Sulfonamides

Sulfonamides were the first antimicrobial agents discovered and used. A group of scientists working on different dyes found a compound known as Prontosil. They discovered its activity against Streptococci and Staphylococci in 1932.

In 1933, another scientist used Prontosil in a 10 month old child suffering from Streptococcal infection.

With further discoveries, different derivatives were derived and named as sulfonamides.

Although they were the first antimicrobial agents for gram positive and gram negative organisms, but with use several problems were discovered. Now they have limited recommendation as antimicrobial agents due to:

1. Potential adverse drug reactions –allergic and hypersensitive reactions
2. Mechanism of resistance in a number of organisms, limiting the effectiveness
3. Newer agents like penicillin were discovered, being both better and efficacious than sulfonamides. They have broader spectrum

Co-trimoxazole is preferred and their use is restricted to fewer medications.

Chemistry

Structural analog of PABA. Sulfonamides with different chemical, physical, pharmacological and anti bacterial properties are produced by substitutions at amido gp (-SO₂ – NH – R) or the amino gp. (-NH2) of sulfanilamide nucleus.

Sulfonamides are insoluble as such; soluble forms are only in the form of sodium salt preparations.

Classification (based on therapeutic use, half life, absorption)

1. Well absorbed by Mouth and Rapidly eliminated

a.         General Purpose

• Sulfadiazine (10-17 hrs.)
• Sulfadimidine
• Sulfamethoxazole (10-12 hrs.)
• Sulfamethizole (9 hrs.)

b.         Mainly for UTI

• Sulfisoxazole (6 hrs.)

2. Well absorbed by GIT and Slowly eliminated

• Sulfadoxine (7-9 days)

3. Poorly absorbed by GIT

• Sulfasalazine

For Topical Application

• Sulfacetamide
• Silver  sulfadiazine
• Mafenide

Sulfonamide Combinations

• Cotrimoxazole (Sulfamethoxazole & trimethoprim)
• Fansidar (Sulfadoxine & Pyrimethamine
• Pediazole (Sulfisoxazole & Erythromycin ethyl succinate)
• Antrima (Sulfadiazine & Trimethoprim)
• Sulfadiazine & Pyrimethamine

Pharmacokinetics

Given orally

Absorption –good, from stomach and intestines. 80-100% of drug given orally is absorbed.

Distribution – Widely distributed in extracellular spaces. Sulfisoxazole has high concentration in ocular spaces, synovial fluids, peritoneal and pleural fluids.

PPB 20 – 90 % to serum albumin. Competes with other agents for binding albumin.

PPL 2 – 6 hrs.

Excretion – Urine. Drug appears within 30 minutes in urine.

Sulfonamides cross blood brain barrier. They have high concentration within cerebro-spinal fluid. Despite this fact, they are not used for meningitis. Most of the organisms causing meningitis are now resistant.

They also cross the placental barrier and reach fetus, causing antibacterial activity and toxic effects. Care is taken in pregnancy and due to premature babies, use is restricted.

They are also excreted in milk.

Metabolism occurs in liver by n-acetylation. The metabolites are excreted in the urine.

Half life is different for different compounds.

Antibacterial spectrum

Use is now limited to only those microorganisms which are sensitive.

• Gram +ve,
• Gram-ve bacteria,
• Some enterobacteria like Shigella, Salmonella, Klebsiella
• Nocardia,
• Chlamydia trachomatis,
• Escherichia coli.

Potentiate Rickettsiae and are not inhibited.

Mechanism of Action

They are bacteriostatic in nature.

Those antimicrobial agents which restrict the growth of bacteria by binding and inhibiting protein synthesis essential for growth of micro-organisms.

As they are the structural analogs of PABA, which takes part in synthesis of purines for DNA formation, PABA incorporation is inhibited

Antagonists of dihydropteroate synthase instead of PABA incorporate into the synthesis of DNA, inhibiting the process.

By competing or causing inhibition of this enzyme they are active only in bacteria that produce own folic acid. This is the reason why they do not cause much damage in mammalian cells.

Resistance

Resistance to sulfonamides is seen. The mechanism is different for different sulfonamide agents.

Resistance is mainly due to:

1. Mutational changes (plasmid coated) thus binding of sulfonamides is altered.

2. Permeability of sulfonamides is decreased either by:

• Influx is low
• Outflux is to active

Thus required concentration is not achieved.

3. Overproduction of PABA takes place. Sulfonamides in therapeutic range are not enough to inhibit.
4. Some other metabolic pathways for production of purines and DNA.

Therapeutic Uses

They were used previously for a wide range of infections. Now the use is restricted to:

1. UTI (Sulfisoxazole)

In uncomplicated UTI, although they are not the first line agents (as better options include co-trimoxazole, fluroquinolones, ampicillin and phosphomycin).

Sulfisoxazole is used as 2^nd line or for resistant type. Dose of 2-4 g is given initially, followed by 1g four times a day for 10 days. One should be careful as adverse effects include:

• Crystal urea
• Hypersensitivity

Used as agents well absorbed and rapidly eliminated. Urological adverse effects are less.

2. As Topical Agents in

a.      Adjunctive therapy for Trachoma  and Bacterial Conjunctivitis (Na -Sulfacetamide)

Used because

1. High concentration is achieved.
2. pH is 7.4 when 3-4% is administered,
3. as is readily soluble,
4. has less irritation,
5. hypersensitivity reactions are less commonly seen when used within ocular region

3. Prevention of infection of burn wounds (Mafenide, Silver sulfadiazine)

Two major problems are seen:

1. Loss of fluid
2. Decolonization of bacteria

Use is limited to superficial wounds, deep wounds are not treated. Mafenide is effective against gram positive and negative organisms. Before application, wound is washed with saline. After debarment of wound, 1-2 mm thick application is done. Exclusive dressing is not applied.

Adverse Drug Reactions

1. Dressing is not applied on the area, lost of fluid can occur, leading to dehydration and shock.
2. Allergic reactions are seen
3. Burning at site of application.
4. Also carbonic anhydrase inhibitor, alkanization of urine occurs leading to metabolic acidosis.
5. Mafenide is converted into a metabolite, para carboxy benzene sulfonamide

4. Ulcerative Colitis, enteritis, other inflammatory Bowel diseases (Sulfasalazine)

Sulfasalazine is poorly absorbed from GI tract, whenever it is administered; it is converted into two compounds:

1. Sulfa pyridine –mainly absorbed, ADRs occur.
2. 5 amino salicylate –not absorbed, excreted in feces. Agent used in ulcerative colitis, enteritis and inflammatory bowel disease.

5. Rheumatoid arthritis (Sulfasalazine)

6. Nocardiosis (Sulfisoxazole, Sulfadiazine)

Infection occurring from soil and involving respiratory tract.                  

7.      Used in combination in

• Pneumocystis Jiroveci – sulfamethoxazole combined with trimethoprim (Co-trimoxazole). Fungal infection
• Resistant Malaria (Sulfadoxine + Pyrimethamine – Fansidar)
• Acute toxoplasmosis – (Sulfadiazine + Pyrimethamine)

8. Sulfisoxazole & Erythromycin ethyl succinate combination is mainly used in children with otitis media.

Adverse effects

1.      Urinary Tract Disturbances:-

• Crystalluria
• Hematuria
•  even obstruction

More common with agents poorly soluble, highly soluble agents are readily excreted. Fluid intake is kept adequate and urine output 1200 ml. high urine output leads to loss of fluid.

2. Hypersensitivity reactions      

• Fever
• Skin rashes
• exfoliative dermatitis
• photosensitivity

• urticaria
• Angioedema & Steven – Johnson syndrome,
• Erythema nodosum

3.      Hematopoietic Disturbances :-

• Hemolytic or Aplastic anemia,
• Granulocytopenia (1-4% of patients),
• Thrombocytopenia,
• Leukemoid reactions
• G6PD deficiency

4. GIT:  

• Nausea,
• vomiting,
• anorexia

5. Super infections:

When topically applied. They are of Candida type

Contraindications

1. Newborns & infants less than 2 months
2. Pregnant woman at term – Kernicterus as are highly bound to plasma proteins and displace other agents including bilirubin, thus increased bilirubin in basal ganglia leads to encephalopathy.
3.  Nursing mother –as excreted in milk
4.  Renal or hepatic failure
5.  Blood disorders, G6PD deficiency