PHARMACOLOGY-III (BP-602T)

UNIT-II
CHEMOTHERAPY

SULFONAMIDES &
COTRIMOXAZOLE
 Sulfonamides

• The first antimicrobials effective against Pyogenic Bacterial

infections.
• Derivatives of Sulfanilamide containing a “sulfonamido “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.
 History – Sulfonamides

• Screening of “Dyes” for their antibacterial properties in

1920s. Domagk used Prontosil dye for bacterial infections.
• Sulfonamido-chrysidine – commonly known as “Prontosil
red” was the first one effective in streptococcal infection
in mice.
• 1937: Prontosil was broken down to release
“sulfanilamide” – many sulfonamides were produced.

Prontosil Para-amino-benzene-sulfonamide
(sulfanilamide)
4 1
 Sulfonamides - Classification
• Short acting (4-8 h): Sulfisoxazole,
Sulfamethiazole
• Intermediate acting (8-12 h): Sulfamethoxazole,
Sulfadiazine
• Long acting (>7 days):
Sulfadoxine,Sulfamethoxypyrazine
• Topically used: Mafenide, Silver sulfadiazine and
Sulfacetamide sodium
• Ulcerative colitis: Sulfasalazine
Sulfonamides – Antibacterial Property
• Bacteriostatic against gm +ve and gm –ve bacteria
• Bactericidal in urine
• Susceptible organisms: Str. pyogens, H. influenzae, H.
ducreyi, Calymatobacterium granulomatosis, V.
cholerae, Chlamydia, etc.
– Few strains of Staph. aureus, gonococci,
meningococci, pneumococci, E. coli and Shigella
• Chlamydiae: Trachoma, lymphogranuloma
venereum., inclusion conjunctivitis. Also
Actinomyces and Nocardia
• Protozoa:
– Plasmodium (Sulfadoxine + Pyrimethamine)
– Toxoplasmosis (Sulfadiazine + Pyrimethamine)
 Sulfonamides - MOA
▪ Woods and Fielde`s Theory: Dihydrofolic acid
✓Bacteriae normally picks up
PABA from surroundings to
synthesize folic acid Dihydropteroic 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

Enzymes: Pteridine synthetase and

Dihydrofolate synthetase
Sulfonamides – MoA Flow-chart
 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
 Sulfonamides – P’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
 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
 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 Trimethoprim.
• 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
 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
Cotrimoxazole – In 1969
Fixed drug combination of
Sulfamethoxazole and Trimethoprim
SYNERGISM
 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
 MoA OF TRIMETHOPRIM
SULFAMETHOXAZOLE

PABA Pteridine
Sulfonamides Dihydropteroic acid synthetase

Dihydropteroic acid

Dihydrofolate synthetase
Dihydrofolic acid

Trimethoprim Dihydrofolate reductase

Tetrahydrofolic acid

Purine synthesis

DNA synthesis
 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
 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.
 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.
 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
 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
 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
THANK YOU