SULFONAMIDES

Tejal Khade
Assistant Professor
KGRDCP & RI
Classification
Mechanism of action
• Sulfanilamide is a structural analogue of p-
aminobenzoic acid (PABA), which is an essential
precursor in the synthesis of folic acid, required for
the synthesis of DNA and RNA in bacteria.
• Sulfonamides compete with PABA for the enzyme
dihydropteroate synthetase and the effect of the
sulfonamide may be overcome by adding excess
PABA.
• This is why some local anaesthetics, which are PABA
esters can antagonise the antibacterial effect of
these agents.
• The action of a sulfonamide is to inhibit growth of
the bacteria, not to kill them; that is to say, it is
bacteriostatic rather than bactericidal.
Synergists of Sulfonamides
• One of the most active agents that exerts a
synergistic effect when used with a sulfonamide is
trimethoprim.
• This compound is a potent and selective
competitive inhibitor of microbial dihydrofolate
reductase, the enzyme that reduces dihydrofolate
to tetrahydrofolate.
• The simultaneous administration of a sulfonamide
and trimethoprim thus introduces sequential blocks
in the pathway by which microorganisms synthesize
tetrahydrofolate from precursor molecules.
Acquired Bacterial Resistance to
Sulfonamides
• 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 of dihydropteroate synthase for
sulfonamides,
(2) decreased bacterial permeability or active
efflux of the drug,
(3) an alternative metabolic pathway for synthesis
of an essential metabolite, or
(4) an increased production of an essential metabolite
or drug antagonist
Pharmacological Properties
of Individual Sulfonamides
1. Rapidly Absorbed and
Eliminated Sulfonamides
 Sulfisoxazole
• rapidly absorbed and excreted sulfonamide.
• Because its high solubility eliminates much of the renal
toxicity
• Sulfisoxazole is bound extensively to plasma proteins.
• oral dose of 2-4 g,
• peak concentrations in plasma of 110-250 μg/mL are
found in 2-4 hours.
• From 28-35% of sulfisoxazole in the blood and ~30% in
the urine is in the acetylated form.
• The kidney excretes ~95% of a single dose in 24 hours.
• Sulfisoxazole acetyl is tasteless and hence preferred
for oral use in children. Sulfisoxazole acetyl is
marketed in combination with erythromycin
ethylsuccinate for use in children with otitis media..
• Adverse events: hematuria or crystalluria (due to
high urine solubility), hypersensitivity reactions,.
• Sulfisoxazole currently is preferred over other
sulfonamides by most clinicians when a rapidly
absorbed and rapidly excreted sulfonamide is
indicated.
 Sulfamethoxazole
• close congener of sulfisoxazole, but its rates of
enteric absorption and urinary excretion are slower.
• It is administered orally and employed for both
systemic and urinary tract infections.
• Precautions must be observed to avoid
sulfamethoxazole crystalluria because of the high
percentage of the acetylated, relatively insoluble
form of the drug in the urine.
 Sulfadiazine
• Sulfadiazine given orally is absorbed rapidly from
the GI tract, and peak blood concentrations are
reached within 3-6 hours after a single dose.
• Sulfadiazine is excreted quite readily by the kidney
in both the free and acetylated forms, rapidly at first
and then more slowly over a period of 2-3 days. It
can be detected in the urine within 30 minutes of
oral ingestion.
2. Poorly Absorbed
Sulfonamides
 Sulfasalazine
• very poorly absorbed from the GI tract. It is used in
the therapy of ulcerative colitis and regional
enteritis.
• Intestinal bacteria break sulfasalazine down to
sulfapyridine, an active sulfonamide that is
absorbed and eventually excreted in the urine,
• Nausea, fever, arthralgias, and rashes occur in up to
20% of patients treated with the drug.
• Sulfasalazine can cause a reversible infertility in
males owing to changes in sperm number and
morphology.
3. Sulfonamides for Topical Use
 Sulfacetamide
• Solutions of the sodium salt of the drug are
employed extensively in the management of
ophthalmic infections.
• The drug penetrates into ocular fluids and tissues in
high concentration.
• Sensitivity reactions to sulfacetamide are rare, but
the drug should not be used in patients with known
hypersensitivity to sulfonamides.
 Silver Sulfadiazine
• Inhibits the growth in vitro of nearly all pathogenic bacteria and
fungi, including some species resistant to sulfonamides.
• used topically to reduce microbial colonization and the
incidence of infections from burns.
• Silver is released slowly from the preparation in concentrations
that are selectively toxic to the microorganisms.
• However, bacteria may develop resistance to silver sulfadiazine.
• Although little silver is absorbed, the plasma concentration of
sulfadiazine may approach therapeutic levels if a large surface
area is involved.
• Adverse reactions—burning, rash, and itching—are infrequent.
• Silver sulfadiazine is considered by most authorities to be an
agent of choice for the prevention of burn infections.
4. Long-Acting Sulfonamides
 Sulfadoxine
• long plasma t1/2 (7-9 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
• However, because of severe and sometimes fatal
reactions, including the Stevens-Johnson syndrome,
and the emergence of resistant strains, the drug has
limited usefulness for the treatment of malaria.
Pharmacokinetic aspects
• Most sulfonamides are given orally and, apart from
sulfasalazine, are well absorbed and widely
distributed in the body.
• There is a risk of sensitisation or allergic reactions
when these drugs are given topically.
• The drugs pass into inflammatory exudates and
cross both placental and blood–brain barriers.
• They are metabolised mainly in the liver, the major
product being an acetylated derivative that lacks
antibacterial action.
Sulfonamide Therapy
Combination of sulfamethoxazole and trimethoprim
1. Urinary Tract Infections:
• Trimethoprim-sulfamethoxazole, a quinolone,
trimethoprim, fosfomycin, or ampicillin are the
preferred agents.
• However, sulfisoxazole may be used when the
organism is known to be sensitive.
• The usual dosage is 2-4 g initially followed by 1-2 g,
orally four times a day for 5-10 days.
• Patients with acute pyelonephritis with high fever
and other severe constitutional manifestations are
at risk of bacteremia and shock and should not be
treated with a sulfonamide.
2. Nocardiosis
• treatment of infections due to Nocardia spp
• Sulfisoxazole or sulfadiazine may be given in dosages of
6-8 g daily.

3. Toxoplasmosis.
• The combination of pyrimethamine and sulfadiazine is
the treatment of choice for toxoplasmosis
• Pyrimethamine is given as a loading dose of 75 mg
followed by 25 mg orally per day, with sulfadiazine 1 g
orally every 6 hours, plus folinic acid (leucovorin) 10 mg
orally each day for at least 3-6 weeks.
• Patients should receive at least 2 L of fluid intake daily to
prevent crystalluria during therapy.
4. Use of Sulfonamides for Prophylaxis:
• streptococcal infections and
• recurrences of rheumatic fever
Untoward Reactions to
Sulfonamides
 1. Disturbances of the Urinary Tract. Although the risk of crystalluria

• was relatively high with the older, less soluble

sulfonamides, the incidence of this problem is very
low with more soluble agents such as sulfisoxazole.
• Crystalluria has occurred in dehydrated patients
with acquired immune deficiency syndrome (AIDS)
who were receiving sulfadiazine for Toxoplasma
encephalitis.
• Fluid intake should be sufficient to ensure a daily
urine volume of at least 1200 mL (in adults).
 2. Disorders of the Hematopoietic System
• Acute Hemolytic Anemia
• Agranulocytosis
• Aplastic Anemia: Complete suppression of bone
marrow activity with profound anemia,
granulocytopenia, and thrombocytopenia is an
extremely rare occurrence with sulfonamide therapy
• Hypersensitivity Reactions: morbilliform, scarlatinal,
urticarial, erysipeloid, pemphigoid, purpuric, and
petechial rashes, as well as erythema nodosum,
erythema multiforme of the Stevens-Johnson type,
Behcet’s syndrome, exfoliative dermatitis, and
photosensitivity.
• Miscellaneous Reactions:
• Anorexia, nausea, and vomiting occur in 1-2% of
persons receiving sulfonamides
• The administration of sulfonamides to newborn
infants, especially if premature, may lead to the
displacement of bilirubin from plasma albumin.
 Drug Interactions
• with the oral anticoagulants, the sulfonylurea
hypoglycemic agents, and the hydantoin
anticonvulsants.
• In each case, sulfonamides can potentiate the
effects of the other drug by mechanisms that
appear to involve primarily inhibition of metabolism
and, possibly, displacement from albumin.
• Dosage adjustment may be necessary when a
sulfonamide is given concurrently