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SULFONAMIDES AND TRIMETHOPRIM

Abhinav SawhneyM. Pharmacy (Pharmacology)

A10654913001Amity Institute of Pharmacy

Amity University NOIDA

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Antifolate drugs

Sulfonamides Trimethoprim Trimethoprim & Sulfamethoxazole

mixture

Discovery of Sulfonamides

The discovery of sulfonamides is a significant milestone event in the human chemotherapeutic history. Sulfonamides are synthetic compounds that have activity against both gram-positive and gram- negative bacteria.

Originally, sulfonamides were synthesized in Germany as azodyes. In an attempt to expand on earlier ideas of using dyes as antimicrobial agents, a man by the name of Domagk

Basic Structure

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Sulfonamides: chemistry

Mechanism of Action (Wood-fields Theory)

Fol i c ai cd Di hydrofol i c aci d Tetrahydrofol i c aci d

Coezyme F

Fol ate Raductase Di hydrofol ate Raductase

The bi osynthesi s of DNA/ RNA

The structure of folic acid

N

N

N

N

Pteridine

H2N

O

HN

HN

OCOOH

COOH

PABA Glutamic acid

Folic acid

HN

N N

N

H2N

O

O P

O

OH

O P

OOH

OH

H

HN2

COOH

PABADihydropteroate synthaseHN

N N

N

H2N

O

NH

COOH

Dihdropteroic acid

HN

N N

N

H2N

O

NH

CONHCHCH2CH2COOH

COOH

H

Glutamic acid

Dihydrofolic acid (DHFA)

H2N

SO2NH2

HN

N N

N

H2N

O

NH

SO2NH2

H False Dihdropteroic acid

HN

N N

N

H2N

O

NH

CONHCHCH2CH2COOH

COOH

H

H

Tetrahydrofolic acid (THFA)

Dihydrofolate Reductase (DHFR)

TMP

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Sulfonamides: antimicrobial activity

Gram positive and negative bacteria Nocardia, chlamydia trachomatis Some protoza Some enteric bacteria

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Sulfonamides: resistance

Overproduction of PABA Low affinity dihydropteroate synthase Loss of permeability to sulfonamides

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Sulfonamides: pharmacokinetics

Oral absorbable Short Medium Long

Oral, nonabsorbable

Serum protein bind 20 ~ 90%

Excreted into urine

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Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim

Drug Half-Life Oral Absorption

Sulfonamides

Sulfacytine Short Prompt (peak levels in 1–4 hours)

Sulfisoxazole Short (6 hours) Prompt

Sulfamethizole Short (9 hours) Prompt

Sulfadiazine Intermediate (10–17 hours) Slow (peak levels in 4–8 hours)

Sulfamethoxazole Intermediate (10–12 hours) Slow

Sulfapyridine Intermediate (17 hours) Slow

Sulfadoxine Long (7–9 days) Intermediate

Pyrimidines

Trimethoprim Intermediate (11 hours) Prompt

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Sulfonamides: clinical uses

Oral absorbable agents Sulfamethoxazole (GANTANLOL 0.5gm tab.)

To treat urinary tract infection Sulfadiazine (0.5 gm QID): toxoplasmosis Sulfadoxine: long acting, in a combination for treatment

of malaria Oral nonabsorbable agents

Ulcerative colitis, enteritis, other inflammatory bowel disease

Topical agents Sulfacetamide (LOCULA 10% eye drops.): ophthalemic Mafenide (SULFAMYLON 1% cream): topical Silver sulfadiazine ( SILVIRIN 15% cream): topically

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Sulfonamides: adverse reactions

Cross allergenic sulfonamide drugs: Thiazide, furosemide, diazoxide, sulfonylurea

hypoglycemic agents, and others Fever, skin rashes, exfoliative

dermatitis,photosensivity, urticaria, nausea, vomiting, diarrhoea

Stevens-Johnson syndrom Urinary tract disturbances

Crystalluria, hemturia Hematopoietic disturbance

Hemolytic or aplastic anemia Granulocytopenia, thrombocytopenia, leukmoid

reaction Hemolysis in G-6PDH deficient patients Kernicterus in newborn of mothers have taken near

the end of pergnancy

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Trimethoprim: chemistry

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Trimethoprim: resistance

Reduced cell permeability Overproduction of DHF reductase Altered affinity of reductase

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Trimethoprim: pharmacokinetics

Usually given orally alone or in combination with sulfamethoxazole

Mainly excreted into urine

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Clinical use Oral trimethoprim

Acute urinary infection Oral trimethoprim-sulfamethoxazole

Pjiroveci pneumonia, shigellosis, systemic salmonella infection, complicated urinary tract infection,

Active against many respiratory pathogens Intravenous trimethoprim-sulfamethoxazole

Gram negative sepsis, pneumocystis pneumonia Shigllosis, typhoid fever

Oral pryrimethamine with sulfanamide With sulfadiazine in Leishmaniasis, toxoplasmosis With sulfadoxine in malaria

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Adverse effects

Megaloblastic anemia Leukopenia, granulocytopenia Can be prevented by folinic acid The AIDS patients have high frequency of

unwanted reactions

COTRIMOXAZOLE

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

Septran, Sepmax, Bactrim, Ciplin

80mg + 400mg tab: 2 BD for 2 days

160mg + 800mg tab (DS): 1 BD

Synergism

ADVANTAGES

Expanded number of organisms inhibited.

Bactericidal .

Decreased resistance.

Decreased toxicity.

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BRANDS AVAILABLE IN MARKET

SILVEZ ( silver sulfadiazine 1% w/w ) Topical used, Laborate

ALBUCID(Sulphacetamide 10% ointment, 10-30% eye drop ) opthalmic , Allergan

AUBRIL ( Sulphadiazine 410 mg + Trimethoprim 90 mg) Tablet, Novartis Pharma

AMALAR ( Sulfadoxine 500 mg + Pyrimethamine 25 mg) tablet, Micro

SEPTRAN ( Sulfamethoxazole + Trimethoprim 80 mg) tablet, GSK

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REFERENCE

Rang H.P; Dale M.M; etal “ Rang and Dale’s Pharmacology, 7th edition, p.no 622-625

Tripathi K.D. “Essentials of Molecular Pharmacology” 6th Edn. P.no 682-687

Goodman & Gillman, “ The Pharmacological Basis of Therapeutics”, 12th edn

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