A Power point presentation on "Sulfonamides and cotrimoxazole" suitable for undergraduate level medical student and others

1. SULFONAMIDES & COTRIMOXAZOLE
Dr. D. K. Brahma
Associate Professor, Pharmacology
NEIGRIHMS, Shillong

2. Sulfonamides
• The first antimicrobials effective against Pyogenic Bacterial
infections.
• Derivatives of Sulfanilamide containing a “sufonamido “ring
(SO2NH2).
• Structurally and chemically related to p-aminobenzoic acid
(PABA).
• Structurally similar to many drugs – thiazides, acetazolamide,
dapsone and sulfonylureas etc.
• Physically – available as white powder, mildly acidic and form
water soluble salts with bases.
• However, indications and practical uses are very few these
days.

3. History –
Sulfonamides
• Screening of “Dyes” for their antibacterial properties in 1920s.
• Sulfonamido-chrysidine – commonly known as “Prontosil red”
was the first one effective in streptococcal infection in mice by
Domagk.
– Cured his daughter
• 1937: Prontosil was broken down to release “sulfanilamide” –
many sulfonamides were produced.
Para-amino-benzene-sulfonamide
(sulfanilamide)
Prontosil

4. Sulfonamides - Classification
• Short acting: Sulfadiazine, Sulfadimidine,
Sulfacetamide
• Intermediate acting: Sulfamethoxazole
• Long acting: Sulfadoxine,
Sulfamethoxypyrazine, Sulfadimethoxine etc.
• Topically used: Mafenide, Silver sulfadiazine
and Sulfacetamide
• Ulcerative colitis: Sulfasalazine

5. Sulfonamides – Antibacterial Property
• Bacteriostatic against gm +ve and gm –ve bacteria
• Bactericidal in urine
• Susceptible organisms: Str. pyogens, H. influenzae, H.
ducreyi, Callymatobacterium grannulomatosis, V. cholerae,
Chlamydia, Actinomyces etc.
– Few strains of Staph aureus, gonococci, meningococci,
pneumococci, E. coli and Shigella
• Chlamydiae: trachoma, lymphogrnuloma venereum.,
inclusion conjunctivitis. Also Actinomyces and Nocardia
• Protozoa:
– Plasmodium (Sulfadoxine + Pyrimethamine)
– Toxoplasmosis (Sulfadiazine + Pyrimethamine)
– PCP (Sulfamethoxazole + Trimethoprim = SXT)

6. Sulfonamides - MOA
Woods and Fielde`s Theory:
 Bacteriae normally picks up
PABA from surroundings to
synthesize folic acid
 Inhibition of bacterial folic
acid synthesis from PABA
(enzyme folate synthase) –
competitive
 Essential metabolic
reactions suffer
Why no human affect??
Preformed folic acid by human.
Evidence of MOA: PABA
antagonizes Sulfonamides, only
the organisms synthesizing FA
Dihydropteroic acid
Dihydrofolic acid
Enzymes: Pteridine synthetase and
Dihydrofolate synthetase

7. Sulfonamides – MOA image

8. Sulfonamides - Resistance
• Many strains – S. aureaus, pneumococci, gonococci,
meningococci, Strep. Pyogens, E. coli and Shigella
• Mechanism:
1. Production of increased amounts of PABA (Staph,
Neisseria)
2. Folate synthase enzyme has low affinity to sulfonamides
3. Adopt alternative pathway of folate synthesis – structural
changes in folate synthase (E coli) – encoded
chromosomally and plasmid mediated
• Resistant to one sulfonamide – resistant to all
• No cross resistance

9. Sulfonamides – Kinetics
• Rapidly and completely absorbed from GIT
• Extend of plasma protein binding differs (10 – 95%)
– Longer acting ones are highly plasma protein bound
– Widely distributed – enters in serous cavity easily
• Metabolized by non microsomal acetyl transferase in
liver – slow and fast acetylators
• Acetylated product – inactive excreted in urine (but,
more toxic than parent) – crystalluria
• Acetylated form accumulates in blood – toxic in renal
faiure
• Reabsorbed in tubule

10. Sulfonamides - ADRs
• Nausea, vomiting and epigastric pain
• Crystalluria – alkanization of urine
• Hypersensitivity (2 – 5%) – rashes, urticaria,
drug fever. Exfoliative dermatitis, SJ syndrome
(long acting ones)
• Hepatitis
• Haemolysis – G-6-PD deficiency
• Kernicterus – displacement of bilirubin

11. Individual Sulfonamides
• Sulfadiazine: General purpose use – absorbed orally and rapidly
excreted. More crystalluria. Preferred in meningitis.
• Sulfamethoxazole: slower absorption and lower excretion. 10 Hrs.
half life. Combination with Trimethop
• Sulfadoxine:Ultra-long acting >1 week. High protein bound – long
excretion. Not suitable for Pyogenic infections – low plasma conc..
Used in Malaria, Pneumocystis jiroveci and toxoplasmosis
• Sulfacetamide: Ophthalmic use – infections by bacteria, chlamydia,
ophthalmia neonatorum etc
• Mafendie: Atypical sulfonamide. Local application – inhibits variety
of bacteria – active in presence of pus – pseudomonas and
clostridia
• Silver sulfadiazine: Bacteria, fungi, Pseudomonas. In burn cases

12. Sulfonamides - Uses
• Rarely used now a days systemically
• UTI: caused by E. coli and P. mirabilis: Sulfisoxazole – 1 gm 4
times daily
• Malaria: sulfadoxine and pyrimethamine combination
• Toxoplasmosis: sulfadiazine + pyrimethamine
• In Combination with Trimethoprim: Cotrimoxazole
• Ulcerative colitis: Sulfasalazine – 1-4 gm initially and 500
mg 6 Hrly.
• Locally:
– Sodium sulfacetamide: 10-30% ophthalmic solution in bacterial
conjunctivitis, trachoma etc.
– Mafenide acetate (1% cream) and Silver sulfadiazine 1% cream):
Burn dressing and chronic ulcers

13. Cotrimoxazole – In 1969
Fixed drug combination of
Sulfamethoxazole and Trimethoprim
SYNERGISM

14. Trimethoprim
• Trimethoprim (trimethyl benzyl pyrimidine) is a
diaminopyrimidine, chemically related to
Pyrimethamine
• Do not confuse: Clotrimazole (antiungal) -
Cotrimoxazole is TMP –SMZ, but Sulfadoxine +
Pyrimethamine is antimalarial
• MOA: Sequential block of folate metabolism
• Trimethoprim is 50,000 or more times more
active against bacterial DHFRase enzyme than
mammalian
• So, no harm to human folate metabolism

15. Tetrahydropteroic acid synthetase
Dihydrofolic acid
Dihyrofolate reductase
Tetrahydrofolic acid
Purine synthesis
DNA synthesis
Sulfonamides
Trimethoprim
MOA OF TRIMETHOPRIM-SULFAMETHOXAZOLE
1.Sulfamethoxazole
inhibits dihydrofolate
synthase.
2.Trimethoprim inhibits
dihydrofolate reductase.
PABA

16. Cotrimoxazole – general points
• Individually, both are bacteriostatic, but combination is –
bactericidal
• Both drugs have almost similar half lives (10 Hrs)
• Maximum synergism if the organism is sensitive to both the agents
• Optimal synergism is obtained at 20 (S) : 1 (T) concentration (MIC of
both is reduced by 3 - 6 times)
– This ratio is obtained at 5:1 dose ratio ( e.g. 800 mg:160 mg)
– Because TMP has large Vd and enters many tissues – plasma conc. is
low
• But, TMP crosses BBB and placenta and SMZ not
• TMP is more rapidly absorbed than SMZ
• TMP is 45% plasma protein bound but SMZ is 65% bound
• TMP is partly metabolized in liver

17. Cotrimoxazole – antibacterial
spectrum
• Similar to sulfonamides
• Additional benefits: Salmonella typhi, Serratia,
Klebsiella Enterobacter, Yersinia and
Pneumocystis jiroveci
– Sulfonamides resistance strains of S. aureus, E. coli,
gonococci, meningococci and H influenzae
• RESISTANCE: Slow to develop
– By mutational changes or plasmid mediated
acquisition of a DHFRase enzyme having lower affinity
for the inhibitior.

18. Cotrimoxazole - ADRs
• All adverse effects of sulfonamides – nausea, vomiting, stomatitis,
rash etc
• Folate deficiency (megaloblastic anaemia) – patients with marginal
folate levels
• Blood dyscrasias
• Pregnancy: teratogenic risk, Neonatal haemolysis and
methaemoglobinaemia
• Patients with renal disease may develop uremia
• Fever, rash and bone marrow hyperplasia
• Elderly – risk of bone marrow toxicity from cotrimoxazole
• Diuretics given with cotrimoxazole have produced a higher
incidence of thrombocytopenia
• Bone marrow hypoplasia among AIDS patients with Pneumocystis
jiroveci infection

19. Cotrimoxazole - Uses
• Uncomplicated infection of the lower urinary tract infection
– Cystitis (5 tablet dose)
– chronic and recurrent urinary tract infections (including
enterobacteriaceae) – 3-10 days
• Respiratory tract infection – lower and upper, chronic bronchitis,
facio-maxillary infections, otitis media due to gm+ve cocci and H
influenzae etc
• Typhoid
• Bacterial diarrhoeas & dysentery: due to campylobacter, E coli,
Shigella etc.
• Pneumocystis jiroveci: Severe pneumonia - Prophylactic use in AIDS
patients with neutropenia. Dose – DS tablet 4-6 times 2-3 weeks
• Chancroid – H. ducreyi
• Alternative to penicillin in agrannulocytosis patients, scepticaemia
etc.

20. Must Know
• Classification of Sulfonamides – examples of
some Sulfonamides
• Uses of some selected Sulfonamides
• Cotrimoxazole – as a whole
• Rationale of combinations – Cotrimoxazole
and Sulfadoxine + pyrimethmine

21. Take Home …….
Students (Sulfonamides)
+
Teachers (Trimethoprim)
• Similar half lives (10 Hrs) – human being
• Both are bacteriostatic – combination is bactericidal - alone nothing - together can
make difference
• Synergism is obtained at 20 (S) : 1 (T) concentration (MIC of both is reduced by 3 -
6 times)
– This ratio is obtained at 5:1 dose ratio ( e.g. 800 mg:160 mg)
– Because TMP has large Vd and enters many tissues – plasma conc. is low
– teachers effort
• Optimal synergism if the organism is sensitive to both the agents – have to reciprocate each
other
• Combination - Lesser toxic (trimethoprim) - have to monitor
• Alone (trimethoprim) - sometimes have to act

22. Thank you