Sulfonamides and trimethoprim
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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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