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

•       -NH₂
group 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