Sulfonamides and Cotrimoxazole

Sulfonamides and Cotrimoxazole

Content

Sulfonamides and Cotrimoxazole

•       Classification

•       Mechanism of action

•       Pharmacokinetics

•       Drug interactions

•       Clinical uses

Objectives

At the end of this session, students will be able to:

•       Classify sulfonamides

•       Describe the mechanism of action of sulfonamide and cotrimoxazole

•       Outline the adverse effects of sulfonamides and cotrimoxazole

•       Discuss the therapeutic uses of sulfonamide and cotrimoxazole

Sulfonamides and Cotrimoxazole

•       Sulfonamides are structural analogues of p-amino benzoic acid (PABA)

•       Obtained from sulphanilamide

•       -NH₂group is responsible for antibacterial property

Classification of sulfonamides

Orally absorbable agents

•       Short acting sulfonamides (t_1/2 6-9 h)

–      Sulfacystine, Sulfadiazine, Sulfisoxazole and Sulfamethizole

•       Intermediate acting sulfonamides (t_1/2 10-12 h)

–      Sulfamethoxazole and Sulfamoxole

•       Long acting sulfonamides (t_1/2 7-8 days)

–      Sulfadoxine

Orally non absorbable agents

•       Sulfasalazine

•       Olsalazine

•       Balsalazine

Topical agents

•       Silver sulphadiazine

•       Mafenide

•       Sulfacetamide

Mechanism of action

•       Bacterium synthesizing its own folic acid are more susceptible

•       Inhibits formation of tetra hydro folic acid

•       Sulfonamides are structurally similar to PABA

•       May lead to synthesis of false folic acid

•       False folic acid metabolically injurious to bacteria

Mechanism of action of sulfonamides 

•       Antibacterial effect of sulfonamides can be overcome if excess of PABA is present (Puss)

•       Puss contains tissue breakdown product thymidine

•       Thymidine could be used by bacteria to bypass the need of folic acid

Cotrimoxazole

•       Combination of sulfamethoxazole + trimethoprim (5:1)

•       Has wider spectrum of activity

•       Delays development of bacterial resistance

•       Synergistic action is due to blockade of folic acid syntheis at two sites

•       Sulfonamides inhibits dihydropteric acid synthase

•       Trimethoprim inhibits dihydrofolate reductase

Antimicrobial spectrum

•       Bacteriostatic to gram positive and gram negative

•       Attain bactericidal concentration in urine than in body fluids

Susceptible organisms

E. coli, Shigella, Salmonella, Haemophillus influenzae, Vibrio cholerae, Proteus, Neisseria gonorrhoeae, N. meiningitidis, Actinomycetes, Rickettsiae, Toxoplasma gondii

Resistance

Mutations leading to

•       Overproduction of PABA

•       Alteration in the nature of DHP synthase enzyme

•       Increased capacity to inactivate the drug

•       Inhibition of drug accumulation

•       Alternate metabolic pathway for the synthesis of essential nutrients

Pharmacokinetics

•       Well absorbed when given orally

•       Peak plasma concentration attained in 4-6 hours

Distribution 

–       well distributed

–      10-95% plasma protein bound

–      In unbound form enters into body fluids like pleural, peritoneal and synovial

–      Sulphdiazine & Sulfisoxazole – enters CSF

Metabolism

•       In liver

•       By acetylation

•       Acetylated derivative responsible for side effects

•       Accumulates in acidic urine – crystalluria

Excretion – Kidneys

Pharmacokinetics of cotrimoxazole

•       Attains plasma concentration ratio of 20:1

•       Trimethoprim – high entry into tissues ; less available in plasma

•       Metabolised in liver

•       Excreted through kidneys

•       Half-life is 10 h

•       Peak plasma level – Trimethoprim – 2 h and Sulphamethoxazole – 4 h

Adverse effects

•       Nausea, Vomiting, epigastric pain, crystalluria

•       Haemolytic anaemia, Agranulocytosis and aplastic anaemia

•       Hypersensitivity reactions

•       Kernicterus – bilirubin deposited in brain- encephalopathy (new born)

•       Contraindicated in pregnant women and lactating mothers

Drug interactions

•       Sulfonamides are enzyme inhibitors

•       Inhibit the metabolism of certain drugs

•       Increases activity of

–      Oral anticoagulants

–      Sulfonyl ureas (Antidiabetics)

–      Anticonvulsants

Clinical uses

Orally absorbable sulfonamides

•       Acute uncomplicated UTI – sulfisoxazole

•       Gum infection

•       Streptococcal pharyngitis

Topical

•       Sodium sulfacetamide – eye drops in conjuctivitis

•       Silver sulfadiazine – infection – in burn cases

•       Mefanide – effective against gram positive and gram negative bacteria

Sulfasalazine – Ulcerative colitis

Cotrimoxazole

•       Chronic UT infection

•       Bacterial respiratory infection – chronic bronchitis

•       GI infections- Typhoid, bacterial dysentry, diarrhoea 

•       Prostrate inflammation

•       STDs

•       Pneumonia

Summary

•       Sulfonamides are structural analogues of p-amino benzoic acid (PABA) obtained from sulphanilamide

•       Sulfonamides show antibacterial action via inhibition of THFA formation

•       Sulfonamides are classified based on duration of action into short acting, Intermediate acting and long acting sulfonamides

•       Cotrimoxazole is a synergistic combination of sulfanethoxazole and trimethoprim - used in the treatment of many infectious diseases

 

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