal haemolysis andmethaemoglobinaemia can occur)• Elderly people are having grater risk of development of bonemarrow toxicity• Patient with renal disease may develop uremia, dose must bereduced renal impairment patients