ANTIBACTERIAL

SULFONAMIDES
Presented by lecturer
Hayman Sardar Abd.
B. SC. Pharmacy
M. Sc. Pharmaceutical Chemistry
Ph. D. Pharmaceutical Chemistry
• The sulfonamide antimicrobial drugs were the first effective
chemotherapeutic agents that could be used systemically for the cure
of bacterial infections in humans. Their introduction led to a sharp
decline in the morbidity and mortality of infectious diseases.
• Today, they occupy a rather small place in the list of therapeutic agents
that can be used for infectious disease.
• The development of a combination of trimethoprim and
sulfamethoxazole and the demonstration of its usefulness in the
treatment and prophylaxis of certain opportunistic microbial infections
led to resurgence in the use of some sulfonamides.
• Prontosil was found to protect against, and cure, streptococcal
infections in mice. Interestingly, Prontosil was inactive on bacterial
cultures.
• Prontosil is totally inactive in vitro but possesses excellent activity in
vivo.
• Following the dramatic success of Prontosil, a host of sulfanilamide
derivatives was synthesized and tested. By 1948, more than 4,500
compounds had been evaluated, of these, only about two dozen have
been used in clinical practice.
• The penicillins were excellent alternatives to the sulfonamides, and
they largely replaced the latter in antimicrobial chemotherapy.
• Today, there are a few sulfonamides and especially sulfonamide-
trimethoprim combinations that are used extensively for opportunistic
infections in patients with AIDS. A primary infection that is treated
with the combination is PCP.
• The sulfonamides can be grouped into three classes on the basis of
their use:
1. Oral absorbable agents, designed to give systemic distribution;
2. Oral nonabsorbable agents such as sulfasalazine; and
3. Topical agents such as sodium sulfacetamide ophthalmic drops.
 Sulfonamides
• The sulfonamides are structural analogs of PABA, which is involved
in the biosynthesis of folate coenzyme.
• Folate coenzymes are biosynthesized from dietary folic acid in
humans and other animals. Bacteria and protozoa must biosynthesize
them from PABA and pteridine diphosphate.
• Microbes cannot assimilate folic acid from the growth medium or
from the host. The reasons for this are poorly understood, but one
possibility is that bacterial cell walls may be impermeable to folic
acid.
 Spectrum of Action of the Sulfonamides
• Sulfonamides inhibit Gram-positive and Gram-negative bacteria.
• Sulfonamides are infrequently used as single agents.
• Once drugs of choice for infections such as PCP, toxoplasmosis,
nocardiosis, and other bacterial infections, they have been largely
replaced by the fixed drug combination TMP–SMX and many other
antimicrobials.
• Sulfonamides are useful in some urinary tract infections because of
their high excretion fraction through the kidneys.
 Crystalluria and the pKa
• Despite the tremendous ability of sulfanilamide to effect cures of
pathogenic bacteria, its benefits were often offset by the propensity of
the drug to cause severe renal damage by crystallizing in the kidneys.
• Sulfanilamides and their metabolites are excreted almost entirely in
the urine. The pKa of the sulfonamido group of sulfanilamide is 10.4,
so the pH at which the drug is 50% ionized is 10.4.
• Because the urine is usually about pH 6 (and potentially lower during
bacterial infections), essentially all of the sulfanilamide is in the
relatively insoluble, nonionized form in the kidneys. The sulfanilamide
coming out of solution in the urine and kidneys causes crystalluria.
• Early approaches to adjusting the solubility of sulfanilamide in the
urine were the following:
• 1. Greatly increasing the urine flow. During the early years of
sulfonamide use, patients taking the drugs were cautioned to “force
fluids.” The idea was that if the glomerular filtration rate could be
increased, there would be less opportunity for seed crystals to form in
the renal tubules.
• 2. Increasing the pH of the urine. The closer the pH of the urine is to
10.4 (for sulfanilamide itself), the more of the highly water-soluble
salt form will be present. Oral sodium bicarbonate sometimes was, and
occasionally still is, given to raise urine pH. The bicarbonate was
administered before the initial dose of sulfanilamide and then prior to
each successive dose.
• 3. Preparing derivatives of sulfanilamide that have lower pKa values,
closer to the pH of the urine.
• 4. Mixing different sulfonamides to achieve an appropriate total dose.
The solubilities of the sulfonamides are independent of each other, and
more of a mixture of sulfanilamides can stay in water solution at a
given pH than can a single sulfonamide.
• The newer, semisynthetic sulfonamides possess lower pKa values,
because electron – withdrawing and heterocyclic rings are attached to
N1 provide additional stability for the salt form, hence the drug
donates a proton more easily, and the pKa values are lowered.
• Simpler electron – withdrawing groups were extensively investigated
but were found to be too toxic, poorly active or both.
 Protein Binding, and Distribution
• Except for the poorly absorbed sulfonamides used for ulcerative colitis
and reduction of bowel flora and the topical burn preparations (e.g.,
mafenide), sulfonamides and trimethoprim tend to be absorbed quickly
and distributed well. As noted, sulfonamides can be found in the urine
“within 30 minutes after an oral dose.”
• The sulfonamides vary widely in plasma protein binding; for example,
sulfisoxazole, 76%; sulfamethoxazole, 60%; sulfamethoxypyridazine,
77%; and sulfadiazine, 38%.
• The fraction that is protein bound is not active as an antibacterial, but
because the binding is reversible, free, and therefore active,
sulfonamide eventually becomes available.
• Generally, the more lipid soluble a sulfonamide is, at physiological
pH, the more of it will be protein bound.
 Mechanisms of Microbial Resistance to
Sulfonamides
• Indiscriminate use of sulfonamides has led to the emergence of many
drug-resistant strains of bacteria.
• Resistance is most likely a result of a compensatory increase in the
biosynthesis of PABA by resistant bacteria, although other
mechanisms such as alterations in the binding strength of
sulfonamides to the pathway enzymes, decreased permeability of the
cell membrane. As a rule, if a microbe is resistant to one sulfonamide,
it is resistant to all.
 Synergistic Activities of Sulfonamides and
Folate Reductase Inhibitors
• If biosynthesis of bacterial (or protozoal) folate coenzymes is blocked
at more than one point in the pathway, the result will be a synergistic
antimicrobial effect.
• This is beneficial because the microbe will not develop resistance as
readily as it would with a singly blocked pathway.
• The synergistic approach is used widely in antibacterial therapy with
the combination of sulfamethoxazole and trimethoprim.
 Toxicity and Side Effects
• Various serious toxicity and hypersensitivity problems have been
reported with sulfonamide in about 5% of all patients.
• Hematological side effects also sometimes occur, especially hemolytic
anemia in individuals with a deficiency of glucose-6-phosphate
dehydrogenase.
• Crystalluria may occur, even with the modern sulfonamides, when the
patient does not maintain normal fluid intake. Nausea and related
gastrointestinal side effects are sometimes noted.
 Structure–Activity Relationships
• Several thousand sulfonamides have been investigated as
antibacterials (and many as antimalarials). From these, several
structure– activity relationships have been proposed.
• The aniline amino group is very important for activity because any
modification of it other than to make prodrugs results in a loss of
activity. For example, all of the N4-acetylated metabolites of
sulfonamide are inactive.
• Various studies have shown that the active form of sulfonamide is the
N1-ionized salt.
 Oral Sulfonamides
Sulfisoxazole Acetyl
• Sulfisoxazole acetyl used for infections involving sulfonamide-
sensitive bacteria. It is claimed to be effective in the treatment of
Gram-negative urinary infections.
• The acetyl derivative is tasteless and, therefore, suitable for oral
administration, especially in liquid preparations. The acetyl compound
is split in the intestinal tract and absorbed as sulfisoxazole; that is, it is
a prodrug for sulfisoxazole.
 Sulfisoxazole Diolamine
• It is used as a salt to make the drug more soluble in the physiological
pH range of 6.0 to 7.5 and is used in solution for systemic
administration of the drug by slow intravenous, intramuscular, or
subcutaneous injection when high enough blood levels cannot be
maintained by oral administration alone.
• It is also used for instillation of drops or ointment in the eye for the
local treatment of susceptible infections.
 Sulfamethazine
• Because it is more soluble in acid urine, the possibility of kidney
damage from use of the drug is decreased.
• The human body appears to handle the drug unpredictably; hence,
there is some disfavor to its use except in combination sulfa therapy
(in trisulfapyrimidines, USP) and in veterinary medicine.
 Sulfapyridine
• Sulfapyridine was the first drug to have an outstanding curative action
on pneumonia; however, because of its relatively high toxicity, it has
been supplanted largely by sulfadiazine and sulfamerazine.
• Several cases of kidney damage have resulted from acetylsulfapyridine
crystals deposited in the kidneys. It also causes severe nausea in most
patients.
• Because of its toxicity, it is used only for dermatitis herpetiformis.
 Sulfamethoxazole
• Following oral administration, sulfamethoxazole is not absorbed as
completely or as rapidly as sulfisoxazole, and its peak blood level is
only about 50% as high.
 Sulfadiazine Sodium
• It is administered as a 5% solution in sterile water intravenously for
patients requiring an immediately high blood level of the sulfonamide.
 Mixed Sulfonamides
• The danger of crystal formation in the kidneys from sulfonamides has
been greatly reduced through the use of the more soluble
sulfonamides, such as sulfisoxazole.
• This danger may be diminished still further by administering mixtures
of sulfonamides.
• When several sulfonamides are administered together, the antibacterial
action of the mixture is the summation of the activity of the total
sulfonamide present, but the solubilities are independent of the
presence of similar compounds.
• Thus, by giving a mixture of sulfadiazine, sulfamerazine, and
sulfacetamide, the same therapeutic level can be maintained with
much less danger of crystalluria, because only one third of the amount
of any one compound is present.
 Trisulfapyrimidines, Oral Suspension
• The oral suspension & oral tablet of trisulfapyrimidines contains equal
amount of sulfadiazine, sulfamerazine and sulfamethazine, either with
or without an agent to raise the pH of the urine (of the oral
suspension).
Sulfadoxine and Pyrimethamine
• The mixture of sulfadoxine and pyrimethamine is used for the
treatment of P. falciparum malaria in patients in whom chloroquine
resistance is suspected.
• It is also used for malaria prophylaxis for travelers to areas where
chloroquine- resistant malaria is endemic.
 Topical Sulfonamides
Sulfacetamide Sodium
• Because the sodium salt is highly soluble at the physiological pH of
7.4, it is especially suited, as a solution, for repeated topical
applications in the local management of ophthalmic infections
susceptible to sulfonamide therapy.
 Triple Sulfa
• Triple sulfa (sulfabenzamide, sulfacetamide, and sulfathiazole) is used
as a vaginal cream in the treatment of Haemophilus vaginalis
vaginitis.
 Mafenide Acetate
• A homologue of the sulfanilamide molecule.
• It is not a true sulfanilamide-type compound. Its antibacterial action
involves a mechanism that differs from that of true sulfanilamide-type
compounds.
• This compound is particularly effective against Clostridium welchii in
topical application.
• It is currently used alone or with antibiotics in the treatment of slow-
healing infected wounds.
 Sulfonamides for Intestinal Infections,
Ulcerative Colitis, or Reduction of Bowel Flora
• Each of the sulfonamides in this group is a prodrug, which is designed
to be poorly absorbable, though usually, in practice, a little is
absorbed.
• Therefore, usual precautions with sulfonamide therapy should be
observed.
• In the large intestine, the N4-protecting groups are cleaved, releasing
the free sulfonamide antibacterial agent.
• Today, only one example is used clinically, sulfasalazine.
 Sulfasalazine
• Sulfasalazine is broken down in the body to m-aminosalicylic acid and
sulfapyridine.
• The drug is excreted through the kidneys and is detectable
colorimetrically in the urine.
 DIHYDROFOLATE REDUCTASE
INHIBITORS
Trimethoprim
• Is closely related to several antimalarials but does not have good
antimalarial activity by itself; it is, however, a potent antibacterial.
• The concern is that when used as a single agent, bacteria now
susceptible to trimethoprim will rapidly develop resistance.
• In combination with a sulfonamide, however, the bacteria will be less
likely to do so. That is, they will not survive long enough to easily
develop resistance to both drugs.
 SULFONES
• The sulfones are primarily of interest as antibacterial agents, though
there are some reports of their use in the treatment of malarial and
rickettsial infections. They are less effective than the sulfonamides.
 Dapsone
• The pure compound is light stable, but traces of impurities, including
water, make it photosensitive and thus susceptible to discoloration in
light.
• Although no chemical change is detectable following discoloration,
the drug should be protected from light.
• Dapsone is used widely for all forms of leprosy, often in combination
with clofazimine and rifampin. Initial treatment often includes
rifampin with dapsone, followed by dapsone alone.
• It is also used to prevent the occurrence of multibacillary leprosy when
given prophylactically.
• Dapsone is also the drug of choice for dermatitis herpetiformis and is
sometimes used with pyrimethamine for treatment of malaria and with
trimethoprim for PCP.
Thank You