Sulfonamides

(Antimetabolites)

Classes of Sulfonamides

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I. Systemic Sulfonamides According to their duration of action they are

divided to:

Short-acting Sulfonamides

Intermediate-acting sulfonamides

Long-acting sulfonamides

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A( Short-acting Sulfonamides

They are rapidly absorbed and rapidly excreted. Their half lives from 4-7 hours and they are administered every 4 to 8 hours.

HN

S

O

O

H2N

Sulfaisoxazole

NO

CH3

CH3

4-amino-N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide

HN

S

O

O

H2N

Sulfamethizole

S

NN

CH3

4-amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide

HN

S

O

O

H2N

N

4-amino-N-(pyridin-2-yl)benzenesulfonamide

Sulfapyridine

Sulfadimidine or sulfamethazine

S

O

O HN

N

N CH3

CH3

H2N

4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide

S

O

O HN N

N

CH3

H2N

4-amino-N-(4-methylpyrimidin-2-yl)benzenesulfonamide

Sulfamerazine

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B( Intermediate-acting sulfonamides

They are absorbed and excreted more slowly than short-acting. Their half lives range from 10 to 12 hours so they are given twice

daily.

S

O

O HN N

N

H2N

4-amino-N-pyrimidin- 2-yl-benzenesulfonamide

SulfadiazineSulfamethoxazole

S

O

O HN

ON

CH3

H2N

4-amino-N-(5-methylisoxazol-3-yl)-benzenesulfonamide

C( Long-acting sulfonamides

They are rapidly absorbed but slowly excreted their half lives are 35 to 40 hours.

S

O

O HN

N N

OCH3

OCH3

H2N

Sulfadimethoxine

S

O

O HN

N N

OCH3

H2N

Sulfadoxine

OCH3

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II. Intestinal sulfonamides Water soluble latent forms which are poorly absorbed from the

GIT (5%) and thus reach a high concentration in the colon lumen,

By means of either bacterial or enzymatic hydrolysis releases the parent sulfonamide.

Examples: sulfasalazine, phthalylsulfathiazole and succinylsulfathiazole (Prodrugs).

Phthalylsulfathiazole

O

OH

O

NH

S

O

O

HN S

N

O

HONH

S

O

O HN

S

N

O

Succinylsulfathiazole

NNH

S

O

O

HN N

O

O

HO

Sulfasalazine Sulfasalazine is mainly used for treatment of inflammatory bowel disease,

including ulcerative colitis and Crohn's disease. It is also effective in several types of arthritis, particularly rheumatoid arthritis

Reductive metabolism by means of azoreductase enzyme converts the drug to sulfapyridine and 5-aminosalicylic acid (anti-inflammatory) both components are active

Intestinal sulfonamides )cont.(

NNH

S

O

O

HN N

O

O

HO

Azoreductase

H2N

S

O

O

HN N

Sulfapyridine

NH2

HO

O

HO

5-aminosalicylic acid

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Ophthalmic sulfonamides They are used in treatment of conjunctivitis and

other superficial ocular infections.

CH3

O

NaN

S

O

O

H2N

Sulfacetamide Sodium

CH3

O

HN

S

O

O

H2N

Sulfacetamide

IV. Sulfonamides for burn therapy

Mafenide is not a true sulfonilamide, it is not effective systemically, but is particularly effective topically in the treatment of burns or for healing infected wounds.

S

O

ONH2

H2N

4-(aminomethyl)benzenesulfonamide

Mafenide

Sulfonamides for burn therapy )cont.(

Silver sulfadiazine is used as effective topical antimicrobial agents, especially against Pseudomonas s. in burn therapy, where treatment failure with other drugs may occur.

Ag+

N- N

N

S

O

O

H2N

Silver sulfadiazine

Mixtures of sulfonamides

1.Sulfonamides aloneThe main purpose is to reduce the risk of crystalluria

a(Trisulfapyrimidine Each drug is administered in one third of the total dose, they behave independently concerning solubility but their therapeutic effects are additive.

OS

HN

N

N

H2N

O

Sulfadiazine

OS

HN

N

N

H2N

O

Sulfamerazine

CH3 OS

HN

N

N

H2N

O

Sulfamethazine

CH3

CH3

b. Multiple )or Triple( sulfas They are a 1:1:1 combination of sulfabenzamide,

sulfacetamide, and sulfathiazole. The combination is primarily used as topical cream for Gardnerella vaginalis in vaginal infections

S

O

O HN

H2N

sulfabenzamide

S

O

O HN

S

N

H2N

Sulfathiazole

CH3

O

HN

S

O

O

H2N

Sulfacetamide

2( Mixtures of sulfonamides with other drugs

Sulfamethoxazole and Trimethoprim There is a synergistic effect obtained from such combination. It is usually given orally and I.V. administration. When taken orally the tablet has a standard ratio of

5 : 1 40 mg of the sulfa and 8 mg trimethoprim. Both drugs are excreted in urine their half lives are about 8-10

hours

N

NH2N

NH2

OCH3

OCH3

OCH3

TrimethoprimSulfamethoxazole

S

O

O HN

ON

CH3

H2N

Trimethoprim is often given in conjunction with the sulfonamide sulfamethoxazole.

The latter inhibits the incorporation of PABA into folic acid, while the former inhibits dihydrofolate reductase.

Therefore, two enzymes in the one biosynthetic route are inhibited.

This is a very effective method of inhibiting a biosynthetic route and has the advantage that the doses of both drugs can be kept down to safe levels. To get the same level of inhibition using a single drug, the dose level of that drug would have to be much higher, leading to possible side-effects.

This approach has been described as

'sequential blocking'.

H2N COOH FOLIC ACID TETRAHYDROFOLATE

Dihydropteroate Synthetase

dihydrofolate reductase

SULFAMETHOXAZOLE TRIMETHOPRIM

Pharmacokinetic factors of the combination

Pairing these two particular antibacterial agents was based upon pharmacokinetic factors and convenient availability.

For such a combination to be useful in vivo the two agents must arrive at the necessary infected tissues at the correct time and in the right ratio.

It is used for oral treatment of urinary tract infections, shigellosis, otitis media, traveler's diarrhea and bronchitis.

Selectivity of Trimethoprim

There is a significant differences between the bacterial and the mammalian dihydrofolate reductases away from the active site.

The bacterial enzyme is sensitive to inhibition by trimethoprim by up to 100,000 times lower concentrations than is the mouse enzyme. This difference explains the useful selective toxicity of trimethoprim.

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Advantages of this combination

The combination of sulfamethoxazole-trimethoprim is not only

synergistic in vitro but is less likely to induce bacterial resistance than

either agent alone.

Thus, these agents block sequentially at two different steps in the same

essential pathway, and this combination is extremely difficult for a naive

microorganism to survive.

It is also comparatively uncommon that a microorganism will

successfully mutate to resistance at both enzymes during the course of

therapy.

It is useful and comparatively nontoxic for AIDS patients who are

infected with the pneumonia causing opportunistic pathogen

Pneumotystis carinii.

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