1

ANTIFOLATE DRUGS:
SULFONAMIDES
PHARMACOLOGY IV
 2

INHIBITORS OF FOLATE SYNTHESIS:

SULFONAMIDE
1. Mafenide
2. Silver sulfadiazine
3. Sulfasalazine
4. Sulfisoxazole
5. Sulfamethoxazole
6. Sulfadiazine
7. Sulfanilamide
 3

INTRODUCTION
The sulfa drugs are seldom prescribed alone except in
developing countries, where they are still employed because of
their low cost and their efficacy in certain bacterial infections,
such as trachoma and those of the urinary tract.

However, when cotrimoxazole was introduced in the mid-1970s,

there was a renewed interest in the sulfonamides.

Sulfa drugs differ from each other not only in their chemical and
physical properties, but also in their pharmacokinetics.
 4

INTRODUCTION
• The basic formulas of the sulfonamides and their structural
similarity to p-aminobenzoic acid (PABA) are shown in next
figure .
• Sulfonamides with varying physical, chemical, pharmacologic,
and antibacterial properties are produced by attaching
substituents to the amido group (–SO2–NH–R) or the amino
group (–NH2) of the sulfanilamide nucleus.
• Sulfonamides tend to be much more soluble at alkaline
than at acid pH.
• Most can be prepared as sodium salts, which are used for
intravenous administration.
Structures of some sulfonamides and
p-aminobenzoic acid
5
 6

Mechanism of action
• Sulfonamide-susceptible organisms, unlike mammals, cannot
use exogenous folate but must synthesize it from PABA. This
pathway is thus essential for production of purines and nucleic
acid synthesis. Because sulfonamides are structural analogs of
PABA, they inhibit dihydropteroate synthase and folate
production.

• Mammalian cells (and some bacteria) lack the enzymes

required for folate synthesis from PABA and depend on
exogenous sources of folate; therefore, they are not
susceptible to sulfonamides.
 7

Actions of sulfonamides and trimethoprim

Combination of a sulfonamide
with an inhibitor of dihydrofolate
reductase (trimethoprim or
pyrimethamine) provides
synergistic activity because of
sequential inhibition of folate
synthesis.

The sulfa drugs, including

cotrimoxazole, are bacteriostatic
 8

Antimicrobial Activity
• Sulfonamides inhibit both gram-positive and gram-negative
bacteria, nocardia, Chlamydia trachomatis, and some protozoa.
• Some enteric bacteria, such as Escherichia coli, klebsiella,
salmonella, shigella, and enterobacter, are also inhibited.

• It is interesting that rickettsiae are not inhibited by

sulfonamides but are actually stimulated in their growth.
• Activity is poor against anaerobes.
 9

Resistance
• Sulfonamide resistance may occur as a result of mutations
that:
1. cause overproduction of PABA
2. cause production of a folic acid-synthesizing enzyme that
has low affinity for sulfonamides
3. impair permeability to the sulfonamide

Dihydropteroate synthase with low sulfonamide affinity is often

encoded on a plasmid that is transmissible and can disseminate
rapidly and widely.
 10

Pharmacokinetics
• Sulfonamides can be divided into three major groups:
1. oral, absorbable
2. oral, nonabsorbable
3. topical
• The oral, absorbable sulfonamides can be classified as short-,
intermediate-, or long-acting on the basis of their half-lives.
• They are absorbed from the stomach and small intestine and
distributed widely to tissues and body fluids (including the central
nervous system and cerebrospinal fluid), placenta, and fetus.
• Protein binding varies from 20% to over 90%.
• Therapeutic concentrations are in the range of 40–100 mcg/mL of
blood.
• Blood levels generally peak 2–6 hours after oral administration.
 11

Pharmacokinetic Properties of Some

Sulfonamides and Trimethoprim
A portion of absorbed drug is acetylated or glucuronidated in
the liver.
Sulfonamides and inactive metabolites are then excreted into
the urine, mainly by glomerular filtration. In significant renal
failure, the dosage of sulfonamide must be reduced.

The sulfa drugs are acetylated, primarily in the liver. The product
is devoid of antimicrobial activity, but retains the toxic potential to
precipitate at neutral or acidic pH. This causes crystalluria
(“stone formation”) and, therefore, potential damage to the
kidney.
 12

Pharmacokinetic Properties of Some

Sulfonamides and Trimethoprim
 13

Clinical Uses
• Sulfonamides are infrequently used as single agents.
• Many strains of formerly susceptible species, including
meningococci, pneumococci, streptococci, staphylococci, and
gonococci, are now resistant.

• The fixed-drug combination of trimethoprim-sulfamethoxazole

is the drug of choice for infections such as Pneumocystis jiroveci
(formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and
occasionally other bacterial infections.
 14

Oral Absorbable Agents

Sulfisoxazole and sulfamethoxazole are short- to medium-
acting agents used almost exclusively to treat urinary tract
infections.

Sulfadiazine in combination with pyrimethamine is first-line

therapy for treatment of acute toxoplasmosis. The combination of
sulfadiazine with pyrimethamine, a potent inhibitor of dihydrofolate
reductase, is synergistic because these drugs block sequential
steps in the folate synthetic pathway blockade .
Folinic acid, 10 mg orally each day, should also be administered to
minimize bone marrow suppression.

Sulfadoxine is the only long-acting sulfonamide and only as a

combination formulation with pyrimethamine a second-line agent in
treatment for malaria .
 15

Oral Nonabsorbable Agents

Sulfasalazine is not absorbed when administered orally or as a
suppository and, therefore, is reserved for treatment of chronic
inflammatory bowel disease (for example, Crohn’s disease or
ulcerative colitis).

Local intestinal flora split sulfasalazine into sulfapyridine

and 5-aminosalicylate, with the latter exerting the anti-
inflammatory effect.

In Crohn's disease and ulcerative colitis, it is thought to be an

antinflammatory drug that is essentially providing topical relief inside
the intestine. It does this via a number of mechanisms such as
reducing the synthesis of inflammatory mediators.
 16

Topical Agents
Sodium sulfacetamide ophthalmic solution or ointment is
effective in the treatment of bacterial conjunctivitis and as
adjunctive therapy for trachoma.

Another sulfonamide, mafenide acetate, is used topically but

can be absorbed from burn sites.

Silver sulfadiazine is a much less toxic topical sulfonamide and

is preferred to mafenide for prevention of infection of burn
wounds.
Because mafenide produces pain on application. Furthermore,
mafenide can be absorbed in burn patients, causing an
increased risk of acid-base imbalance.
 17

Adverse Reactions
All sulfonamides, including The most common adverse
antimicrobial sulfas, diuretics, effects are:
diazoxide, and the sulfonylurea 1. Fever
hypoglycemic agents, have 2. Skin rashes
been considered to be partially 3. Dermatitis
cross-allergenic. 4. Photosensitivity
Stevens-Johnson syndrome, 5. Urticaria
although relatively uncommon 6. Nausea
(ie, < 1% of treatment courses), 7. Vomiting
is a particularly serious and 8. Diarrhea
potentially fatal type of skin and 9. Urinary tract disturbances
mucous membrane eruption 10. Hematopoietic disturbances
associated with sulfonamide.
 18

Adverse Reactions
Urinary Tract Disturbances
• Sulfonamides may precipitate in urine, especially at neutral or
acid pH, producing crystalluria, hematuria, or even obstruction.
• This is rarely a problem with the more soluble sulfonamides
(eg, sulfisoxazole).
• Sulfadiazine when given in large doses, particularly if fluid
intake is poor, can cause crystalluria.
• Crystalluria is treated by administration of sodium bicarbonate
to alkalinize the urine and fluids to maintain adequate
hydration.
 19

Adverse Reactions
Hematopoietic Disturbances
• Sulfonamides can cause hemolytic or aplastic anemia,
granulocytopenia, thrombocytopenia, or leukemoid
reactions.

• Sulfonamides may provoke hemolytic reactions in patients with

glucose-6-phosphate dehydrogenase deficiency.

 G6PD deficiency is a hereditary condition , occurs when a person is missing or

doesn't have enough of an enzyme called glucose-6-phosphate dehydrogenase,
(which helps red blood cells work properly), so red blood cells break down when
the body is exposed to certain drugs or infection.
 20

Adverse Reactions
Kernicterus: It is a bilirubin-induced brain dysfunction.
This disorder may occur in newborns, because sulfa drugs
displace bilirubin from binding sites on serum albumin. The
bilirubin is then free to pass into the CNS, because the baby's
blood-brain barrier is not fully developed.

• Sulfonamides taken near the end of pregnancy increase the

risk of kernicterus in newborns.
 21

Contraindications
Due to the danger of kernicterus, sulfa drugs should be
avoided in newborns and infants less than 2 months of age
as well as in pregnant women at term.

Sulfonamides should not be given to patients receiving

methenamine for UTIs. The combination increases the risk of
crystalluria.
 22

T
H
A
N
K
Y
O
U
;)