PHARMACOLOGY PHARMACOLOGY OF OF SULFONAMIDESSULFONAMIDES

History History

• Sulfonamide drugs were the first Sulfonamide drugs were the first antimicrobial drugs, and paved the antimicrobial drugs, and paved the way for the antibiotic revolution in way for the antibiotic revolution in medicine. The first sulfonamide was medicine. The first sulfonamide was trade named trade named ProntosilProntosil, which is a , which is a prodrugprodrug

SulfonamidesSulfonamides

• Effective against a broad range of Effective against a broad range of microorganismsmicroorganisms

• Block specific step in biosynthetic Block specific step in biosynthetic pathway of folic acidpathway of folic acid

• Interfere with PABA and folic acid Interfere with PABA and folic acid formation, thereby destroying formation, thereby destroying bacteriabacteria

Classification of Classification of SulfonamidesSulfonamides

Oral, absorbableShort-actingMedium-actingLong-acting

Oral, nonabsorbable;Topical;

Oral, absorbableOral, absorbable

Short-acting;4-8hrShort-acting;4-8hr SulfadiazineSulfadiazine

Medium-acting;8-12hrMedium-acting;8-12hr SulfamethaxazoleSulfamethaxazole

Long-acting;~7hrLong-acting;~7hr Sulfadoxine,SulmethopyrazineSulfadoxine,Sulmethopyrazine

Oral, nonabsorbable; Sulfasalazine,Topical; Sodium sulfacetamide

ophthalmic solution or ointment,

Mafenide acetate, SML; Silver sulfadiazine, SD-Ag

• Mechanism of actionMechanism of action

Bacteriostatic actionBacteriostatic actionPrevent synthesis of folic Prevent synthesis of folic acid required for synthesis acid required for synthesis of purines and nucleic acidof purines and nucleic acidDoes not affect human Does not affect human cells or certain bacteria—cells or certain bacteria—they can use preformed they can use preformed folic acidfolic acid

Antimicrobial Spectrum of Antimicrobial Spectrum of Sulfa Drugs Sulfa Drugs

• Sulfonamides have broad spectrum Sulfonamides have broad spectrum activity against both gram-positive activity against both gram-positive and gram-negative bacteria and gram-negative bacteria

Bacterial Resistance to Bacterial Resistance to Sulfonamides Sulfonamides

• Resistance to sulfonamide antibiotics Resistance to sulfonamide antibiotics is also common, and they are is also common, and they are frequently used in combination with frequently used in combination with trimethoprim; a combination that trimethoprim; a combination that blocks two steps in folic acid blocks two steps in folic acid metabolism and thus helps prevent metabolism and thus helps prevent the emergence of strains of bacteria the emergence of strains of bacteria resistant to sulfa drugs. resistant to sulfa drugs.

PharmacokineticsPharmacokinetics

①① Oral administration, absorbed well, Oral administration, absorbed well, ②② Distributed widely to tissues and Distributed widely to tissues and

body fluids, including CNS and body fluids, including CNS and cerebrospinal fluid, placenta, and cerebrospinal fluid, placenta, and fetus; 20-90% protein binding rate; fetus; 20-90% protein binding rate;

③③ AcetylatedAcetylated or glucuronidated in or glucuronidated in the liver, the liver,

④④ Sulfonamides and inactive Sulfonamides and inactive metabolites are excreted into metabolites are excreted into the urine, the urine, they are more soluble they are more soluble at alkaline than at acid pHat alkaline than at acid pH. In . In renal failure patient, drug dose renal failure patient, drug dose must be reduced. must be reduced.

Clinical uses of Clinical uses of SulfonamidesSulfonamides

SD+TMPSD+TMPa.a. Treatment of urinary tract Treatment of urinary tract

infectionsinfections

b.b. Respiratory tract infections, Respiratory tract infections, sinusitis, bronchitis, pneumonia, sinusitis, bronchitis, pneumonia, otitis media, and dysentery,otitis media, and dysentery,

SMZ+TMPSMZ+TMP

First-line therapy for treatment of First-line therapy for treatment of acute toxoplasmosisacute toxoplasmosis

Sulfadoxine+TmpSulfadoxine+Tmp

Used as a second-line agent in treatment for malaria.

Sulfasalazine

widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease.

Mafenide acetateMafenide acetate Prevent bacterial colonization and Prevent bacterial colonization and

infection of burn wounds,infection of burn wounds,

Silver sulfadiazineSilver sulfadiazine

For prevention of infection of burn For prevention of infection of burn woundswounds

Adverse effects ofAdverse effects of SulfonamidesSulfonamides

• Allergenic reactionsAllergenic reactions

All sulfonamides and their All sulfonamides and their derivatives, including carbonic derivatives, including carbonic anhydrase inhibitors, thiazides, anhydrase inhibitors, thiazides, furosemide, bumetanide, furosemide, bumetanide, torsemide, diazoxide, and the torsemide, diazoxide, and the sulfonylurea hypoglycemic agents sulfonylurea hypoglycemic agents are cross- allergnic. are cross- allergnic.

1.1.Urinary tract disturbancesUrinary tract disturbances Sulfonamides may precipitate in Sulfonamides may precipitate in

urine, especially at neutral or acid urine, especially at neutral or acid pH, producing crystalluria, hemturia, pH, producing crystalluria, hemturia, or even obstruction. or even obstruction.

SD & SMZ, when in large doses, fluid SD & SMZ, when in large doses, fluid intake is poor, can cause crystalluria. intake is poor, can cause crystalluria.

Sodium bicarbonate to alkalinize the Sodium bicarbonate to alkalinize the urine, adequate fluids,urine, adequate fluids,

2. Hematopoietic disturbances2. Hematopoietic disturbances

Hemolytic or aplastic anemia, Hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, granulocytopenia, thrombocytopenia, or leukemoid reactions. or leukemoid reactions.

Provoke hemolytic reactions in Provoke hemolytic reactions in patients whose red cells are deficient patients whose red cells are deficient in glucose-6-phosphate in glucose-6-phosphate dehydrogenase. dehydrogenase.

The most common adverse effects are The most common adverse effects are fever, skin rashes, exfoliative fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea.nausea, vomiting, diarrhea.

Stevens-Johnson syndrome, is a Stevens-Johnson syndrome, is a particularly serious and potentially particularly serious and potentially fatal type of skin and mucous fatal type of skin and mucous membrane eruption associated with membrane eruption associated with sulfonamide use.sulfonamide use.

Patient Suffering from Stevens–Johnson syndrome

Sulfonamides’ Side Effects :Sulfonamides’ Side Effects :

• RashRash

• NauseaNausea

• Drug feverDrug fever

• VomitingVomiting

• JaundiceJaundice

• Blood complicationsBlood complications

• Kidney damageKidney damage

ReferencesReferences

• Beers Mark H., and Robert Berkow, Beers Mark H., and Robert Berkow, eds. eds. The Merck ManualThe Merck Manual, 2nd ed. home , 2nd ed. home edition. West Point, PA: Merck & Co., 2004.edition. West Point, PA: Merck & Co., 2004.

• Marx, John A. Marx, John A. Rosen's Emergency Rosen's Emergency Medicine: Concepts andClinical PracticeMedicine: Concepts andClinical Practice, , 5th ed. St. Louis, MO: Mosby & Co, 2002.5th ed. St. Louis, MO: Mosby & Co, 2002.

• Mcevoy, Gerald K., et al. Mcevoy, Gerald K., et al. AHFS Drug AHFS Drug Information 2004.Information 2004.  BethesdaBethesda, MD: American , MD: American Society of Healthsystems Pharmacists, Society of Healthsystems Pharmacists, 2004.2004.