SEVENTH SEMESTER !

Course Title: Veterinary Pharmacology & Toxicology(Chemotherapy)

Course Code: VPT-413
Lecture notes -3

Sulphonamides and
their combination
with trimethoprim;
Dr. Jibachha Sah,
M.V.Sc(Veterinary Pharmacology)
Lecturer, College of veterinary science
, NPI, Bhojard, Chitwan, Nepal

Jibachhashah@gmail.com http://
 Index
SULPHONAMIDE/TRIMETHOPRIM

1 HISTORY, SOURCE AND CHEMISTRY

2 SPECTRUM AND ANTIBACTERIAL ACTIVITY

3 MECHANISM OF ACTION AND DRUG RESISTANCE

4 CLASSIFICATION, PHARMCOKINETICS

5 TOXICITY AND ADVERSE REACTION,CLINICAL USES,

Summary
1.HISTORY, SOURCE AND CHEMISTRY
Sulfonamides (U.S) : sulphonamides (U.K)

History
Gerhard Domagk 1935- developed sulfa from the prod drug azodye,
Prontosil (used to treat streptococcal infection in mice. He got Nobel
Prize for medicine in 1939).

Source - Sulfa is a non antibiotic- called as antibacterial.

Chemistry
●White crystalline powder, insoluble in water, soluble in alkaline PH

● Sodium salts are soluble in water

● Weak organic acids.

● Pka 4.99 t0 8.56 (used to indicate the strength of an acid)

● Parenteral preparations are alkaline- care should be taken while

administration through iv route to prevent perivascular damage
I/m and S/C preparations should be properly buffered.

● Sulfacetamide- neutral preparation for ophthalmic use.

SPECTRUM AND ANTIBACTERIAL ACTIVITY
●Broad spectrum, bacteriostatic but at higher concentration in urine –ba
ctericidal
● Antimicrobial activity

● Bacteria, Chlamydia, Toxoplasma, Coccidia

● Bacterial susceptibility
● Good susceptibility - Actinomyctes, Bacillus, Brucella, Listeria,
Streptococci, Chlamydia, Cryptosporidium.
● Moderate susceptibility - Staphylococcus and Enterococcus and
some anaerobes.

● Resistant: Mycobacteria, Mycoplasma, Richettsia, Spirochetes, Pseudo

monas
MECHANISM OF ACTION
DRUG RESISTANCE

●Gonococci, Pneumococci, Staph. aureus, Meningococci, E. coli, Shigella

● Resistant mutant may Produce increased amounts of PABA Have low affini
ty for folate synthase Acquire an alternative pathways in folate metabolism
 CLASSIFICATION

●Short acting sulfonamides (4-8 hours) - Sulfadiazine

● Intermediate acting sulfonamides (8-12 hours)- Sulfamethoxazole, Sulfamoxole

● Long acting sulfonamide (approx 7 days)- Sulfadoxine, sulfamethopyrazine

● Special purpose sulfonamide- Sulfacetamide sod, sulfasalazine, mafenide, silver sulfadiazine

PHARMCOKINETICS

●Rapid and complete absorption from GIT

● Widely distributed, cross BBB & placenta

● Metabolism in liver, non-microsomal, acetylation at N4

● Glomerular filtration, less soluble in acidic urine --> crystalluria

● Contraindicated in near term females and neonates

PRINCIPLES TO BE FOLLOWED IN SULPHONAMIDE

●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

Drug interaction

●PABA antagonizes sulfonamides

● Calcium and antacids inhibits absorption

● Pus and tissue debris - rich in thymidine and purines so bacterial requirement of FA is less.

● Synergistic with diaminopyrimidines - Trimethoprim, ormethoprim,

● Sulfonamides + chlortetracycline act as Growth promoter prevent clostridial ET.

TOXICITY AND ADVERSE REACTION

●Acetylated derivatives of sulpha deposited in renal tubules, pelvis and ureter cause renal colic,

haematuria, obstruction of renal tubule and increased BUN level.

● Decreased water consumption and acidic urine precipitate crystalluria . Ensure adequate water in

take and administration of sodium bicarbonate . Incidence is less with sulfisoxazole.

● Triple sulfa- sulfamerazine, sulfapyridine sulfadiazine. Therapy not more than seven days.

● Hypersensitivity reaction- skin rashes due to anaphylactic shock- rare

● Acute toxic effect- rapid I/V excessive dose – muscle weakness, ataxia, blindness collapse

● Poultry - decreased egg production and thin shelled eggs

CLINICAL USES

●Colibacillosis, pasteurellosis, foot rot, coccidiosis

● Poultry - prevention of treatment of coccidiosis , infectious coryza, pullorum

disease, fowl typhoid

● Dapsone - diaminophenyl sulphone, dermatitis herpetiform in dogs, Leprosy

in human.
 COTRIMOXAZOLE/TRIMETHOPRIM

INTRODUCTION

●Eg.Trimethoprim, ormetoprim,Pyrimethamine
● Weak organic bases, Pka7.6 accumulate in acidic urine, milk and ruminal fluid
● Trimethoprim- poorly soluble in water
● Fixed dose combination of sulfamethoxazole + trimethoprim(Co-trimoxazole)
● Readily absorbed after oral administration except in ruminants – trapped and
undergo microbial degradation.
● 30 % to 60% protein bound, widely distributed in tissues including prostate.
Partly metabolized in liver and excreted in urine by glomerular filtration and tubul
ar secretion.
MECHANISM OF ACTION

●Selectively inhibits bacterial dihydrofolate reductase

● Wide distribution, crosses BBB & placenta

● Partly metabolized in liver excreted in urine

Uses

●UTI enteric infection, salmonella and brucellosis

● Cattle - Salmonellosis, diarrhoea pneumonia 30mg/kg

● Poultry - E.coli – 30mg/kg/day

Trimethoprim-Sulfadiazine or Trimethoprim-Sulfamethoxazole

Species Usage Dose

Cats For soft tissue infections and uncomplicated UTIs 15mg/kg PO q12h for 7-14d (extra-label use)

Label dose 30mg/kg PO q24h or 15mg/kg PO q12h

Dogs
30-45mg/kg PO or SQ q12h for 3-5d (extra-label us
For systemic infections or bacteremia
e)
Co-trimoxazole

●Mixture of trimethoprim with sulfamethoxazole.

Sulfamethoxazole – 400 mg. Ratio 1:5

Trimethoprim – 80 mg.

● Trimethoprim has a large volume of distribution, so its dose is decreased.

● It is quickly absorbed and after absorption, the ratio is plasma becomes 1:20 (works
best at this ratio). PPB(Parts per billion) of trimethoprim is also less than
sulfamethoxazole.
 Commercially available in market
(Trade name)

Sulcoprim

Duaprim Intertrim Cotrimoxzole

Advantages of Using Co-Trimoxazole

●Bactericidal. (Individual drugs are bacteriostatic)

● Wide antibacterial spectrum.
● Increased efficacy
● Less dose of each drug.
● Less incidence of toxicity.
● Have same half life (TMP 11 hrs. SMZ 10 hrs.)
● Both inhibit the same metabolic pathway, so synergize each others effect.
● Decreased chances of resistance (because if bacterium is resistant to one
drug, it will be sensitive to other)
Pharmacokinetics

●Can be given orally or I/V. after oral administration absorption is good, peak plasma levels appear

within 2 hours. Given I/V for infectious conditions.

● Trimethoprim is a weak base with pH of 7 .2. It is found in bile, sputum, high concentration in

CSF, also concentrates in acidic media of prostate and vagina.

● PPB of trimethoprim is 40-45% while that of sulfamethoxazole is 60%.

● Volume of distribution of trimethoprim is 9 times more than sulfamethoxazole.

● Most products are excreted in urine; traces of drug appear within 24 hours. Dose is adjusted as

required (esp. in renal insufficiency).

Adverse Effects

Hematological
●Trimethoprim – Megaloblastic Anemia, Leukopenia, thrombocytopenia, Granulocytopenia

● Prevented by simultaneous administrations of folic acid 6 – 8 mg/D which does not enter bacteria

for 3-6 weeks

● Hypersensitivity reactions -Rashes, Fever, Vasculitis

● CNS effects –headache, depression, hallucinations

● GIT disturbance – Nausea, Vomiting, Glossitis & stomatitis.

● HIV patients with pneumocystis pneumonia or immune compromised show fever, rashes,

leukopenia, diarrhea, elevation of hepatic aminotransferases, hyperkalemia, hyponatremia.

Summary

1.What is the action of Sulfonamides?

(i) Inhibit bacterial synthesis of folic acid

2.What is an example of short-acting Sulfonamides?

(i) Sulfisoxazole

3.What does Trimethoprim do?

(i) Interferes with bacterial folic acid synthesis

4.When are sulfonamides more soluble?

(i) at an alkaline pH than an acidic pH

5. What is the mechanism of action of sulfonamides?

(i) inhibit dihydropteroate synthase and folate production

6.Mutations that cause sulfonamide resistance cause what?

1: overproduction of PABA
2: production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides
3: impair permeability to the sulfonamide
7.What are the three major groups of sulfonamides?
1: oral, absorbable
2: oral, nonabsorbable
3: topical

8. What are sulfisoxazole and sulfamethoxazole used for?

(i)short to medium acting agents used almost exclusively to treat urinary tract infections

9.What is sulfadiazine in combination with pyrimethamine used for?

(i) first-line therapy for treatment of acute toxoplasmosis

10.What are the toxic reactions of sulfa drugs?
1: crystal formation in urinary tract

2: hemolytic anemia found in G6PD deficiency

3: agranulocystosis following sulfadiazine
4: aplastic anemia (supression of bone marrow)
5: hypersensitivity dermatitis, fever, pruritus
6: Stevens-Johnson syndrome(it begins with flu-like symptoms, followed by a painful red or
purplish rash that spreads and blisters).

11.What are the mechanisms of resistance to sulfa drugs through random mutations?
1: lower the binding affinity of the dihydropteroate synthase for sulfa drug
2: develop an active transport in the cell wall to remove sulfa drug
3: develop an alternate pathway for synhthesis of folic acid
4: increase the synthesis of PABA to overcome block by sulfa