Sulphonamides

Sulfonamides
The first antimicrobial effective against Pyogenic
Bacterial infections.
Derivatives of Sulfanilamide containing a
sufonamido ring (SO2NH2).
Structurally and chemically related to paminobenzoic 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.

Sulfonamides - History
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
Prontosil
Para-amino-benzeneproduced.
sulfonamide (sulfanilamide)

1920s
Investigations into the antimicrobial properties of dyes
Prontosil emerged as a viable compound
metabolized to
Para-amino-benzene-sulfonamide (sulfanilamide)

1
4

N4 is essential for
antibiotic activity

Substitution at amide (N1) -By heterocyclic aromatic

nuclei yields highly potent compounds
(Eg.,
sulphamerazine, sulphadiazine & sulphadimidine)
SO2NH2 is not as such essential but S sh/be linked
to benzene ring directly.
Any substitution at benzene ring leads to loss of
antibacterial activity
Acetylation At N1 position = no change in
chemotherapeutic activity but water solubility
increase (less toxic) eg. Sulphaacetamide
Acetylation At N4 position decrease water solubility
(renal toxicity), may abolish antibacterial activity

Sulfonamides Classification
Short acting(<12hr): Sulfadiazine, Sulfadimidine,
Sulfacetamide
Intermediate acting(12-24hr):
Sulfamethoxazole
Long acting: Sulfamethoxypyridazine,
Sulphaethoxypyridazine, sulphadiaethoxine
Ultra Long acting(>48hr): sulphaoxine,
sulphamethopyrazine
Topically used: Mafenide, Silver sulfadiazine and
Sulfacetamide
Gut acting:
succinylsulphathiazole,phthalylsulphathiazole
Sulfasalazine & sulphaguanidine

Sulfonamides Antibacterial
Property
Bacteriostatic against gm +ve and gm ve bacteria
Bactericidal in urine
Susceptible organisms: S. pyogens, H. influenzae,
H. ducreyi, cholerae, Chlamydia, Bacillus,
Actinomyces etc.
Enterobacteriaceae, Clostridium, Leptospira &
Pseudomonas are resistant
Coccidia & Toxoplasma sensetive
Protozoa:
Plasmodium (Sulfadoxine + Pyrimethamine)
Toxoplasmosis (Sulfadiazine + Pyrimethamine)

Sulfonamides - MOA
Woods
and
Fielde`s
Theory:
Dihydrofolic
Bacteriae normally
acid
picks up PABA from
Dihydropteroic acid
surroundings
to
synthesize folic acid
Inhibition of bacterial
folic
acid
synthesis
from PABA (enzyme
folate
synthase)

competitive
Essential metabolic
reactions suffer
Why no human/animal Enzymes: Pteridine
synthetase and
affect??
Dihydrofolate synthetase
Preformed folic acid by

Sulfonamides MOA

Sulfonamides - Resistance
Many strains
S. aureaus, Gonococci,
Meningococci, Strep. Pyogens, E coli and Shigella
Mechanism:
Production of increased amounts of PABA (Staph,
Neisseria)
Folate synthase enzyme has low affinity to
sulfonamides
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

Sulfonamides Kinetics
Absorption- rapidly absorbed from GIT, except
gut acting sulfas
Available as bolus, tablets, feed mix, dispersible
powder
Sulfasalazine is broken to sulfapyridine and 5amino salicylic acid in colon (25mg/kg TID for 24 wks in dogs) used to treat chronic colitis
I/V- alkaline so slowly administer to prevent
shock and perivascular reaction and the I/M, S/C
preparations suitably buffered
Intrauterine treatment along with urea
increases solubility and inhibits reaction with
protein and neutralizes antagonists to sulfa

 Distribution - Exists predominantly in non ionized

form in biofluids- diffuses through the cell
membrane,cellular barriers-widely distributed in
CSF, Synovial fluid- variable binding to plasma
protein albumin- varies with species and
compounds. Highly binding increases the half life
because of acidic nature, low concentration in milkpassive diffusion limited use in mastitis
Metabolism - Liver - Acetylation - less soluble deposit in renal tubule, pelvis, ureter cause
crystalluria.
Aromatic hydroxylation and Glucoronide
conjucation makes more water soluble
Excretion Kidney glomerular filterate, tubular
secretion and reabsorption. Alkalinisation of urine
increases the solubility and elimination

Drug interaction
PABA antagonizes sulfonamides
Calcium
and
antacids
inhibits
absorption(decrease bioavailability)
Salicylates, indomethacin, probencid can
displace sulphonamide from their binding site
and can increase plasma concentration
Pus and tissue debris - rich in thymidine and
purines so bacterial requirement of FA is less.
Synergistic
with
diaminopyrimidines
Trimethiprim, ormethoprim,
Sulfonamides + chlortetracycline act as
Growth promoter prevent clostridial ET.

Sulfonamides - ADRs
Acute
Renal Toxicity
Blood dyscrasias
Hypersensetivity
reactions(2 5%)

Chronic Toxicity
Hypoprothombinaemia
Hepatic necrosis
Aplastic anaemia&
thrombocytopenia
Keratoconujnctivitis
sicca
Inhibition of Carbonic
anhydrase enzyme
Kernicterus

Sulfonamides - Uses
used via systemic route & topical route
UTI: caused by E. coli and P. mirabilis:
Sulfisoxazole 1 gm 4 times daily
Toxoplasmosis: sulfadiazine + pyrimethamine
Ulcerative colitis Sulfasalazine
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

Strong alkaline solution sh/not be given by

IM/SC route may cause severe tissue
irritation & sloughing

Principles to be followed in
therapy

Start therapy at early stage of infection

Ineffective in chronic cases
In severe infection administer by iv route
Administer adequate quantity of drinking water during
therapy
Alkalinisation of urine prevents crystalluria
Treatment should not exceed seven days
If no favourable response within four to five days,
discontinue the therapy
Treatment continued 48 hours after remission to prevent
recurrence for some cases
Immune response of the host should be well maintained

Cotrimoxazole
Potentiated
sulphonamides
Fixed drug combination of
Sulfamethoxazole and Trimethoprim
SYNERGISM

Trimethoprim
Trimethoprim (trimethyl benzyl pyrimidine) is a
diaminopyrimidine, chemically related to Pyrimethamine
Cotrimoxazole is TMP SMZ,
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 folate metabolism
Individually, both are bacteriostatic, but combination is
cidal
Maximum synergism if the organism is sensitive to both the
agents
1part (trimethoprim)+ 5 part sulphamethoxazole

MOA OF TRIMETHOPRIMSULFAMETHOXAZOLE
PABA
Sulfonami
des

Tetrahydropteroic acid synthetase

Dihydrofolic acid

Trimethoprim

Dihyrofolate reductase

Tetrahydrofolic acid

Purine synthesis
DNA synthesis

1.Sulfamethoxazo
le inhibits
dihydrofolate
synthase.
2.Trimethoprim
inhibits
dihydrofolate
reductase.

Cotrimoxazole general
points
Both drugs have almost similar half lives (10 Hrs)
Optimal synergism is obtained at 20 (S) : 1 (T)
concentration (MIC of both is reduced by 5-6 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
Elderly animal 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 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
Genitourinary tract, gastro-intestinal tract
Treatment of coccidiosis in small animals

Cotrimoxazole tablet , powder form

Other combinations
Trimethoprim+ Sulphadiazine (Cotriazine)
Trimethoprim +Sulphadoxine
Ormetoprim+ Sulphadimethoxine
Baquiloprim+ Sulphadimethoxine
(reccomended for dogs & cats)