SULPHONAMIDES!!

-Synthetic organic chemicals

Derivatives of Sulphanilamide
First chemotherapeutic agents used
systemically
-Most widely used antimicrobials in
veterinary practice due to:
•Low cost
•Their relative efficacy in some
common bact. diseases

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• The antibacterial activity was first discovered by
Domagk in 1935
• He said that prontosil, an azo dye, is effective
against streptococcal infection in mice
• Soon it was discovered that antibacterial activity
was due to an active metabolite, the
sulphanilamide.
• Then sulphanilamide was synthetically prepared
and used against various bacterial infections
• Although bacterial resistance has been developed
but still sulphas are used in various infections
including UTI in animals

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Synergistic action of Sulpha with specific
Diaminopyrimidines has added a sig.
dimension to sulpha therapy.
Pka for sulpha of therapeutic interest ranges
from 4.79 to 8.56
In general Sulphas behave as weak organic
acids.
In acidic urine, sulphas may form crystals
because of their decreased solubility
Combination of 2 or more sulphas is
occasionally used to increase solubility and
efficacy and to decrease toxicity.

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 Sulphas have low water solubility & in
body they are more or less acetylated &
become more or less soluble in water,
but acetylsulphadiazine is more
insoluble and form crystalluria.
Highly soluble Sulphas are retained in
lumen of GIT for prolonged periods &
are called “gut active Sulphas”

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Objectives for developing newer
Sulphas:
• More soluble at urinary PH
• To prolong their half life
• In a mixture of Sulpha, each component of
drug shows its own solubility therefore a
combination of Sulphas is more water
soluble than a single drug at the same total
concentration.

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 Mode of Action:
Sulphas are structural analogs of Para Amino
Benzoic Acid (PABA) and competitively inhibit an
enzymatic step (dihydropterate synthetase) during
which PABA is incorporated into synthesis of
dihydrofolic acid (folic acid or B2)
Acting as antimetabolite to PABA, Sulphas
eventually block the enzyme needed for biogenesis
of purine bases. This results in supression of
protein synthesis, imparement of metabolic
processes and inhibition of growth and
multiplication of organisms.

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Bacteriostatic Activity of Sulphas can be
reduced by:
• Excessive PABA (Drugs whose metabolism
yieldsPABA) e.g. procaine
• Folic Acid, niacin, choline (vitamin B
complex) and amino acids e.g. glutamic acid
and methionine
• Thymine, Purine, Methionine
• Proteins such as gelatin, albumin and
peptone which bind with sulphas and reduce
their availability.

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Synergists of sulphonamides:
• With some diaminopyrimidines such as
trimethoprim.
• TMP is a selective competitive inhibitor of
dihydrofolate reductase enzyme in susceptible
microorganisms
• Thus combination of sulphas and TMP produces
sequential blocks in synthesis of folic acid.

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CLASSIFICATION!
Into several types, based mainly on
indications and duration of action in body:
A. Systemically acting sulphonamides:
1. Short acting (< 12 hrs.)
• Sulphadiazine, Sulphathiazole,
Sulphamerazine, Sulphanilamide etc.
2. Intermediate acting (12-24 hrs.)
Sulphadimidine, sulphamethoxazole etc.
3. Long acting ( 24-48 hrs.)
Sulphadimethoxine, sulphaethoxypyridazine
etc.

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4. Ultra-long acting ( >48 hrs.)
Sulphadoxine and sulphamethopyrazine
B. Locally acting:
1. Gut acting sulphonamides:
Succinylsulphathiazole, sulphaguinidine,
sulphasalazine etc.
2. Topically acting sulphonamides:
Sulphacetamide, silver sulphadiazine etc.

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C. Potentiated Sulphas:
Sulphas are used in combination with
pyrimethamine to treat protozoal diseases
like Leishmaniasis & Toxoplasmosis e.g
• Sulphamethoxazole+TMP = Septran
• Sulphadiazine+TMP = Tribrissen
• Sulphadoxine+TMP = Trivertin

** TMP= Trimethoprim

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 Antimicrobial Spectrum:
• Against G+ and G- bacteria
• Broad Spectrum (Bacteriostatic)
Sensitive organisms are:
• Streptococci
• Staphylococci
• Corynebacterium
• E. coli
• Salmonella
• Klebsiella
• Pasteurella etc.

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 Resistant Strains:
• Leptospira, Pseudomonas, Mycobacterium,
Mycoplasma etc. are resistant.
Resistance can be avoided by:
• Stopping unjustified/indiscriminate use
• Initiate therapy early in acute stage of
disease
• Establish and maintain bacteriostatic conc.
of drug in animal host.
• Therapy should be continued till complete
recovery from infection occurs

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Bacterial Resistance:
a. An alteration in enzymes those utilise PABA
b. An increased capacity of bacteria to destroy or
inactivate sulphas
c. An increased production of PABA or essential
metabolites
d. Adoption of alternate pathway for synthesis of
essential macromolecules.
e. Decreased drug permeability into the bacterial
cell or active efflux of drug from the target
bacteria.

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 PHARMACOKINETICS!
Absorption: PO, IV, IP, IM, IU or topically. 70-
100% absorbed orally
Distribution: throughout body tissues/fluids.
Biotransformation: extensively metabolized.
In general, drugs with high pKa show low
degree of protein binding.
Acetylated form is protein bound to a greater
extent.
Hydroxylated & conjugated forms are less
likely to precipitate in urine.
Excretion: Excreted in urine, bile, feces, milk,
sweat, tears etc.
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 SIDE EFFECTS!
• Acute toxicity:
Renal toxicity, blood dyscrasias,
Hypersensitivity reactions, anorexia, nausea,
vomiting etc.

• Chronic toxicity: Hypoprothrombinaemia,

keratoconjunctivitis sicca, inhibition of
carbonic anhydrous enzyme, hepatic
necrosis, aplastic anaemia and
thrombocytopenia etc.

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 DRUG INTERACTIONS!
• Antacids tend to inhibit GI absorption of
Sulphas
• Alkalization (sodium lactate, sodium
bicarbonate and sodium citrate) of urine
promotes Sulphas excretion and urinary
acidification increases risk of
crystalluria.
• Sulphas may increase the effect of oral
anticoagulants and methotrexate
• Drugs which release PABA, some
members of vitamin B complex and some
amino acids antagonise action of sulphas.

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Cardinal Principles of Sulpha Therapy:
• 1. Should be given as early as possible
• 2. Parenteral injection should be preferred in
critical cases
• 3. Maintenance doses should be given to maintain
effective concentration in blood
• 4. Plenty of water and urinary alkalizers should be
given
• 5. In anuria and dysuria, stop sulpha therapy
• 6. Treatment should not be continued for longer
than 7-8 days.
• 7. If no response of sulpha is shown within first 2-
3 days, stop giving sulpha
• 8. Dosing should be continued for 48 hrs even after
disappearance of symptoms
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Salient Features of some
Sulphonamides:
Short acting: Rapidly absorbed and rapidly
eliminated:
Used for UTI
Sulphadiazine:
• Prototype of short acting sulphas
• 14 % bound to plasma proteins
• Used in combination with sulphamerazine,
sulphadimidine and TMP
• Acetylated derivatives are less soluble in urine so
leads to crystalluria
• Half lives 3-36 hrs.

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Sulphamerazine:
• Used orally or parenterally to treat infections
• Used in combination with sulphadimidine,
sulphadiazine and tylosin

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• Intermediate acting: Rapidly absorbed and slowly
eliminated:
• Sulphadimidine:
• 70 % is bound to plasma proteins
• Metabolites are highly soluble so less chances of
crystalluria
• Half lives 4-16 hrs.
• Residues persist in the milk
• Sulphamethoxazole:
• Orally for urinary and systemic infections
• Produces acetylated metabolite which causes
crystalluria
• May be used in combination with TMP

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• Long acting: Well absorbed and slowly eliminated:
• Sulphadimethoxine:
• Orally, absorbed from GI tract
• Well distributed in body
• High plasma protein binding (80-85%)
• Metabolised by acetylation and excreted as
changed or unchanged metabolites
• Half lives 11-15 hrs.
• Used for respiratory, genitourinary, enteric and
soft tissue infections
• Also used in poultry to treat coccidiosis

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Gut acting Sulphonamides:
• Poorly absorbed from GI tract and are excreted
unchanged in faeces
• Provide high concentration of drug in GI tract due
to low absorption and may also release active
sulphonamide due to bacterial hydrolysis
• Sulphasalazine:
• Used in treatment of ulcerative cilitis and enteritis
• A pro-drug that is broken down by intestinal
bacteria into active sulphapyridine
• Sulphaguinidine:
• Poorly absorbed orally
• Becomes ionised at GI pH
• For gut infection in animals
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Topically acting Sulphonamides:
• Sulphacetamide:
• Non irritant to tissues
• Used in eye infections
• Used as eye drops or eye ointments
• Silver Sulphadiazine:
• Used topically. Slowly release silver ions, which
appear to be largely responsible for antimicrobial
action.
• 1 % cream is used on burns and chronic ulcers

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 POTENTIATED SULPHAS!!

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• Group of Diaminopyrimidines (Trimethoprim,
Methoprim, Ormetoprim, Aditoprim,
Pyrimethamine etc.)
• Inhibit dihydrofolate reductase in bacteria and
protozoa
• Bactericidal activity with sulphas
• The Basic drugs, accumulate in acidic media as
urine, milk and ruminal fluid
Examples of Potentiated sulphas:

1. Sulphadiazine+TMP
2. Sulphamethoxazole+TMP
3. Sulphadoxine+TMP
4. Sulphadimethoxine+Ormetoprim
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Combination of Sulphas with Trimethoprim
(TMP)
• Effectiveness of Sulphas can be improved by
combining them with inhibitors of bacterial
dihydrofolate reductase like TMP.
• TMP
1. Decreases Amount of sulpha
2. Increases therapeutic index
3. Widens antibacterial spectrum

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• The action of combinations is bactericidal and are
effective against
Actinomyces, Bacillus anthracis, Brucella,
Clostridium,
Corynebacterium, E. coli, Haemophilus, Klebsiella,
Proteus, Salmonella, Staph, Strepto, Vibrio etc.

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Sulphadiazine+TMP(Trisolizine, Tribrissen): 5:1
• Orally in calves, foals, sheep, goat, cat and dog
• Plasma level is rapidly achieved
• Recommended for gut infections
• Parenteral, powder, tablet, oral paste, oral
suspension, oral granules and bolus for ingestion
Sulphadoxine+TMP (Trivertin):
• Given parenterally
• Recommended in severe systemic infections

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Mode of action of Sulphonamides with
TMP:
• Dihydropteridine + PABA
Synthetase Inhibition by Sulpha
• Dihydropteroic Acid
Glutamic Acid
• Dihydrofolic Acid
Reductase Inhibitor by TMP
• Tetrahydrofolic Acid

• Protein Synthesis

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Renal Toxicity:
• Sulphanilamide and Sulphathiazole, precipitation
of crystals in collecting tubules of kidney and
pelvis
• Obstruction of urine flow
• Injury to tubular epithelium or epithelial lining

PRECIPITATION occurs
1. Solubility of drug in urine is low
2. pH of urine is low
3. Conc. of drug in urine is high

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• As weak organic acids, sulphas are more soluble in
alkaline than acidic solutions
URINARY PRECIPITATION OF SULPHAS can be
checked by
• Use drugs of high urine solubility
• Increase pH of urine (Sodium lactate, sodium
bicarbonate or sodium citrate)
• Use of combination of 2-3 sulphas

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THANK YOU
SULPHA!!

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