By

Dr. Nehal Aly Afifi Professor of Pharmacology

Cairo university

E-mail: drnehal_affifi@cu.edu.eg

http://scholar.cu.edu.eg/prof-nehalafifi

Sulphonamides

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GENERAL PROPERTIES

Sulfonamides are the oldest & remain the most widely

used antibacterial agents in veterinary medicine.

Chiefly because of low cost & their efficacy in some

common bacterial diseases (urinary, GI infections).

The synergistic action of sulfa with Trimethoprim renders

Salfa/ combination drugs much more effective than sulfa alone.

All Sulfa are derivatives of sulfanilamide(the first sulfa

discovered in 1940 to have antimicrobial activity(the nucleus).

Addition or substitution of various functional groups→ drugs

with varying pharmacologic, & antibacterial properties.

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All sulfa are white crystalline powder except Sulfaquinoxaline(yellow

Sulfa generally are weak organic acid, insoluble in water but

much more soluble in alkaline aqueous sol than in neutral or acidic

Solubility enhanced when sulfa formulated as sodium salts or in

solution of more alkaline pH.(highly irritant).

Water-soluble sodium or disodium salts used for Parenteral administ

Sulfa tend to undergo crystallization in urine(acid pH), especially in

man & carnivores animals (crystalluria).

To minimize crystalluria "triple sulfas" (3 sulfonamides formulated

in solution together) are given.

Each sulfa in a mixture exhibits its own solubility;i.e.do not affect the

solubility of each other.

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A combination of sulfa is more water soluble than a single drug at

the same total conc.

This is the basis of triple sulfonamide mixtures used clinically.

Antimicrobial effect is additive; thus use of "triple sulfas" allows

increased efficacy without increased risk of adverse effects.

The highly insoluble sulfonamides (phthalylsulfathiazole &

succinylsulfathiazole) are retained in the lumen of the GI tract

for prolonged periods and are known as “gut-active” sulfa.

Trimethoprim & ormetoprim are basic drugs.

Potentiated sulfonamides (Sulfa/ trimethoprim combinations)

used to reduce the incidence of resistance & to increase the

efficacy of sulfa from bacteriostatic to bactericidal drugs.

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Antimicrobial Spectra

The spectrum of all sulfonamides is generally the same.

Sulfonamide inhibit both Gram-positive & Gram negative

bacteria, Nocardia, Actinomyces spp, & some Protozoa

as Coccidia & Toxoplasma spp.

More active sulf. inhibit several spp of Streptococcus,

Staphylococcus, Salmonella, Pasteurella, & E. coli .

Strains of Pseudomonas, Klebsiella, Proteus, Clostridium,

Chlamydia, Leptospira spp, rickettsiae, and

mycoplasmas, are most often highly resistant.

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Mode of Action

Sulfa : Antimetabolites i.e; Inhibit metabolism of organisms

by interfering with normal production of folic acid, RNA,

protein synthesis & microbial replication.

Sulfa are structural analogues of Para-amino benzoic acid (PA

Competitively inhibit dihydropterate synthetase enz that

facilitates PABA as a substrate for synthesis of folic acid

(dihydrofolic acid).

Dihydrofolate is a precursor for formation of folinc acid

(tetrahydrofolate);component of coenz. responsible

for metabolism in cells.

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Antimetabolites Bacteriostatic Sulfonamides

Sulfa and PABA are similar in chemical structure.

All sulfa inhibit synthesis of folic acid by being mistakenly

substituted for PABA.

Sulfa block conversion of PABA to dihydropteroic acid by inhibiting

dihydropterate synthase enz.

Trimethoprim block synthesis of tetrahydrofolic acid from

dihydrofolic acid by Competative inhibition dihydrofolate reductase.

Inhibition of growth & replication occur in organisms that cannot use

preformed dietary folate,i.e; org must synthesize their own folic acid.

The effect is bacteriostatic.

Mammalian cell metabolism is not inhibited because it utilize

performed folic acid obtained from the diet.

sulfa /Trimethoprim Combination → Synergistic, Bactericidal

actions on susceptible organisms ( potentiated sulfonamide)

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Optimal ratio in vitro for combination of trimethoprim or

ormetoprim & a sulfonamide is usually ~1:20.

the commercially available preparations use a ratio1:5

Because of pharmacokinetic considerations that result in the

optimal ratio at the site of infection.

Trimethoprim /sulfadiazine, Ormetoprim /sulfadimethoxine

Sulfonamides are most effective in early stages of acute

infections (organisms rapidly multiplying).

Bacterial growth resume when the conc. of PABA increase or

when level of sulfonamide falls below enzyme-inhibitory conc

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Sulfonamides efficacy reduced by excess PABA, folic

acid , thymine, methionine, blood, & tissue depress.

Bacteriostatic sulf need adequate cellular & humoral

defense mechanisms for successful sulf. therapy

PHARMACOKINETIC FEATURES

There are notable differences among sulfonamides with

respect to their pharmacokinetic fate.

The standard classification of short-, medium-, and long-

acting sulfonamides used in human therapeutics is usually

inappropriate in veterinary medicine.

Absorption:

Sulfa administered PO, IV, IP, IM, , intrauterine or Topically.

Most sulfa are rapidly & completely absorbed from GI tract of

monogastric animals.

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Absorption

Absorption of sulfa from the ruminoreticulum is delayed, especially

if ruminal stasis present.

Therapeutic doses usually administered PO; frequently added to

drinking water except in acute infections , IV infusions is used

to establish adequate Bl. Conc.

Absorption is rapid from , IV, IP, IM (Parenteral sites).

Sulfonamide solution is too alkaline for Parenteral use.

The poorly absorbed sulfa intended for local ttt of intestinal infectio

Sulfa Absorption occurs readily from parenteral injection sites;

Effective antibacterial conc. reached in <1 hr, & peak conc in ~4 hr.

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Distribution Sulfonamides distributed throughout all body tissues.

Distribution depends on ionization state of sulf., vascularity

of tissues & fraction of adm dose bound to plasma proteins.

The unbound drug fraction is freely diffusible

Sulf. bound to plasma proteins to a greater or lesser extent

Concs in pleural, peritoneal, synovial, and ocular fluids

is 50%–90% of that in blood.

Sulfadiazine is ≥ 90% bound to plasma proteins.

Conc. in the kidneys exceed plasma conc, & those in

skin, liver, and lungs.

Passive diffusion into milk → but the achieved conc. is

inadequate to control infections.

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Biotransformation

Sulfonamides metabolized, mainly by several oxidative

pathways, acetylation, and conjugation with sulfate or

glucuronic acid.

Species differences are marked in metabolism.

The acetylated, hydroxylated, & conjugated forms have

little antibacterial activity.

Acetylation (poorly developed in dogs) reduces the

solubility of most sulfonamides .

The hydroxylated & conjugated forms less precipitate

in urine.

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Most sulfonamides are excreted primarily in the urine.

Bile, feces, milk, sweat are also excretory routes .

Glomerular filtration, active tubular secretion, and

tubular reabsorption are the main processes involved.

The conc & solubility of sulfonamide and their

metabolites determine crystals precipitate.

Crystals precipitate prevented by: 1. alkalinizing urine,

2. increasing fluid intake, 3.reducing dose rates in renal

insufficiency. 4.using triple-sulfonamide or 5. Using

sulfonamide/ Trimethoprim combinations.

Excretion

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Pharmacokinetic Values • There are great differences between pharmacokinetic values of

various sulfa in animals.

• Plasma half-life of sulfadiazine is 10.1 hr (cattle) & 2.9 hr (pigs)

• The recommended dose & frequencies reflect this disparity in

elimination kinetics.

Sulfathiazole: 66 mg/kg, PO, tid for Horses

66 mg/kg, PO, every 4 hr Cattle, sheep, pigs

Sulfadiazine: 50 mg/kg, PO, bid All

Sulfaethoxypyridazine : 55 mg/kg/day, PO Cattle

110 mg/kg/day, PO (initial dose, half for subsequent doses) Pigs

• Plasma half-life of Trimethoprim is prolonged in most species;

Effective conc. maintained for >12 hr, → the frequency of

administration is 12–24 hr.

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THERAPEUTIC INDICATIONS

Sulfa used to treat or prevent acute systemic or local infections.

Diseases treated with sulfa include actinobacillosis, coccidiosis,

metritis, colibacillosis, mastitis ,respiratory inf.& toxoplasmosis.

Sulfa more effective when adminis early in the course of disease.

Chronic infections, with large amounts of exudate or tissue debris

present, are not responsive to sulfa.

In severe infections, the initial dose should administer IV .

For drugs with a long elimination half-life, initial dose should be

double the maintenance dose.

Adequate drinking water should be available at all times.

A course of treatment should not exceed 7 days .

If a favorable response seen within 72 hr, ttt should continue

for 48 hr to prevent relapse and the risk of bacterial resistance.

for successful sulfonamide therapy, immunstimulant agents must

to mount iR..

Sulfonamides Classes

sulfonamide categorized into several types, based mainly

on their indications and duration of action in the body.

Probably the most common classification based on water

solubility versus lipid solubility or duration of effect.

In most species, sulph. administered 1–4 times/day,

depending on the drug, to control systemic infections

caused by susceptible bacteria.

sulfonamide administration can be less frequent if

eliminated slowly .

sulfathiazole, sulfamethazine (sulfadimidine),

sulfamerazine, sulfadiazine, sulfapyridine,

sulfabromomethazine, sulfaethoxypyridazine,

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Highly Soluble Sulfonamides Used for

Urinary Tract Infections

A few very water-soluble sulfonamides, eg,

Sulfisoxazole (sulfafurazole)& Sulfasomidine

are very water-soluble sulfonamides,

rapidly excreted via the urinary tract (>90% in 24 hr)

Excreted mostly in an unchanged form → primarily

used to treat urinary tract infections.

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Poorly Soluble Sulfonamides Used for Intestinal Infections

Some sulfonamides, as Sulfaguanidine, are so insoluble

that are not absorbed from the GI tract (<5%).

Phthalylsulfathiazole & succinylsulfathiazole undergo

bacterial hydrolysis in lower GI tract with the consequent

release of active sulfathiazole.

Sulfasalazine also hydrolyzed in large intestine to sulfa

pyridine & 5-aminosalicylic acid, an anti-inflammatory agent

that used for management of ulcerative colitis in dogs.

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Topical Sulfonamides

Several sulfonamides 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.

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Potentiated Sulfonamides

A gp of Diaminopyrimidines (Trimethoprim, methoprim,

ormetoprim, pyrimethamine)

inhibit dihydrofolate reductase in bacteria & protozoa more

efficiently than in mammalian cells.

, these agents are not particularly effective against bacteria

if used alone(bacteriostatic).

when combined with sulfonamides, a sequential blockade

of microbial enz systems occurs with bactericidal effect.

Examples :trimethoprim/sulfadiazine (co-trimazine),

Trimethoprim/sulfamethoxazole (co-trimoxazole),

Trimethoprim/sulfadoxine (co-trimoxine),

ormetoprim/sulfadimethoxine.

Sulfonamides used in combination with pyrimethamine to

treat protozoal diseases as leishmaniasis & toxoplasmosis.

Resistance to sulfonamides is both Chromosomally,

and Plasmid mediated.

Staphylococci have acquired sulfonamide resistance

from enterococci.

Example, in staphylococci, chromosomally mediated

resistance reflect mutations in genes encoding for

dihydropterate synthetase and plasmid-mediated

resistance reflects mutations in dihydrofolate reductases

Cross-resistance between sulfonamides is common.

Bacterial Resistance

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Adverse Effects and Toxicity

Adverse reactions to sulfonamide due to hypersensitivity or

direct toxic effects.

Hypersensitivity reactions include urticaria, skin rashes ,

anaphylaxis, fever ,polyarthritis, & hemolytic anemia.

Keratitis sicca is a recognized adverse effect.

Because dogs are deficient in acetylation, they at risk of

increased formation of Crystalluria with hematuria, and

even tubular obstruction.

Acute toxic signs seen after too rapid IV or if excessive

dose is injected.

Clinical signs include muscle weakness, ataxia, blindness,

and collapse.

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GI disturbances as nausea & vomiting, when sulf conc. are

sufficiently high in GI tract .

Depress function of ruminal microflora, &vitamin B synthesis.

Several adverse effects after prolonged treatment, including

bone marrow depression (aplastic anemia).,stomatitis,

photosensitization, conjunctivitis, & keratitis sicca in sensitive

species as dogs,

sulfonamides lead to decreased egg production & growth.

Topically, sulf retard healing of uncontaminated wounds.

Up to 10 times recommend dose of trimethoprim given

with no adverse effects.