Sulphonamides

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K.B.I.P.E.R.
 Introduction
• Sulfonamides were the first antimicrobial agents effective
against pyogenic bacterial infections.
• The agent was prontosil, a dye that proved to
be an inactive prodrug but which is metabolised
in vivo to give the active product, sulfanilamide.
• Prontosil used to treat experimental streptococcal infection
in mice and found it to be highly effective.

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 SAR
• Sulfonamide are derivatives of para-aminobenzene
sulfonamide (sulfanilamide)
• The structural formulas of selected members of this class are
shown in Figure.
• Most of them are relatively insoluble in water, but their
sodium salts are readily soluble.
• Individual members differ in the nature of N1 (Sulfonamido N)
substitution, which governs solubility, potency and
pharmacokinetic property.
• A free amino group in the para position (N4) is required for
antibacterial activity.

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 Classification
 Orally absorbable Agents
 Short acting Sulfonamides (t1/2 : 6-9 hr)
Sulfadiazine, Sulphamethizole, Sulfisoxazole
 Intermediate acting Sulfonamides (t1/2 : 10-12 hr)
Sulfamethaxazole, Sulfamaxole
 Long acting Sulfonamides (t1/2 : 7-8 hr)
Sulfadoxins
 Orally Non Absorbable Agents
Sulfasalazine, Olsalazin, Balsalazin
 Topical Agents
Sulfacetamide, Silver sulfadiazine, Mafemide

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 Antibacterial Spectrum
• Bacteriostatic
• Against Gram +ve and Gram –ve bacteria.
• sensitive are
 Streptococcus pyogenes
 Streptococcus pneumoniae
 Haemophilus influenzae
 Haemophilus ducreyi
 Nocardia
 Actinomyces
 Calymmatobacterium granulomatis
 Chlamydia trachomatis

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Respond but majority are resistant
Staphylococcus aureus
Gonococci
Meningococci
Pneumococci
Escherichia coli
Shigella

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Mechanism
of
action

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• Human cells also require FA, but they utilize preformed FA
supplied in diet and are unaffected by sulfonamides.
• Evidences in favour of this mechanism of action of
sulfonamides are
 PABA, in small quantities, antagonizes the antibacterial action of
sulfonamides.
 Only those microbes which synthesize their own FA, and cannot take
it from the medium are susceptible to sulfonamides.
• Pus and tissue extracts contain purines and thymidine which
decrease bacterial requirement for FA and antagonize
sulfonamide action. Pus is also rich in PABA.

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 Resistance to sulfonamides
• Most bacteria are capable of developing resistance to
sulfonamides.
• Prominent among these are
 gonococci
 Pneumococci
 Staph. Aureus
 Meningococci
 E. coli
 Shigella
 Strep. Pyogenes
 Strep. Viridans
 Anaerobes.

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 Resistance to sulfonamides
• The resistant mutants either
Produce increased amounts of PABA,
Their folate synthase enzyme has low affinity for
sulfonamides
 Adopt an alternative pathway in folate metabolism

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PHARMACOKINETICS

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 Absorption
• Rapidly and nearly completely absorbed from GIT.
• Approximately 70% to 100% of an oral dose is absorbed
• The small intestine is the major site of absorption, but some
of the drug is absorbed from the stomach.
• Absorption from other sites, such as the vagina, respiratory
tract, or abraded skin, is unreliable and cause toxic reactions
in susceptible persons or produce sensitization.

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 Metabolism
• The primary pathway of metabolism of sulfonamides is
acetylation by nonmicrosomal acetyl transferase, primarily in
liver.
• The acetylated derivative is inactive, but can contribute to the
adverse effects.
• It is generally less soluble in acidic urine than the parent drug,
may precipitate and cause crystalluria.
• The acetylated form accumulates in blood in patients with
renal failure along with the parent drug-toxicity increases.

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 Excretion
• Sulfonamides are excreted mainly by the kidney through
glomerular filtration.
• Both renal tubular secretion and reabsorption also occur.
• The more lipid-soluble members are highly reabsorbed in the
tubule, therefore are longer acting.

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 Adverse effects
 Nausea, vomiting and epigastric pain.
 Crystalluria. Precipitation in urine can be minimized by taking
plenty of fluids and by alkalinizing the urine in which sulfonamides
and their acetylated derivatives are more soluble.
 Hypersensitivity reactions occur in 2–5% patients. These are
mostly in the form of rashes, urticaria and drug fever.
Photosensitization is reported.
 Hepatitis, unrelated to dose, occurs in 0.1% patients.
 Topical use of sulfonamides is not recommended because of risk of
contact sensitization. However, ocular use is permitted.
 Cause haemolysis
 Neutropenia
 Displacement of bilirubin from plasma protein binding sites and
more permeable blood-brain barrier.

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 Interactions
• Sulfonamides inhibit the metabolism of phenytoin,
tolbutamide and warfarin enhance their action.
• They displace methotrexate from binding and decrease its
renal excretion toxicity can occur.
• Fixed dose combinations of sulfonamides with penicillin are
banned in India.

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 Therapeutic Uses
• Can be employed for suppressive therapy of chronic urinary tract
infection, streptococcal pharyngitis and gum infection.
• Combined with trimethoprim (cotrimoxazole) sulfamethoxazole is
used for many bacterial infections.

• Ocular therapy : Use in Conductivities.

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 Sulfadiazine
• Rapidly absorbed orally and rapidly excreted in urine.
• It is 50% plasma protein bound and 20–40% acetylated.
• The acetylated derivative is less soluble in urine, Crystalluria is
likely.
• It has good penetrability in brain and CSF was the preferred
compound for meningitis.
• Dose: 0.5 g QID to 2 g TDS;

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 Sulfamethoxazole
• Slower oral absorption and urinary excretion
• t½ in adults averages 10 hours.
• It is the preferred compound for combining with trimethoprim
because the t½ of both is similar.
• However, a high fraction is acetylated, which is relatively
insoluble crystalluria can occur.
• Dose: 1 g BD for 2 days, then 0.5 g BD.

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 Sulfadoxine, Sulfamethopyrazine
• Ultralong acting compounds, action lasting > 1 week because
of high plasma protein binding and slow renal excretion.
• t½ 5–9 days.
• They attain low plasma concentration (of free form) and are
not suitable for treatment of acute pyogenic infections.
• They are used in combination with pyrimethamine in the
treatment of malaria, especially chloroquine resistant P.
falciparum; Pneumocystis jiroveci pneumonia in AIDS patients
and in toxoplasmosis.

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 Sulfacetamide sod.
• highly soluble compound yielding neutral solution which is
only mildly irritating to the eye in concentrations up to 30%.
• It is used topically for ocular infections due to susceptible
bacteria and chlamydia.
• It attains high concentrations in anterior segment and
aqueous humour after topical instillation.
• The incidence of sensitivity reactions with ocular use of
sulfacetamide sod. has been low; but it must be promptly
stopped when they occur.

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 Mafenide
• used only topically inhibits a variety of gram +ve and gram-ve bacteria.
• In contrast to typical sulfonamides, it is active in the presence of pus and
against Pseudomonas, clostridia which are not inhibited by typical
sulfonamides.
• It has been mainly employed for burn dressing to prevent infection, but
not to treat already infected cases.
• The biggest limitation is that mafenide produces burning sensation and
severe pain when applied to raw surface.
• It is rapidly absorbed from the raw surface, metabolized and excreted in
urine.
• Mafenide and its metabolite are carbonic anhydrase inhibitors
• must not be applied over large areas. Allergic reactions, particularly rashes
also occur.

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 Silver sulfadiazine
• Used topically as 1% cream,
• It is active against a large number of bacteria and fungi, even
those resistant to other sulfonamides, e.g. Pseudomonas.
• It slowly releases silver ions which appear to be largely
responsible for the antimicrobial action.
• It is considered to be one of the most effective drugs for
preventing infection of burnt surfaces and chronic ulcers and
is well tolerated.
• However, it is not good for treating established infection.

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