Topic describes pharmacological accepts of Sulfonamides, trimethoprim and co-trimoxazole

1. Sulfonamides and Trimethoprim
S. Parasuraman, M.Pharm., Ph.D.,
Senior Lecturer, Faculty of Pharmacy
AIMST

2. Sulfonamides
Sulfonamide = Sulfone + amide
Sulfonamides derivative of p-amino-benzene sulfonamide are commonly
referred as sulfa drugs.
1932: Gerhard Domagk discovered sulfonamido-chrysoidine (Prontosil Red-
dye)
In 1933: First clinical case study reported presented
prontosil (pro-drug): active against streptococcal infection in 10-moth-old
infant.
In 1937: Prontosil is a pro-drug. After metabolism prontosil converted into
sulfanilamide which was the active antibacterial agent (excepts
combinations).
1969- Combinations
E.g.: sulfonamide + trimethoprim (cotrimoxazole) and sulfonamide +
trimethoprim
Discovery of sulfonamides: a milestone event in the discovery of AMAS

3. Basic Structure of sulfonamide

4. Classification of sulfonamides
• Short acting (4-8 h): Sulfadiazine
• Intermediate acting (8-12 h): Sulfamethoxazole
• Long acting ( ~ 7 days): Sulfadoxine, Sulfamethopyrazine
• Special purpose sulfonamides: Sulfacetamide sodium,
Mafenide, Silver sulfadiazine, Sulfasalazine

5. Antibacterial spectrum of sulfonamides
• Primary bacteriostatic against many gram-positive and gram-
negative bacteria. In higher concentration it may be act as
bactericidal.
• Sensitivity patterns among microbes changed time-to-time
and place-to-place. Sulfonamides are sensitive to
Streptococcus pyogenes, Haemophilus influenza, Vibrio
cholerae.
• Sulfonamides are primarily used to prevent urinary tract
infections.

6. N
N
N
N
Pteridine
H2N
O
H
N
H
N
O
COOH
COOH
PABA Glutamic acid
Folic acid
Mechanism of action

7. N
N
N
N
Pteridine
H2N
O
H
N
H
N
O
COOH
COOH
PABA Glutamic acid
Folic acid
Mechanism of action

8. Mechanism of action
• Bacteria synthesize their own folic acid
(FA) of which p-aminobenzoic acid (PABA)
is a constituent, and is taken up from the
medium.
• Sulfonamides, are structural analogues of
PABA, inhibit bacterial folate synthase
and formation of folate get inhibited.
• Sulfonamides competitively inhibit the
PABA with pteridine residue to form
dihydropteroic acid which conjugates
with glutamic acid to produce
dihydrofolic acid.
• Sulfonamide altered folate an which is
metabolically injurious
Pteridine +
p-Aminobenzoic acid (PABA)+
Glutamic acid
Dihydropteroic acid
Dihyderopteroate
synthetase
Glutamate
Dihydrofolic acid
Tetrahydrofolic acid
DNA
Sulfonamides
Dihydrofolate
reductase

9. Mechanism of action
Cont.,
• Sulfonamides will affect the Human folic acid synthesis?
 Human cells also require FA, but they utilize preformed FA supplied
in diet and are unaffected by sulfonamides.
 Only those microbes which synthesize their own FA and cannot take
it from the medium are susceptible to sulfonamides.

10. Resistance to sulfonamides
• Most bacteria are capable of developing resistance to
sulfonamides. E.g.: gonococci, pneumococci, Staph. aureus,
meningococci, E. coli, Shigella, Strep. pyogenes, Strep. viridans
and anaerobes.
• Bacterial resistance to sulfonamide presumably originates by
mutation or by transfer of resistance by plasmids.
• The resistant mutants either:
(a) produce increased amounts of PABA, or
(b) Microbes folate synthase enzyme has low affinity for sulfonarnides
(c) adopt an alternative pathway in folate metabolism
• When an organism is resistance to one sulfonamide, it is
resistance to all sulfonamide. No cross resistance. Resistance
limited to clinical case component.

11. Pharmacokinetics
• Sulfonamides are
– usually not given topically, because of the risk of
sensitization and allergic reactions
– readily absorbed in the G.I.T and reach maximum
concentrations in the plasma in 4-6 h
– cross the placental and blood-brain barriers and available
free in inflammatory site
– metabolised in liver by acetylation (N-acetylation)
– excreted by the kidney through glomerular filtration
(Metabolites are insoluble in urine, hence crystalluria can occur)

12. Sulfadiazine (Short acting sulfonamide)
• Absorption: Rapid oral absorption. It has good penetrability in
brain and CSF-was the preferred compound for meningitis.
• Metabolism: Liver by acetylation. It is 50% plasma protein
bound and 20-40% acetylated.
• Excretion: Trough urine. The acetylated derivative is less
soluble in urine, crystalluria is likely.
• Dose: 0.5 g QID to 2 g TDS; oral tablets

13. Sulfamethoxazole (Intermediate acting)
• Absorption: Slow oral absorption. It is the Preferred
compound for combining with trimethoprim because the t1/2
of both is similar.
• Metabolism: Liver by acetylation.
• Excretion: Trough urine. Acetylated fraction of
sulfamethoxazole is relatively insoluble- crystalluria can occur
• Dose: 1 g BD for 2 days, then 0.5 g BD; oral tablets

14. Sulfadoxine, Sulfamethopyrazine
(Long acting)
• These are ultralong acting compounds, action lasting > 1 week
because of high plasma protein binding and slow renal
excretion (t1/2 5-9 days).
• They attain low plasma concentration (of free form) and are
not suitable for treatment of acute pyogenic infections. They
are used in combination with pyrimethamine in the treatment
of malaria, (especially chloroquine resistant P. falciparum),
Pneumocystis jiroveci pneumonia in AIDS patients and in
toxoplasmosis. Because they have caused serious cutaneous
reactions, large-scale use of the combination for prophylaxis
of malaria is not recommended.

15. Sulfacetamide sodium
(Special purpose sulfonamides)
• Highly soluble compound - Mildly irritating to the eye
(concentrations up to 30%).
• Used topically for ocular bacterial infections and chlamydia,
including ophthalmia neonatorum caused by chlamydial
oculogenitalis. Incidence of sensitivity reactions with ocular
use has been low, but it must be promptly stopped when they
occur.
• Dose: 10%, 20% and 30% eye drops.

16. Sliver sulfadiazine
(Special purpose sulfonamides)
• Its act against large number of bacteria and fungi, even those
resistance to other sulfonamides (e.g.: Pseudomonas).
• Slow releases silver ions which appear to be largely
responsible for the antimicrobial action.
• Most effective drugs for preventing infection of burnt surfaces
and chronic ulcers (skin). However, it is not good for treating
established infection.
• Dose: 1% cream
• Local side effect: burning sensation and itching.

17. Adverse effects
• Adverse effects to sulfonamides are relatively
common. Sulfonamides
– produce mild-to-moderate nausea, vomiting,
headache and mental depression
– produce hypersensitivity reactions (rashes, fever,
eosinophilia)
– Rarely cause Stevens-Johnson syndrome, erythema
multiforme associated with lesions of skin and
mucous membranes
– Produce kenicterus (bilirubin-induced brain
dysfunction) in neonates because of the
displacement of bilirubin form serum albumin
binding site
– Sever adverse effects includes hepatitis, bone
marrow depression and crystalluria.
– In person with glucose-6-phosphate dehydrogenase
deficiency, sulfonamide can cause hemolytic aplastic
anemia.
Stevens-
Johnson
syndrome

18. Interactions
• Sulfonamides inhibit the metabolism of phenytoin,
tolbutamide and warfarin.

20. Trimethoprim
• Trimethoprim is a bacteriostatic antibiotics.
• Trimethoprim is diaminopyrimidine related pyrimethamine (folate
antagonist), which is selectively inhibits bacterial dihydrofolate
reeducates (DHFRase).
• Trimethoprim is >50,000 times more active against bacterial
DHFRase than against the mammalian enzyme.
• Used for treatment of urinary track and respiratory infections.
• Trimethoprim is weak base and is concentrated in acidic prostate
tissue and vaginal fluids via ion trapping, so it is useful for the
treatment of bacterial prostatitis and vaginitis.

21. Spectrum of activity
• Trimethoprim is a bacteriostatic antibiotics. It is active against many
aerobic gram-negative bacilli and a few gram-positive organism.
• sulfonamide and trimethoprim are bacteriostatic, but the
combination becomes bactericidal against many organisms.
Pharmacokinetics
• Given orally, fully absorbed in the gastrointerstinal tract and widely
distributed throughout the tissue and body fluid (t1/2=10h).
• Reaches high concentration in lungs and kidneys.
• Trimethoprim is partly metabolized in liver and excreted in urine.
Adverse effect
• Nausea, vomiting, skin rashes
• Folate deficiency, results megaloblastic anemia.
• Trimethoprim effect can be prevented by folinic acid.

23. Cotrimoxazole
• The fixed dose combination of trimethoprim and
sulfamethoxazole is called cotrimoxazole.
• Cotrimoxazole introduced in 1969 to block the bacterial
folate metabolism (sequential)
• Both the compounds are bactriostatic, but the
combination becomes cidal against many pathogens.
Maximum synergism is seen when the organism is
sensitive to both the compound.

24. Cotrimoxazole
• Sulfamethoxazole was selected
for combining with trimethoprim
because both have nearly the
same t1/2 (~10 h).
• Optimal synergy in case of most
organisms is exhibited at a
concentration ratio of
sulfamethoxazole: trimethoprim
(20:1), the MIC of each
component may be reduced by 3-
6 times.
Pteridine +
p-Aminobenzoic acid (PABA)+
Glutamic acid
Dihydropteroic acid
Dihyderopteroate
synthetase
Glutamate
Dihydrofolic acid
Tetrahydrofolic acid
DNA
Sulfonamides
TrimethoprimDihydrofolate
reductase

25. Cotrimoxazole
• Dose ratio of sulfamethoxazole: trimethoprim is 5:1. The 5:1 dose
ratio produce a 20:1 plasma concentration ratio because
trimethoprim has a grater volume of distribution than does
sulfamethoxazole.
• Trimethoprim adequately crosses blood-brain barrier and placenta,
while sulfamethoxazole has a poorer entry.
• Trimethoprim is more rapidly absorbed than sulfamethoxazole and
the concentration ratios may vary with time. Trimethoprim is 40%
plasma protein bound, while sulfamethoxazole is 65% bound.

26. Spectrum of activity
• Exhibits bactericidal activity
• Active against Salmonella typhi, Serratia, Enterobacter,
Pneumocystis and many sulfonamide resistant strains of Staph.
aureus, Staph. Pyogenes, shigella, E. coli, infuenzae, gonococci and
meningococci.
Resistance
• Bacteria are acquiring resistance to trimethoprim through
mutational or plasmid mediated acquisition of DHFRase
having lower affinity. Combinations reduced responsiveness
of over 20% originally sensitive strains.

27. Uses
• Urinary tract infections: Used to prevent or treat urinary tract
infections or prostate infections. singe dose therapy with 4 tablets
for acute cystitis. Courses of 3 -10 days have been advised for lower
and upper UTI.
• Respiratory tract infections: Upper and lower respiratory tract
infections (chronic bronchitis and facio-maxillary infections) and H.
influenzae. Drug of choice for respiratory infection caused by
Pneumocystis jiroveci and Nocardia asteroides.
• Typhoid
• Bacterial diarrheas and dysentery
• Pneumonia (caused by Pneumocystis jiroveci)
• Chancroid (bacterial sexually transmitted infection)

28. Adverse effect
• All adverse effects seen with sulfonamides can be produced
by cotrimoxazole.
• Folate deficiency (megaloblastic anemia)
• Blood dyscrasias occurs rarely.
Caution
• Should not given during pregnancy (Neonatal haemolysis and
methaemoglobinaemia can occur)
• Elderly people are having grater risk of development of bone
marrow toxicity
• Patient with renal disease may develop uremia, dose must be
reduced renal impairment patients

29. Thank you