Sulphonamides:

• First chemotherapeutic agent used systemically for prevention and treatment of various bacterial infections
• Primarily bacteriostatic against many gram-positive and gram-negative bacteria

Classification:

Mechanism of action:

• Sulphonamides are structural analogue of para-aminobenzoic acid (PABA)
• PABA is essential component of folic acid. PABA are utilized by bacteria to form folic acid which in turn utilized for the synthesis of thymidine, purine, methionine, glycine.

Sulphonamides blocks utilization of PABA. Inhibit dihydropteroate synthase

Prevention of union of PABA with pteridine to form dihydropteroic acid

Inhibition of dihydropteroic acid further inhibits synthesis of dihydrofolic acid

Inhibition of synthesis of tetrahydrofolic acid (reduced form of folic acid)

Bacteria metabolic process alters and ceases to multiply

Pharmacokinetics:
well absorbed after oral administration from small intestine

• After absorption diffuse well into body tissues and fluids
• Metabolized by acetylation in liver
• Excreted mainly in urine. Also excreted in tears, faeces, bile and sweat
• Gut-acting Sulphonamides are poorly absorbed from G.I tract and are primarily excreted in faeces

Side effects/Adverse effects:

Acute toxicity:

• Renal toxicity: hematuria, obstruction of renal tubules, ureter and bladder
• Blood dyscrasias
• Hypersensitive reactions: Exfoliative dermatitis
• Anorexia, Vomiting, Nausea, Abdominal discomfort

Chronic toxicity:

• Hypoprothrombinaemia due to Vit.K deficiency because of inhibition of enzyme Vit.K epoxide reductase
• Keratoconjunctivitis
• Inhibition of carbonic anhydrase resulting in accumulation of carbon dioxide leading to acidosis
• Hepatic necrosis
• Aplastic anemia and thrombocytopenia
• Reduction in weight
• Decrease in egg production
• Formation of methemoglobin
• Hypoglycemia, Cardiomyopathy

Contraindications:

• In patients with hypersensitive to sulpha drugs
• In patients with renal failure
• In patients with hepatic impairment, defective blood coagulation
• Pregnant animals

Indications:

• In bacterial infection

# Antagonist of Sulphonamides:

Antibacterial action of Sulphonamides is antagonized by supply of metabolites whose synthesis is inhibited by them. These include:

• Presence of PABA or drugs which yields PABA. Ex: procaine & procaine penicillin
• Supply of vit. B complex such as niacin, folic acid and choline and amino acids like glutamic acid and methionine
• Some proteins such as gelatin, albumin and peptone which bind with sulphonamides and reduce their availability
• Products of cell and tissue death, especially pus. They supply products which neutralizes sulphonamides or act as non-vascular barrier and reduce diffusion of drugs

# Synergistic Action:

Sulphonamides show synergistic action with trimethoprim. Combination of sulphonamides and trimethoprim produce sequential blocks in synthesis of tetrahydrofolate.

# Antimicrobial Spectrum:

• Broad spectrum antimicrobial drugs
• Primarily bacteriostatic with moderate to good activity
• Susceptible bacteria: Streptococcus pyogens, Streptococcus pneumoniae, H. influenzae, Actinomyces spp., Bacillus spp., Brucella spp., Chlamydia spp., Pasteurella spp., Klebsiella spp., Enterobacteriaceae, Clostridium spp.
• Resistant bacteria: Leptospira, Pseudomonas, Mycobacterium, Mycoplasma, Rickettsia, Spirochetes

# Bacterial Resistance:

• Bacteria are developing resistance fast to sulphonamides
• Bacterial resistance to sulphonamides may develop due to following causes:
• Alteration in enzymes those utilize PABA
• Increased capacity of bacteria to destroy or inactivate sulphonamides
• Increased production of PABA or essential metabolites
• Adoption of alternate pathway for synthesis of essential macromolecules
• Decreased drug permeability into bacterial cell or active efflux of drug from target bacteria.

# Ways to reduce bacterial resistance:

• Sulphonamides therapy should be initiated in acute stages of disease
• Sulphonamide therapy should be continued till complete recovery from infection occurs
• Initial dose of sulphonamide may be kept high to establish therapeutic blood concentration. This may be followed by smaller maintenance dose
• It should be used only when the infection is from sulphonamide susceptible microorganism. Indiscriminate use of sulphonamide should be avoided.

1. Systemically acting sulphonamides:
2. Short-acting sulphonamides:

• Rapidly absorbed and eliminated
• They have short duration of action (4-8 hrs)
• They are specifically used for urinary tract infections because they are rapidly eliminated in urine
• Sulphadiazine is the prototype of short-acting sulphonamides

Sulphadiazines:

• Sparingly soluble in water, alcohol and acetone but freely soluble in solutions of potassium and sodium hydroxides and in ammonia in water.
• Rapidly absorbed from G.I tract and excreted readily by kidney
• Elimination half-life in different species are:

Cattle= 3 hr

Pigs= 4 hr

Dogs= 10 hr

Ewe= 36 hr

• Mostly used in potentiated form with trimethoprim

Dose:

Dogs and cats: 50-100 mg/kg, PO or IV, 2 times daily

Cattle: 100 mg/kg

Calves: 30 mg/kg, IV

2. Intermediate acting sulphonamides:

• These drugs have duration of 12-24 hours
• They are rapidly absorbed but relatively slowly excreted from the body.

Sulphadimidine:

• Intermediate to long acting sulphonamide
• Rapidly absorbed after oral administration
• About 70% of drugs are protein bound
• Elimination half-lives of sulphadimidine in different species are:

Cattle= 4-6 hr

Goat= 4-8 hr

Sheep= 4-10 hr

Pig= 10-16 hr

• Used occasionally in ruminants and swine for treatment of systemic infections caused by susceptible bacteria.
• Available commercially as solution for IV use and bolus for oral use

Dose:

Cattle and sheep: 200 mg/kg, SC or IV as initial dose followed by 100 mg/kg, once daily

Pigs: 20-50 mg/kg, IV or PO, once daily

3. Long acting sulphonamides:

• Well absorbed but slowly excreted from body
• Highly bound to plasma proteins
• Have high renal tubular reabsorption

Sulphamethoxine:

• Less soluble in water, slightly soluble in alcohol
• Readily absorbed from G.I tract after oral administration in sheep & swine but slowly in cattle
• Mainly metabolized by acetylation to acetyl sulphadimethoxine in liver
• Elimination half-live in various species:

Swine= 14 hr

Sheep= 15 hr

Horses= 11 hr

Cattle= 12.5 hr

• Most frequently used in veterinary medicine for treatment of systemic infections including respiratory, genitourinary, enteric and soft tissue infections
• It is also added in drinking water of poultry to treat systemic bacterial infections and coccidiosis.

Dose:

Dogs & cats: 25-50 mg/kg, PO, IV or SC, once daily

Cattle: 50-100 mg/kg, PO or IV, once daily

4. Ultra- long acting sulphonamides:

• Very long duration of action >48 hours

Sulphadoxine:

• Action usually lasts for about a week after single dosing due to high plasma protein binding.
• Usually combined with pyrimethamine in treatment of malaria and toxoplasmosis in human.

1. Locally acting:
2. Gut- Acting sulphonamides:

• Poorly absorbed from G.I tract
• Excreted largely unchanged in feces

Succinylsulphathiazole & phthalylsulphathiazole:

• They are hydrolysed in G.I tract after oral administration to release succinic or phthalic acid and sulphathiazole
• Lack antibacterial activity in vivo because they are pro drug of sulphathiazole
• Therapeutic use is limited in veterinary medicine

2. Topically acting:

Sulphacetamide:

• Only sulphonamide whose sodium salt have a neutral pH and non-irritant to tissues. So, it is used as a topical treatment for ophthalmic infections
• After topical administration it is well-diffused throughout ocular tissues including anterior segment and aqueous humor.
• Available commercially as eyedrops.