This document discusses sulfonamides and sulfonamide combinations used in animals. It covers their introduction, therapeutic indications including treatment of various infections, mode of action by inhibiting bacterial folic acid synthesis, administration routes, pharmacokinetics of absorption, distribution, metabolism and excretion, adverse effects including hypersensitivity reactions, and drug interactions. The document provides details on various individual sulfonamides and potentiated sulfonamide combinations used in veterinary medicine.

1. Sulfonamides and
Sulfonamide
Combinations Use in
Animals

2. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

3. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

4. › Sulfonamides are the oldest and remain among the most widely used antibacterial
agents in veterinary medicine, chiefly because of their low cost and relative efficacy in
some common bacterial diseases.
Introduction

5. Classification of Sulfonamides
› Sulfonamides and sulfonamide derivatives can be categorized into several types, based
on;
1. Indications
2. Duration of action in the body
3. Water soluble
4. Lipid soluble
Cont. …

6. › Sulfonamides used in animals are;
1. Sulfamethazine (sulfadimidine)
2. Sulfamerazine
3. Sulfadiazine
4. Sulfabromomethazine
5. Sulfaethoxypyridazine
6. Sulfadimethoxine.
Cont. …

7. › The synergistic action of sulfonamides with specific diaminopyrimidines renders these
drugs much more effective than sulfonamides alone, they are called potentiated
sulfonamides.
› A group of diaminopyrimidines (trimethoprim, methoprim, ormetoprim, aditoprim, and
pyrimethamine) inhibit dihydrofolate reductase in bacteria and protozoa far more
efficiently than in mammalian cells.
› When used alone, these agents are not effective against bacteria, and resistance
develops rapidly.
› When combined with sulfonamides, a sequential blockade of microbial enzyme systems
occurs with bactericidal consequences.
Potentiated Sulfonamides in Animals

8. › Examples of such potentiated sulfonamide preparations include;
1. Trimethoprim-sulfadiazine
2. Trimethoprim-sulfamethoxazole
3. Trimethoprim-sulfadoxine
4. Ormetoprim-sulfadimethoxine
› The optimal ratio in vitro for the combination of trimethoprim and sulfonamide
depends on the type of microorganism, but is usually 1:20.
› However, the commercially available preparations use a ratio of 1:5 because of
pharmacokinetic considerations that presumably result in the optimal ratio at the site of
infection.
Cont. …

9. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

10. › The sulfonamides are commonly used to treat or prevent acute systemic or local
infections.
› Disease syndromes treated with sulfonamides include;
1. Coccidiosis
2. Mastitis
3. Metritis
4. Actinobacillosis
5. Colibacillosis
6. Pododermatitis
7. Polyarthritis
8. Respiratory infections
9. Toxoplasmosis
Therapeutic Indications

11. › Treatment duration
– Should not exceed 7 days under usual circumstances.
– If a favorable response occurs within 72 hours, treatment should be continued for 48 hours after
remission to prevent relapse and the emergence of resistance.
› Sulfonamides are more effective when administered early in the course of a disease,
because it is bacteriostatic.
› Chronic infections, particularly with large amounts of exudate or tissue debris present,
often are not responsive.
› In severe infections, the initial dose should be administered IV to decrease the lag time
between dose and effect.
› For drugs with a long elimination half-life, the initial dose should be double the
maintenance dose.
Notes

12. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

13. › The sulfonamides are structural analogues of para-aminobenzoic acid (PABA)
› Sulfonamides competitively inhibit dihydropterate synthetase (DPS) (an enzyme that
facilitates the synthesis of dihydrofolic acid (folic acid) from PABA.
› Dihydrofolate is a precursor for formation of tetrahydrofolate (folinic acid), an essential
component of the coenzymes responsible for single-carbon metabolism in cells.
› Sulfonamides are antimetabolites that substitute for PABA, resulting in blockade of
several enzymes needed for the biogenesis of purine bases and other metabolic
reactions necessary for formation of RNA.
› Accordingly, protein synthesis, metabolic processes, and inhibition of growth and
replication occur in organisms that cannot use preformed folate.
Mode of Action of Sulfonamides in Animals

14. Sulfonamides Trimethoprim/Diaverdine
Combination
Diaveridine
• Tetrahydrofolic acid(THF)is a coenzymein the
synthesisof purine bases andthymidine.
• Theseare constituentsof DNA and RNA and are
requiredfor cell growthand replication.
• Lack ofTHF leads to inhibition of cell
proliferation.
Catalyzedby dihydrofolate
reductase
The sulfonamides are
structural analogues of para-
aminobenzoic acid(PABA)
and competitivelyinhibit
dihydropterate synthetase
(DPS),

15. › The effect is;
– Bacteriostatic at the normal concentration
– Bactericidal action at the high concentrations
› The efficacy of sulfonamides can be decreased radically by excess PABA, folic acid,
thymine, purine, methionine, plasma, blood, albumin, tissue autolysates, and
endogenous protein-degradation products.
Cont. …

16. › Although all of the sulfonamides have the same mechanism of action, some differences
are evident in the respect to activity, pharmacokinetic fate, and even antimicrobial
spectrum at usual concentrations.
› The differences are due to the variety of physiochemical characteristics seen among the
sulfonamides.
Differences Between Sulfonamides

17. › Sulfonamides are most effective in the early stages of acute infections when organisms
are rapidly multiplying.
› They are not active against quiescent (inactive) bacteria.
› Typically, there is a latent period before the effects of sulfonamide treatment become
evident because the bacteria use existing stores of folic acid, folinic acid, purines,
thymidine, and amino acids.Once these stores are depleted, bacteriostasis occurs.
› Bacterial growth can resume when the concentration of PABA increases or when the
level of sulfonamide decreases below an enzyme-inhibitory concentration.
Onset of Action

18. › Because of the bacteriostatic nature of sulfonamides, adequate cellular and humoral
defense mechanisms are critical for successful sulfonamide treatment when used as
sole agents.
› Even potentiated sulfonamides, which are bactericidal, are time dependent in their
antibacterial efficacy.
Cont. …

19. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

20. › The spectrum of all sulfonamides is generally the same;
1. Gram-positive bacteria
2. Gram-negative bacteria
3. Some protozoa (eg, coccidia andToxoplasma spp)
› More active or potentiated sulfonamides may have activity against several species;
1. Streptococcus
2. Staphylococcus
3. Salmonella
4. Pasteurella
5. Corynebacterium
6. Escherichia coli
Antimicrobial Spectrum of Sulfonamides in
Animals

21. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

22. › Sulfonamides may be administered;
1. PO
2. IV
3. IP
4. IM
5. Intrauterine
6. Topically
› Several sulfonamides are used topically for specific purposes.
› Sulfacetamide is not highly efficacious but is occasionally used to treat ophthalmic infections.
› Mafenide and silver sulfadiazine are used on burn wounds to prevent invasion by many gram-negative and
gram-positive organisms.
› Sulfathiazole is commonly included in wound powders for the same purpose.
Route of Administration Sulfonamides in
Animals

23. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

24. › There are notable differences among sulfonamides with respect to their
pharmacokinetic fate in the various species.
› The standard classification of short-, medium-, and long-acting sulfonamides used in
human therapeutics is usually inappropriate in veterinary medicine because of species
differences in disposition and elimination.
Pharmacokinetic Features

25. › Sulfonamides are frequently added to drinking water or feed either for therapeutic
purposes or to improve feed efficiency.
› PO in Monogastric animals;
– Most of sulfonamides are rapidly and completely absorbed from theGI tract.
– Trimethoprim is rapidly absorbed (plasma concentrations peak in ~2–4 hours)
– For sulfachlorpyridazine, bioavailability is greatly decreased via feeding.
› PO Ruminants
– Sulfonamides absorption from the ruminoreticulum is delayed, especially if ruminal stasis is present.
– Trimethoprim tends to be trapped in the ruminoreticulum and appears to undergo a degree of
microbial degradation.
Absorption of Sulfonamides in Animals

26. › IV infusions
– A few highly water-soluble preparations may be injected IM (sodium sulfadimethoxine) or IP (some
irritation of the peritoneum can occur).
– In acute life-threatening infections, IV infusions are used to establish adequate blood concentrations
as rapidly as possible and may be followed by PO administration.
– Absorption occurs readily from parenteral injection sites; effective antibacterial concentrations are
reached in < 1 hour, with peak concentrations in ~4 hours.
– Generally, sulfonamide solutions are too alkaline for routine parenteral use.
Cont. …

27. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

28. › Sulfonamides are weak acids and hydrophilic, leading to distribution via the extracellular
fluid.
› The distribution pattern depends on;
1. The ionization state of the sulfonamide.
2. The vascularity of specific tissues.
3. The presence of specific barriers to sulfonamide diffusion.
4. The fraction of the administered dose bound to plasma proteins, the unbound drug fraction is freely
diffusible.
Distribution of Sulfonamides in Animals

29. › Plasma protein binding
– Sulfonamides are bound to plasma proteins to a greater or lesser extent.
– Sulfonamides concentrations in pleural, peritoneal, synovial, and ocular fluids may be 50%–90% of
that in blood.
– Sulfadiazine is ≥90% bound to plasma proteins.
› Tissue concentration
– Kidneys, exceed plasma concentrations.
– Skin, liver, and lungs are only slightly less than blood concentrations.
– Muscle and bone are ~50% of those in the plasma.
– CSF may be 20%–80% of blood concentrations, depending on the particular sulfonamide.
– Low concentrations are found in adipose tissue.
Cont. …

30. › Sulfonamides in intestinal content
– After parenteral administration, sulfamethazine is found in jejunal and colonic contents at about the
same concentration as in blood.
› Sulfonamides in milk
– Passive diffusion into milk also occurs; although the concentrations achieved are usually inadequate
to control infections, sulfonamide residues may be detected in milk.
Cont. …

31. › Trimethoprim is basic and tend to accumulate in more acidic environments such as
acidic urine, milk, and ruminal fluid.
› Trimethoprim diffuses extensively into tissues and body fluids.
› Tissue concentrations are often higher than the corresponding plasma concentrations,
especially in lungs, liver, and kidneys.
› Approximately 30%–60% of trimethoprim is bound to plasma proteins.
Trimethoprim

32. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

33. › With some species differences, sulfonamides are usually extensively metabolized,
mainly via;
1. Several oxidative pathways
2. Acetylation
3. Conjugation with sulfate or glucuronic acid
› The acetylated, hydroxylated, and conjugated forms have little antibacterial activity.
› Acetylation decreases the solubility of most sulfonamides except for the sulfapyrimidine
group.
› The hydroxylated and conjugated forms are less likely to precipitate in urine.
Metabolism

34. › The extent of metabolic transformation of trimethoprim has not yet been established,
although there is a suggestion that hepatic biotransformation can be extensive, at least
in ruminants.
› This may not be the case in all species; >50% of a dose is excreted unchanged in many
instances.Trimethoprim is largely excreted in the urine via glomerular filtration and
tubular secretion.
› A substantial amount may also be found in the feces.
› Concentrations in milk are often 1–3.5 times as high as those in plasma.
Trimethoprim

35. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

36. › Mainly, sulfonamides are excreted in the urine.
– Glomerular filtration, active tubular secretion, and tubular reabsorption are the main processes
involved.
› The proportion reabsorbed is influenced by;
1. Lipid solubility of sulfonamides and their metabolites
2. Urinary pH.
› Routes of less importance are bile, feces, milk, tears, and sweat.
Excretion of Sulfonamides in Animals

37. › Crystals precipitation depends on;
1. Urinary pH
2. Renal clearance
3. Concentration and solubility of sulfonamides and their metabolites
› This can be prevented by;
1. Alkalinizing the urine
2. Increasing fluid intake
3. Reducing dose rates in renal insufficiency
4. Using triple-sulfonamide or sulfonamide-diaminopyrimidine combinations
Cont. …

38. › HighlySolubleSulfonamides forUrinaryTract Infections inAnimals
› A few water-soluble sulfonamides are rapidly excreted via the urinary tract (>90% in 24
hours) mostly in an unchanged form, because of this, they are primarily used to treat
urinary tract infections.
1. Sulfisoxazole
2. Sulfasomidine
Cont. …

39. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

40. › Adverse reactions to sulfonamides may be due to;
1. Hypersensitivity
2. Direct toxic effects
Adverse Effects and Toxicity of
Sulfonamides in Animals

41. › Adverse reactions to
sulfonamides may be due to;
1. Hypersensitivity
2. Direct toxic effects
Adverse Effects and Toxicity of
Sulfonamides in Animals
› Possible hypersensitivity reactions include
urticaria, angioedema, anaphylaxis, skin rashes,
drug fever, polyarthritis, hemolytic anemia, and
agranulocytosis.
› The allergic response targets, in part,
metabolites of the aryl amine of sulfonamides.
› Because dogs are deficient in acetylation, they
may be at risk of increased formation of phase I
metabolites associated with adverse effects.

42. › Adverse reactions to
sulfonamides may be due to;
1. Hypersensitivity
2. Direct toxic effects
Adverse Effects and Toxicity of
Sulfonamides in Animals
› Acute toxic manifestations may occur after;
1. Too-rapid IV administration
2. An excessive dose is injected
› Clinical signs include thrombophlebitis,
anaphylaxis, muscle weakness, ataxia,
blindness, and collapse.

43. › Adverse reactions to
sulfonamides may be due to;
1. Hypersensitivity
2. Direct toxic effects
Cont. …
› Gastrointestinal disturbances, in addition to
nausea and vomiting, may occur when
sulfonamide concentrations are sufficiently high
in the tract to disturb normal microfloral
balance and vitamin B synthesis.
› Sulfonamides depress the cellulolytic function
of ruminal microflora; however, the effect is
usually transient (unless excessively high
concentrations are reached).

44. 1. Bone marrow depression (aplastic anemia, granulocytopenia, and thrombocytopenia)
2. Hepatitis and icterus.
3. Peripheral neuritis and myelin degeneration in the spinal cord and peripheral nerves.
4. Photosensitization, stomatitis, conjunctivitis, and keratitis sicca.
5. Several sulfonamides can lead to decreased egg production and growth.
6. Topically, the sulfonamides retard healing of uncontaminated wounds.
Adverse Effects After Prolonged
Treatment

45. › Up to 10 times the recommended dose of trimethoprim has been given with no adverse
effects.
› Prolonged administration of trimethoprim at reasonably high concentrations leads to
maturation defects in hematopoiesis due to impaired folinic acid synthesis.
› Clinical signs of folate deficiency include anemia, thrombocytopenia, and even
pancytopenia.
› Supplementation with folic acid may be necessary in young or pregnant animals
undergoing long-term high-dose treatment.
› Treatment with trimethoprim-sulfamethoxazole has been associated with immune-
mediated hemolytic anemia in horses.
Trimethoprim

46. › Introduction
› Therapeutic indications
› Mode of action
› Spectrum of sulfonamides
› Route of administration
› Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
› Adverse effects
› Drug interaction

47. › Sulfonamide solutions are incompatible with calcium- or other polyionic-containing fluids.
› Acidic drugs with higher binding affinities to plasma-protein may displace sulfonamides from
their binding sites.
› Antacids tend to inhibit theGI absorption of sulfonamides.
› Alkalinization of the urine promotes sulfonamide excretion, and urinary acidification increases
the risk of crystalluria.
› Some sulfonamides act as microsomal enzyme inhibitors, which may lead to toxic
manifestations of concurrently administered drugs such as phenytoin.
› The IV administration of potentiated sulfonamides and detomidine sensitizes the myocardium
and may result in potentially fatal cardiac dysrhythmias and hypotension.
› Procaine, found in procaine penicillinG, is a PABA analogue that may decrease efficacy of
potentiated sulfonamides.
Interactions With Sulfonamides in Animals

48. › Sulfonamides are prohibited from extra label use in lactating dairy cattle in theUS; this
definition therefore includes all dairy cattle >20 months of age.
› While not expressly prohibited, the extra label use of sulfonamides in milking sheep and
goats is discouraged.
› There are three sulfonamides approved for lactating dairy cattle, and these drugs must
be used according to label directions;
1. Sulfadimethoxine
2. Sulfabromomethazine
3. Sulfaethoxypyridazine
Regulatory Considerations of
Sulfonamides in Animals

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