Sulfa revolution in medicine. Prontosil which is a

Sulfa drugs are the basis of
several groups of drugs. The original antibacterial sulfa drugs are synthetic
antimicrobial agents that contain the sulfonamide group. Some sulfa drugs are also devoid
of antibacterial activity. The sulfonylureas and thiazide diuretics are teo newer drug
groups which are based on the antibacterial sulfa drugs.12

Allergies
to sulfa drugs are common. According to data the overall incidence of adverse
drug reactions to sulfa antibiotics is approximately 3%. 3 Hence
medications containing sulfa drugs are prescribed carefully. There is a great
distinction between sulfa drugs and other sulfur-containing drugs and
additives, such as sulfates and sulfites,
which are chemically unrelated to the sulfonamide group. They do not cause the
same hypersensitivity reactions seen in the sulfa drugs .

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Uses of sulfa drugs

Antibacterial
sulfonamides act as competitive inhibitors of the
enzyme dihydropteroate synthase (DHPS), an enzyme
involved in folate synthesis. Sulfa drugs are bacteriostatic and therefore do
not kill bacteria, but inhibit growth and multiplication of them. In contrast
to bacteria, humans acquire folate (vitamin B9) through the diet.4

Sulfa drugs are also used to treat allergies
and cough, as well as antifungal and antimalarial functions. The moiety is also
present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochlorothiazide, metolazone,
and indapamide,
among others), loop diuretics (including furosemide, bumetanide,
and torsemide), acetazolamide, sulfonylureas (including glipizide, glyburide,
among others), and some COX-2
inhibitors (e.g., celecoxib).

Sulfasalazine,
is also used in the treatment of inflammatory bowel disease, in addition to
its use as an antibiotic.

History

Sulfa drugs  drugs were the first antibiotics to be used
systemically, and paved the way for the antibiotic revolution in medicine. Prontosil
which is a prodrug
was the first sulfa drug. Prontosil was the first medicine ever discovered
that could effectively treat a range of bacterial infections inside the body.
It showed a strong protective action against infections caused by streptococci,
including blood infections, childbed fever, and erysipelas,
and a lesser effect on infections caused by other cocci. Later, Bovet,7 Federico
Nitti and J. and Th. Jacques Tréfouël, a French research team
led by Ernest Fourneau at the Pasteur
Institute discovered that the drug was metabolized into two pieces
inside the body, releasing from the inactive dye portion a smaller, colorless,
active compound called sulfanilamide.8 The
discovery helped establish the concept of “bioactivation” and dashed
the German corporation’s dreams of enormous profit; the active molecule
sulfanilamide (or sulfa) had first been synthesized in 1906 and was widely used
in the dye-making industry; its patent had since expired and the drug was
available to anyone.9

In
the protonated form,
the sulfanilamide compound is more active. The drug has very low solubility and
due to its first pKa of around 10, sometimes can crystallize in
the kidneys. Newer analogous compounds prevent this complication because they
have a lower pKa, around 5–6 making them more likely to
remain in a soluble form.

Many
thousands of molecules containing the sulfanilamide structure have been created
since its discovery yielding improved formulations with greater effectiveness
and less toxicity. Sulfa drugs are still widely used for acne and urinary tract
infections, and are receiving renewed interest for the treatment of infections
caused by bacteria resistant to other antibiotics.

Side
effects

Patient suffering from Stevens–Johnson syndrome

Allergic urticaria on the skin induced
by an antibiotic

Sulfa
drugs have the potential to cause a variety of unwanted reactions, for example,
urinary tract disorders, hypersensitivity reactions, porphyria,
and haemopoietic disorders. They may cause a strong allergic reaction if used
in large doses. Two of the most serious are toxic epidermal necrolysis and Stevens–Johnson syndrome.3

Almost
3% of the general populations have adverse reactions when treated with sulfa
drugs antimicrobials. Patients with HIV have a much higher prevalence, at about
60%.15

Hypersensitivity
reactions are less common in non-antibiotic sulfa drugs, and, though
controversial, the available evidence suggests those with hypersensitivity to sulfa
drugs antibiotics do not have an increased risk of hypersensitivity reaction to
the non antibiotic agents.16 
allergic response are found to sulfonamide antibiotics which have the arylamine
group at N4, found in sulfamethoxazole, sulfasalazine and sulfadiazine. Available
evidence suggests, other sulfonamide drugs that do not contain this arylamine
group do not causes allergic reaction and may therefore safely take
non-arylamine sulfonamides.17 
Two regions of the sulfonamide antibiotic chemical structure are implicated in
the hypersensitivity reactions associated with the class.

·        
The first is the N1 heterocyclic ring,
which causes a type I hypersensitivity reaction.

·        
The second is the N4 amino nitrogen
that, in a stereospecific process, forms reactive metabolites that cause either
direct cytotoxicity or immunologic response.

The
nonantibiotic sulfonamides lack both of these structures.19

The
most common appearance of a hypersensitivity reaction
to sulfa drugs are rash and hives. However, Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic
anemia, thrombocytopenia, fulminant hepatic necrosis,
and acute pancreatitis are examples of several
life-threatening manifestations of hypersensitivity to sulfa drugs among
others.20

List of sulfonamides

Children’s
antibacterial drugs

·        
Sulfafurazole (in Pediazole)13

Antimicrobialsedit

Short-acting14

·        
Sulfacetamide

·        
Sulfadiazine

·        
Sulfadimidine

·        
Sulfafurazole (sulfisoxazole)

·        
Sulfisomidine (sulfaisodimidine)

Intermediate-acting

·        
Sulfadoxine

·        
Sulfamethoxazole

·        
Sulfamoxole

·        
Sulfanitran

Long-acting

·        
Sulfadimethoxine

·        
Sulfamethoxypyridazine

·        
Sulfametoxydiazine

Ultra long-acting

·        
Sulfadoxine

·        
Sulfametopyrazine

·        
Terephtyl

 

Sulfadiazine 

Sulfadiazine is an antibiotic.2 it
is Used together with pyrimethamine, in the treatment of toxoplasmosis.4 It
is also used for the treatment of otitis media,
prevention of rheumatic fever, chancroid, chlamydia and
infections by Haemophilus influenzae.2 It
is orally taken .2

There
are several side effects include nausea, diarrhea, headache, fever, rash,
depression, and pancreatitis.2 It
should be avoided by the people who having severe liver problems, kidney
problems, or porphyria.4 It
may increase the risk of kernicterus in
the baby if it is used during pregnancy .2 As
well as it should avoid during breastfeeding,
use is believed to be safe if the baby is otherwise healthy.1 It
is in the sulfonamide class of medications.2

Sulfadiazine
is available as a generic medication.2

Medical uses

It
eliminates bacteria that cause infections by stopping the production
of folate inside
the bacterial cell. It is commonly used to treat urinary tract infections, and burns.

It
can be used to treat toxoplasmosis, a disease caused by Toxoplasma
gondii, in combination with sulfadiazine and pyrimethamine.

Mechanism of action

 

This
drug works by inhibiting the enzyme dihydropteroate synthetase. In combination
with pyrimethamine  and sulfadiazine is used to
treat active toxoplasmosis.

Side effects

·        
nausea

·        
upset stomach, 

·        
loss of
appetite

·        
dizziness.

 

Sulfadimethoxine 

Sulfadimethoxine is a long-lasting sulfonamide antimicrobial medication. It used in veterinary
medicine. It is used to treat many respiratory, urinary tract, enteric, and
soft tissue infections.3
It can be given as a standalone or combined with ormetoprim to broaden the
target range.2 
Sulfadimethoxine inhibits bacterial synthesis of folic acid by acting as a
competitive inhibitor against PABA. It is the most common drug prescribed to dogs affected
by coccidiosis.4

Mechanism

Like
other sulfa drugs, sulfadimethoxine is a dihydropteroate synthase inhibitor.
It has the strongest effect in the beginning stages of an infection, when the
pathogen is rapidly dividing. Bacteria and some protozoa are unable to
obtain folic acid from the environment. They
synthesize it by converting PABA (para-aminobenzoate) to dihydropteroate using the enzyme dihydropteroate synthase. Sulfa drugs act
as a competitive inhibitor. They are structurally
similar to PABA and able to bind to the enzyme’s active site. In this way they
prevent the synthesis of folic acid from progressing. Folic acid is necessary
for these organisms to produce nucleic acids and nucleic acids which are
required for cell division.5 Thus,
it has a microbiostatic effect rather than a microbiocidal one.
It prevents pathogen growth rather than killing them. As sulfadimethoxine is
microbiostatic, it still requires the animal to still be able to mount an immune
response to kill the pathogen.63

With
ormetoprim

Sulfadimethoxine
can either be given alone as well as in combination with ormetoprim to as a
“potentiated sulfonamide” to increase antimicrobial activity.2 Ormetoprim
is a diaminopyridine, inhibiting dihydrofolate reductase.

Pharmacokinetics

Like
all sulfonamides, it diffuses easily when it is in its unionized, lipid-soluble form,
and easily reaches many tissues. Therefore, levels tend to be higher in less
acidic tissue and body fluids or in diseased tissues having high concentrations
of leucocytes.736 Sulfadimethoxine
to maintain higher blood levels than most other long-acting sulfonamides due to
its ability to bind to plasma
proteins is very high. Only low doses can give rapid and
sustained therapeutic blood levels.3 
So, sulfadimethoxine is marketed as acetylatesulfadimethoxine
for most animals. Dogs are the exception – since they are unable acetylate
sulfanamides, they excrete sulfadimethoxine mostly unchanged in the urine. Their
inability to transform sulfadimethoxine also makes them more susceptible to
negative side effects.8910

Sulfadimethoxine
has a relatively high solubility at the pH normally occurring in the kidneys,
and is easily reabsorbed into the renal tubules,
adding to its long half-life.118 The
use of sulfadimethoxine raises concerns because it may precipitate in the
kidneys, leading to crystalluria. It can be avoided entirely by
adding a diaminopyrimidine such as ormetoprim.116 

 Usage

 It
is used for:

·        
Treating skin and soft-tissue infections
caused by Staphylococcus aureus or E. coli8

·        
Treating cattle for bovine respiratory disease complex, necrotic
pododermatitis, pneumonia when caused by Pasteurella,
and calf diphtheria caused by Fusobacterium necrophorum1

·        
When combined with ormetoprim:2

·        
Treating soft tissue infections, skin
infections, urinary tract infections, and intesintal
coccidia infections in animals

·        
Prevention of fowl cholera and
coccidioisis by Eimeria in poultry

·        
Treating salmon and trout for furunculosis

It
is also one of the only sulfonamides allowed for treating lactating dairy
cattle.6

 

Sulfamethoxazole 

Sulfamethoxazole is an antibiotic.
It is used for bacterial infections such as urinary tract infections, bronchitis,
and prostatitis. It
is effective against both gram negative and positive bacteria such as Listeria monocytogenes and E. coli.1

Side effects

The
most common side effects of sulfamethoxazole is
gastrointestinal disturbances such as nausea, vomiting, anorexia and allergic
skin reactions such as rash and urticaria.8 There
have been rare instances where severe adverse reactions have resulted in mortality.
These include aplastic anemia, toxic epidermal necrolysis, Stevens-Johnson
Syndrome, agranulocytosis, fulminant hepatic necrosis, and other blood
dyscrasias.8

Allergic
reactions to Sulfonamides have been shown to include the entire Gel-Coombs
spectrum of hyperactivity reactions. One study has shown the allergic reaction
rate to be about 3.0% over 359 courses of therapy.11 Of
the allergic reactions, skin rashes, eosinophilia and drug fever were the most
common, while serious reactions were less common.

 

It
is a bacteriostatic antibiotic. It resembles a
component of folic acid. It also prevents folic acid
synthesis in the bacteria. Mammalian cells and some bacteria which do not
synthesize but require preformed folic acid (vitamin B9), are insensitive to
sulfamethoxazole.2

 It
is now mostly used in combination with trimethoprim .4

Mechanism of action

It
is a structural analog of para-aminobenzoic acid (PABA).
They compete with PABA to bind to dihydropteroate synthetase and
inhibit conversion of PABA and dihydropteroate diphosphate to dihydrofolate.
Inhibiting the production of dihydrofolate intermediate interferes with the
normal bacterial synthesis of folate. Folate is an essential metabolite
for bacterial growth and replication. It is used in DNA synthesis,
primarily at thymidylate and purine biosynthesis, and
amino acids synthesis, including serine, glycine and methionine.12 Hence,
blockage of folate production inhibits the folate-dependent metabolic processes
for bacterial growth. Since it inhibits bacterial growth, sulfamethoxazole is
considered a bacteriostatic antibiotic.1

Excretion

Sulfamethoxazole
is renally excreted via glomerular filtration and tubular secretion.8 About
20% of the sulfamethoxazole in urine is the unchanged drug, about 15–20% is the
N-glucuronide conjugate, and about 50–70 % is the acetylated metabolite.11 Sulfamethoxazole
is also excreted in milk.8

Sulfamethoxypyridazine

Sulfamethoxypyridazine has recently been introduced as a new
antibacterial sulfonamide with good gastrointestinal absorption and prolonged
action. It has been proposed for use both as a prophylactic agent and for the
therapy of subacute or chronic infections.1

Sulfamerazine

Sulfamerazine
is a sulfadrug that is used as an antibacterial agent. It is a long-acting antibacterial
agent. Sulfamerazine is
bacteriostatic in nature.
Sulfamerazine is found in individuals that have used or taken this drug.

Mechanism
of Action

Sulfamerazine is a sulfonamide drug that inhibits
bacterial synthesis of dihydrofolic acid by
competing with para-aminobenzoic acid (PABA) for binding to dihydropteroate synthetase
(dihydrofolate synthetase) .
Inhibition of dihydrofolic acid synthesis
decreases the synthesis of bacterial nucleotides and DNA.

Side effects

Sulfamerazine may cause hypersensitivity, nausea, diarrhea,
and vomiting reactions. Anemia, agranulocytosis, thrombocytopenia and hemolytic
anemia in patients with glucose-6-phosphate dehydrogenase deficiency may also
occur. Sulfamethoxazole may also
displace bilirubin from
albumin binding sites causing jaundice or kernicterus in newborns.