SULFONAMIDES Recognized since 1932. In clinical usage since 1935. First compounds found to be effective antibacterial agents in safe dose ranges. Mainstay.

SULFONAMIDES

• Now largely superceded by antibiotics and trimethoprim-sulfamethoxazole.

• They continue to occupy a small place in therapy.

Wheel of BugsGram-negative

Gram-positive

Ana

erob

ic

P. aeruginosa

H. influenzaeNeissseria spp

E. Coli(coliforms)

S. aureus

Streptococcus spp

Bacteroides spp

Clostridium spp

Enterococcus spp

2HN COOH

DIHYDROPTERIDINE

PYROPHOSPHATE DERIVATIVE

DIHYDROPTEROIC ACID

DIHYDROFOLIC ACID

FOLIC ACID BIOSYNTHESIS

Glutamic Acid

2 ATP

2HN SO2NH2

Dihydropteroate

Synthetase

BLOOD

Protein Bound

Metabolites

Free

Oral

X Topical Parenteral

CSF

Body Fluids & Tissues

Kidney

Other-Sweat, Saliva, Prostatic fluid, Stool

KERNICTERUS IN THE NEWBORN

• Displacement of bilirubin from plasma protein binding sites.

SO2N

METABOLISM

Acetylated sulfonamides-inactive, toxic, and less soluble

H

RNC3HC

O

• They are excreted in the urine partly as the parent and partly as the metabolite.

• Some sulfonamides are very insoluble in the acid urine.

EXCRETION

EXCRETION

• Half life of the sulfonamides depends on renal function.

• Dosage should be modified or the sulfonamides should not be used in renal failure.

• Rapidly absorbed and rapidly eliminated (prototype- sulfisoxazole).

• Poorly absorbed sulfonamides (sulfasalazine).

• Topical sulfonamides (sulfacetamide, silver sulfadiazine).

• Long-acting sulfonamides (sulfadoxine)

SULFONAMIDE PREPARATIONS

CONTRAINDICATIONS

DRUG-DRUG INTERACTIONS

• Inhibit metabolism of some drugs.

• Displace certain drugs from plasma albumin.

TRIMETHOPRIM-SULFAMETHOXAZOLE

2HN CH2

OCH3

OCH3

OCH3

80 mg TRIMETHOPRIM

O

2HN SO2NH

N CH3

400 mg SULFAMETHOXAZOLE

COTRIMOXAZOLE

• Optimal ratio of the two drugs is 5:1 sulfa :trimethoprim.

Synergism

• Expanded number of organisms inhibited.

• Bactericidal .

• Decreased resistance.

• Decreased toxicity.

ADVANTAGES

THERAPEUTIC USES

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PNEUMOCYSTIS PNEUMONIA (PCP)

PNEUMOCYSTIS PNEUMONIA (PCP)

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PNEUMOCYSTIS PNEUMONIA (PCP)

• The most common opportunistic infection in advanced AIDS (80% of AIDS patients have at least one episode).

• Now considered a fungus (P.jurovecii).

• Multiple infections are often present simultaneously with the PCP.

PROPHYLAXIS

• Routine prophylaxis has been successful in improving survival.

• PCP prophylaxis is indicated if the patient has a CD4 T lymphocyte count lower than 200 cells/mm3, or has oral candidiasis regardless of the CD4 count.

TREATMENT OF PCP

• Early therapy is essential as success of therapy is related to severity of the disease at the time of initiation of therapy.

TMP-SMX

• Treatment of choice.

• Oral form used for mild-moderate cases or after initial response to IV therapy and for prophylaxis.

TMP-SMX

• Excellent tissue penetration.

• Produces a rapid clinical response.

DRUG INTERACTIONS

• Same as with sulfonamides

0

2

4

6

1 2 3 4 5 6 7 8 9Time of incubation (hrs)

Via

ble

org

anis

ms

control

sulfonamide

• Results from multiple mechansims.

• Altered dihydropteroate synthetase.

• Cross-resistance among all sulfonamides.

RESISTANCE

PABA

DIHYDROPTEROIC ACID

DIHYROFOLIC ACID

TETRAHYDROFOLIC ACID

+ Pteridine

SULFONAMIDE

TRIMETHOPRIMDihydrofolate Reductase

Dihydrofolate Synthetase

Dihydropteroate Synthetase

• Hypersensitivity reactions -common– allergic rashes– photosensitivity– drug fever– Stevens-Johnson syndrome

ADVERSE EFFECTS

CRYSTALLINE AGGREGATES, HEMATURIA, OBSTRUCTION

ADVERSE EFFECTS

• Headache, nausea, vomiting and diarrhea.

• Hematological effects -anemia, agranulocytosis.

ADVERSE REACTIONS

• Dermatological reactions including skin rashes.

• GI (nausea and vomiting).