The document discusses a group project on sulfonamides. It includes information on various sulfonamide drugs including trimethoprim, cotrimoxazole, sulfasalazine, and sulfadiazine. For each drug, it summarizes the mechanism of action, pharmacokinetics, uses, and adverse effects. It also discusses resistance to sulfonamides and future goals in developing new molecules that target the pterin binding site rather than the PABA binding site targeted by current sulfonamides.
3. TRIMETHOPRIM
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Trimethoprim is an antibiotic used to treat
bacterial infections.
It is an anti-folate drug.
Often combined in a single pill with
sulfamethoxazole. (co-trimaxozole)
It was first used in 1962.
5. Pharmacokinetics
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Peak concentrations in the circulation occur
about 1-4 hours after an oral dose.
Approximately 40-70% is bound to plasma
proteins.
The half life is approximately 8-10 hours.
About 40-60% of a dose is excreted
unchanged in the urine within 24 hours,
together with metabolites.
6. Mechanism of action:
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Trimethoprim binds to dihydrofolate reductase
and inhibits the reduction of dihydrofolic acid
(DHF) to tetrahydrofolic acid (THF).
THF is an essential precursor in the thymidine
synthesis pathway and interference with this
pathway inhibits bacterial DNA synthesis.
Trimethoprim's affinity for bacterial
dihydrofolate reductase is several thousand
times greater than its affinity for human
dihydrofolate reductase
8. Resistance
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Presence of altered dihydrofolate reductase
with lower affinity for trimethoprim.
Overproduction of the enzyme dihydrofolate-
reductase enzyme.
Decrease drug permeability.
9. Medical uses
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Resistance to trimethoprim is increasing,
but it is still a first line antibiotic in many
countries.
Treating bacterial infections of the urinary
tract.
Preventing recurrent bacterial infections of the
urinary tract.
Treating bacterial infections of the lungs and
airways (respiratory tract), eg acute bronchitis,
flare-ups of chronic bronchitis or pneumonia
caused by the bacterium Pneumocystis
jirovecii.
10. Adverse effects
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Nausea, vomiting.
The blood disorders : can be reversed by
the simultaneous administration of folinic
acid, which does not enter bacteria.
Megaloblastic anemia due to folate
deficiency
Known hypersensitivity to trimethoprim
12. COTRIMOXAZOLE
A combination of
Sulfamethoxazole and
Trimethoprim.
It consists of one
part trimethoprim to five
parts sulfamethoxazole.
Bactericidal
COTRIMOXAZOLE
STRUCTURE
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13. MECHANISM OF ACTION
Sulfamethoxazole, a sulfonamide, induces its
therapeutic effects by interfering with
synthesis of folate inside microbial organisms
such as protozoa, fungi and bacteria.
It does this by competing with p-
aminobenzoic acid(PABA) in the biosynthesis
of dihydrofolate.
Trimethoprim serves as a competitive inhibitor
of dihydrofolate reductase (DHFR), hence
inhibiting the synthesis of tetrahydrofolate.
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15. SPECTRUM OF ACTION
Trimethoprim have same spectrum as
sulphamethoxazole
Effective against Salmonella typhi, Enterobacter,
E. Coli etc.
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16. RESISTANCE TO
COTRIMOXAZOLE
The bacteria acquire a Dihydro folate
reductase having lower affinity for the
inihibitor through mutation. This makes them
resistant to cotrimoxazole.
However , resistance to cotrimoxazole
develops slowly.
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17. PHARMACOKINETICS
Orally effective
Both drugs have almost similar half lives
(10~12h)
TMP more lipophilic.
TMP is partly metabolized in liver
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18. USES
UTI
Respiratory tract infections
It also used for treating bacterial diarrhoeas and
dysentry.
ADVERSE EFFECTS
Nausea, vomiting headache, and rashes are
common side effects.
Megaloblastic anemia may occur occasionally.
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20. Sulfasalazine
Sulfonamide drug , Poorly absorbed from GIT,
hence used in treatment of IBD ( Ulcerative
Colitis) ,regional enteritis and as antibiotic ( X
Folate synthesis).
1930s by Dr. Nana Svartz (Swedish
Rheumatologist) for the treatment of “infective
polyarthritis”
Sulfasalazine is preferred in patients with mild
infection.
Sulfasalazine consists of 5-aminosalicylic acid
and sulfapyridine joined by an azo-bond.
Marketed under the trade name Azulfidine
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21. Mechanism Of Action:
Sulfasalazine is broken down by the GI bacteria
into two compounds:
a) Sulfapyridine :(cause of adverse / toxic
effects)
b) 5-aminosalicylat :(Active agent against IBD)
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22. Mechanism Of Action of
Sulfonamides
Competitive antagonists of PABA. Hence
they interfere and prevent the normal
utilization of PABA for the synthesis of Folic
Acid (Pteroylglutamic Acid).
More Specific: Pteridine + PABA
Sulfasalaz
ine
Dihydroptero
ate
Synthetase
Dihydropteroic
Acid
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24. Sulfasalazine
Common Side Effects:
Rare Side Effects:
Note: sulfasalazine can cause
reversible infertility in males due to
change in sperm number and24
28. Why is it necessary for all the
sulfonamides to be the analog of
PABA
Dihydropteorate synthase has two binding sites
Pterin binding pocket
PABA binding pocket
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29. Normal mechanism
When drug binds to the the PABA binding site it
forms sulpha pterin product and the further
reaction starts.
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30. Resistance mechanism
PABA can be produced by hydrolysis of
procaine
mutations to residues which lie within the
second loop region
i-e Y63 (insertion of a tyrosine residue at
position 63)
GS60 (insertion of a Gly-Ser dipeptide
beginning at position 60)
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31. Future goals
To identify molecules that occupy the pterin
binding pocket which is distinct from the pABA
binding pocket that binds sulfonamides.
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BRAND NAME : PRIMSOL
In order to grow and multiply in numbers, bacterial cells need to produce genetic material (DNA). To produce DNA they require folic acid (folate). However, bacterial cells can't take up folic acid supplied in the diet like human cells can. Instead, they synthesise it themselves.
Trimethoprim works by preventing the bacteria from producing folate. Without folate, the bacteria cannot produce DNA and so are unable to increase in numbers. Trimethoprim therefore stops the spread of infection. The remaining bacteria are killed by the immune system or eventually die.
CAN BE USED FOR BOTH AEROBIC GRAM POSITIVE GRAM NEGATIVE.
Combination shows greater anti-microbial activity.
Trimethoxy-benzyle pyrimidine
Sulphamethoxazole
Overdose : gastric lavage and forced alkaline diuresis may be used.
