Sulfonamides: and other folate

antagonists
History
In a landmark discovery in the 1930s, Domagk
demonstrated that it was possible for a red dye to
influence the course of a bacterial infection. Prontosil,
was the first medicine ever discovered that could
effectively treat a range of bacterial infections caused
by streptococci, including blood infections, childbed
fever and a lesser effect on infections caused by other
cocci. The agent prontosil, proved to be an inactive
prodrug but which is metabolised in vivo to give the
active product, sulfanilamide.
• Many sulfonamides have been developed since, and
some are still useful drugs although their importance
has declined in the face of increasing resistance.
• Examples include sulfadiazine, sulfadimidine (short
acting), sulfamethoxazole (intermediate acting),
sulfametopyrazine (long acting), sulfasalazine (poorly
absorbed in the gastrointestinal tract and
sulfamethoxazole (in combination with trimethoprim as
cotrimoxazole). In the UK, only sulfamethoxazole,
sulfadiazine and trimethoprim are used clinically.
 Sulfonamides
Sulfonamides are synthetic bacteriostatic
antibacterials that competitively inhibit
conversion of p-aminobenzoic acid to
dihydropteroate, which bacteria need for folate
synthesis and ultimately purine and DNA
synthesis. Humans do not synthesize folate but
acquire it in their diet, so their DNA synthesis is
less affected.
 Classification of sulfonamides
CLASSIFICATION:
Based upon the clinical utility sulfonamides can be
classified as:
Used for the treatment of local gastrointestinal
infections:
• Sulfaguanidine
• Sulfapyridine
• Saccinyl sulfathiazole
• Sulfasalazine
Used topically in eye:
• Sulfacetamide
Used topically on skin in burns:
• Silver Sulfadiazine.
Used topically in infections of ENT:
• Mafenide
Classification based upon rapidity of are
absorption and excretion:
(1) agents that are absorbed and excreted rapidly,
e.g sulfisoxazole and sulfadiazine
(2) agents that are absorbed very poorly, hence are
active in the bowel lumen, such as sulfasalazine
(3) agents that are used mainly topically, e.g
sulfacetamide, mafenide, and silver sulfadiazine
(4) long-acting sulfonamides, such as sulfadoxine,
that are absorbed rapidly but excreted slowly
MECHANISM OF ACTION
Most of the bacteria do not absorb folic acid and
rely on their ability to synthesize folic acid from
PABA and pteridine.
Sulfonamides are structural analogues of PABA
• They compete with PABA and competitively inhibit the
enzyme dihydrofolate synthetase thus prevent folic acid
formation in bacteria.
• This deprives bacterial cell of essential cofactor for
purines and pyrimidines synthesis and bacterial cell
growth is prevented.
Rapidly Absorbed and Eliminated Sulfonamides
1. Sulfisoxazole
• Sulfisoxazole (Gantrisin) is a rapidly absorbed and
excreted sulfonamide with excellent antibacterial activity.
• Its high solubility eliminates much of the renal toxicity.
• Extensively bound to plasma proteins.
• It can be indicated for bladder infections, ear infections,
or meningitis.
• The combination of erythromycin and sulfisoxazole (a
sulfa drug) is used to treat certain ear infections caused
by bacteria. E.g Eryzole (containing Erythromycin,
Sulfisoxazole) but this is no longer used in market.
Untoward effects:
• It must be used with caution with impaired renal
function
• Like all sulfonamides, it may produce hypersensitivity
reactions.

2. Sulfamethoxazole
• Sulfamethoxazole is a close congener of sulfisoxazole.
• Its rates of enteric absorption and urinary excretion are
slower. It is employed for both systemic and urinary
tract infections.
• It causes crystalluria because of the high percentage of
the acetylated, relatively insoluble form of the drug in
the urine.
• It also is marketed in fixed-dose combinations with
trimethoprim.

3. Sulfadiazine
• Sulfadiazine given orally is absorbed rapidly from the GI
tract.
• It is excreted quite readily by the kidney in both the free
and acetylated forms
• In adults and children who are being treated with
sulfadiazine, they should take adequate quantity of
fluid.
• If this cannot be accomplished, sodium bicarbonate
may be given to reduce the risk of crystalluria.

Poorly Absorbed Sulfonamides

Sulfasalazine (Azulfidine) is very poorly absorbed from
the GI tract. It is used in the therapy of ulcerative colitis
and regional enteritis.
• Relapses tend to occur in about one-third of patients
who experience a satisfactory initial response.
• Corticosteroids are more effective in treating acute
attacks, but sulfasalazine is preferred to corticosteroids
for mild or moderate ulcerative colitis
• Also used in mild cases of regional enteritis and
granulomatous colitis.
• Toxic reactions include Heinz-body anemia, acute
hemolysis in patients with glucose-6-phosphate
dehydrogenase deficiency and agranulocytosis.
Sulfonamides for Topical Use
Sulfacetamide
• Sulfacetamide is the N1-acetyl-substituted derivative of
sulfanilamide. Its aqueous solubility (1:140) is
approximately 90 times that of sulfadiazine.
• Solutions of the sodium salt of the drug (Isopto-
cetamide, others) are employed extensively in the
management of ophthalmic infections.
• It is advantageous to other sulfonamides for topical use
because of its high aqueous solubility and effectiveness
against susceptible microorganisms.
• Sensitivity reactions are rare but should be used in
patients with sulfonamide hypersensitivity.
Silver Sulfadiazine
• Silver sulfadiazine (Silvadine) inhibits the growth in vitro
of nearly all pathogenic bacteria and fungi, including
some species resistant to sulfonamides. It is used
topically to reduce microbial colonization and infections
of wounds from burns.
• It should not be used to treat an established deep
infection.
• It is considered as drug of choice for burn infections.
Mafenide
• This sulfonamide is marketed as mafenide acetate
(Sulfamylon).
• When applied topically, it is effective for the prevention
of colonization of burns by a large variety of gram-
negative and gram-positive bacteria.
• Mafenide is rapidly absorbed systemically and
converted to para-carboxybenzenesulfonamide. The
drug and its primary metabolite (para-
carboxybenzenesulfonamide) inhibit carbonic
anhydrase, and the urine becomes alkaline.
• Metabolic acidosis with compensatory tachypnea and
hyperventilation may ensue; these effects limit the
usefulness of mafenide.
• Superinfection with Candida occasionally may be a problem.

Long-Acting Sulfonamides
Sulfadoxine has a particularly long half-life (7 to 9 days). It is
used in combination with pyrimethamine (500 mg
sulfadoxine plus 25 mg pyrimethamine as Fansidar) for the
prophylaxis and treatment of malaria caused by mefloquine-
resistant strains of Plasmodium falciparum. Because of
severe and sometimes fatal reactions, including Stevens-
Johnson syndrome, the drug should be used for prophylaxis
only where the risk of resistant malaria is high.
Acquired Bacterial Resistance to Sulfonamides
• Bacterial resistance to sulfonamides is by random
mutation and selection or by transfer of resistance by
plasmids. The in vivo acquisition of resistance has little
or no effect on either virulence or antigenic
characteristics of microorganisms.
• Resistance to sulfonamide probably is the consequence
of an altered enzymatic constitution of the bacterial
cell; the alteration may be characterized by
(1) a lower affinity for sulfonamides by dihydropteroate
synthase
(2) decreased bacterial permeability or active efflux of the
drug
(3) an alternative metabolic pathway for synthesis of an
essential metabolite
(4) an increased production of an essential metabolite or
drug antagonist. For example, some resistant
staphylococci may synthesize 70 times as much PABA as
do the susceptible parent strains. Plasmid-mediated
resistance is due to plasmid-encoded drug-resistant
dihydropteroate synthetase.
 Sulfonamide therapy
• The number of conditions for which the
sulfonamides are therapeutically useful and
constitute drugs of first choice has been
reduced sharply by the development of more
effective antimicrobial agents and by the
gradual increase in the resistance of a number
of bacterial species to this class of drugs.
However, combination of trimethoprim and
sulfamethoxazole is therapeutically active.
Urinary Tract Infections
Trimethoprim–sulfamethoxazole, a quinolone,
trimethoprim, fosfomycin, or ampicillin are the
preferred agents.
Nocardiosis
Sulfonamides are of value in the treatment of
infections due to Nocardia spp. Sulfisoxazole or
sulfadiazine may be given
Toxoplasmosis
The combination of pyrimethamine and
sulfadiazine is the treatment of choice for
toxoplasmosis.
Use of Sulfonamides for Prophylaxis
The sulfonamides are as efficacious as oral
penicillin in preventing streptococcal
infections and recurrences of rheumatic fever
among susceptible subjects
 Other folate antagonists
• Antifolates are drugs that antagonize or block the
actions of folic acid (vitamin B9).
• Folic acid's primary function in the body is as a cofactor
to various methyltransferases involved in serine,
methionine, thymidine and purine biosynthesis.
• Consequently antifolates inhibit cell division, DNA/RNA
synthesis and repair and protein synthesis. Some such
as proguanil, pyrimethamine and trimethoprim
selectively inhibit folate's actions in microbial organisms
such as bacteria, protozoa and fungi. The majority of
antifolates work by inhibiting dihydrofolate reductase
(DHFR).
1. Methotrexate:
Antineoplastic & immunosuppressant
Mechanism: Inhibit mammalian DHFR . It is
myelosuppressive
Indications:
Malignancies (esp. haematologic malignancies and
osteosarcoma), ectopic pregnancy and autoimmune
conditions (esp. rheumatoid arthritis, psoriasis,
Wegener's granulomatosis, Goodpasture's syndrome,
etc.)
Adverse effects: include renal or hepatic failure,
Stevens-Johnson syndrome, toxic epidermal
necrolysis, infection, aplastic anaemia, opportunistic
infections and GI effects.
2. Pemetrexed
Antineoplastic
Mechanism: inhibit mammalian DHFR, TS (Thymidylate
synthetase), GARFT (Glycinamide ribonucleotide
formyltransferase)
Indications
Non-small cell lung carcinoma & mesothelioma
Adverse effects:
Nausea, vomiting, dyspnoea, constipation, chest
pain, diarrhoea, weight loss, stomatitis, rash,
fever, periphery neuropathy, dehydration,
kidney, Stevens-Johnson syndrome, toxic
epidermal necrolysis and erythema multiforme.
3. Proguanil
Antimalarial
Mechanism: Inhibit protozoal DHFR
Indications
Malaria, prevention and treatment.
Adverse effects:
Abdominal pain, headaches, increased LFTs,
myalgia, nausea, opportunistic infections,
diarrhoea, vomiting, etc. Less commonly
Stevens-Johnson syndrome, toxic epidermal
necrolysis, agranulocytosis, liver failure,
anaphylaxis, etc.
4. Pyrimethamine
Antiprotozoal
Protozoal DHFR
Indications:
Malaria
Toxoplasmosis
Pneumocystis jiroveci pneumonia.
Adverse effects: Stevens-Johnson syndrome,
toxic epidermal necrolysis, agranulocytosis
and aplastic anaemia.
5. Trimethoprim
Broad-spectrum antimicrobial
Microbial DHFR
• Numerous (especially when in combination with the
sulfonamide, sulfamethoxazole); treatment &
prophylaxis for pneumocystis jiroveci pneumonia,
malaria and toxoplasmosis.
• Treatment of melioidosis, shigellosis, listeria, urinary
tract infections, acute infectious exacerbations of
chronic bronchitis, infection prophylaxis in HIV-positive
individuals, etc.
• Stevens-Johnson syndrome, toxic epidermal necrolysis,
agranulocytosis and aplastic anaemia.
Trimethoprim–Sulfamethoxazole:
• Trimethoprim in combination with sulfamethoxazole
constitutes an important advance in the development of
clinically effective antimicrobial agents.
• If two drugs act on sequential steps in the pathway of
an obligate enzymatic reaction in bacteria, the result of
their combination will be synergistic
• Combination is known as cotrimoxazole.
• In addition to its combination with sulfamethoxazole
(Bactrim, Septra), trimethoprim also is available as a
single-entity preparation (Proloprim).
Mechanism of Action
The antimicrobial activity of the combination of
trimethoprim and sulfamethoxazole results from its
actions on two steps of the enzymatic pathway for the
synthesis of tetrahydrofolic acid.
Sulfonamide inhibits the incorporation of para-
aminobenzoic acid (PABA) into folic acid, and
trimethoprim prevents the reduction of dihydrofolate to
tetrahydrofolate.
• Tetrahydrofolate is essential for one-carbon transfer
reactions, e.g., the synthesis of thymidylate from
deoxyuridylate.
• Trimethoprim is a highly selective inhibitor of
dihydrofolate reductase of lower organisms: About
100,000 times more drug is required to inhibit human
reductase than the bacterial enzyme
• The most effective ratio for the greatest number of
microorganisms is 20 parts sulfamethoxazole to 1 part
trimethoprim
Efficacy of Trimethoprim–Sulfamethoxazole in
Combination
• Chlamydia diphtheriae and N. meningitidis are
susceptible to trimethoprim–sulfamethoxazole. Although
most S. pneumoniae are susceptible, there has been a
disturbing increase in resistance.
• From 50% to 95% of strains of Staphylococcus aureus,
Staphylococcus epidermidis, S. pyogenes, the viridans
group of streptococci, E. coli etc are inhibited by this
combination.
• Methicillin-resistant strains of S. aureus, although also
resistant to trimethoprim or sulfamethoxazole alone,
may be susceptible to the combination.
Bacterial Resistance
Bacterial resistance to trimethoprim–sulfamethoxazole is
a rapidly increasing problem, although resistance is
lower than it is to either of the agents alone.
Resistance often is due to the acquisition of a plasmid
that codes for an altered dihydrofolate reductase.
Thank you