Sulphonimides

Question 1

Potentiated sulfa drugs

Answer 1

-sulfadiazine (with trimethoprim; TMS)
-sulfadimethoxine (with ormetoprim)
-sulfadoxine (with TMS)

**different sulfonamides used in different formulations depending on the situation with a diaminopyrimidines

Question 2

Non-potentiated sulfa drugs

Answer 2

-sulfa on their own without trimethoprim or ormetoprim

-used for scour boluses, gi/resp infections, medicated waters

Question 3

Borgal and Trimidox

Answer 3

-potentiated products (sulfa +trimethoprim)
-IM or SC; some extralabel IV

Question 4

Sulfonamide mechanism of action

Answer 4

-Similar structure to PABA
-competitive inhibition for enzyme dihydropteroate synthase preventing formation of dihydropteroic acid AND therefore prevent purine and thymidine production

**bacteriostatic- when used alone

Question 5

Diamuopurimidines mechanism of action

Answer 5

-includes trimethoprim, ormetoprim, pyrimethamine

-inhibits dihydrofolate reductactase therefore preventing tetrahydrofolic acid formation and therefore purines and thymidine

**Bactericidal when added to sulfa

Question 6

Do sulfonimides impact mammal folate synthesis?

Answer 6

Bacteria must make their own folate BUT mammals utilize dietary folate (Vit B9)

Question 7

Sulfonamide implications from competitive inhibition of PABA

Answer 7

-if lots of PABA available in a local environment, then the bacteria will be resistant to sulfa drugs
Eg. don’t work for abscesses because components of folic pathway already present inside

Question 8

Sulfonamide spectrum of activity

Answer 8

-some gram + isolates
-some gram - isolates
-many anaerobes
-some protozoa and coccidia

Question 9

What do sulfonimides not work well against?

Answer 9

-pseudomonas
-enterococcus
-resistance emerging rapidly in many bacterial species (strep equi. e coli, salmonella)

Question 10

Sulfonimides synergism

Answer 10

Potentiated drugs- combination of sulfonimides with Diamuopurimidines (trimethoprim) resulted in a lower MIC and better effect!

Question 11

Sulfonimide variability

Answer 11

-often labelled for various infectious conditions but highly variability among individual isolates

Question 12

Sulfonimides resistance

Answer 12

COMMON
-chromosomal or plasmid-mediated
-hyper-production of PABA
-altered dihydropteroic synthase or DHFR (trimethoprim) enzymes
-increased production of DHFR
-reduced drug penetration into bacteria

Question 13

Does cross resistance exist between sulfas?

Answer 13

Yes
-means that if resistance to one sulfa than resistant to other sulfas

-emerges more slowly with potentiated sulfas than with sulfas alone

Question 14

Sulfonimide PK

Answer 14

**not uniform between drugs and species

-good bioavailability
-distributes to tissues (including CSF, synovial fluid, urine)
-differences in protein binding between sulfas and species = differences in elimination half lives

Question 15

Elimination of sulfonimides

Answer 15

-hepatic metabolism (to inactive metabolites)

-renal excretion (glomerular filtration)

Question 16

Sulfa vs potentiated component PK

Answer 16

Significant differences between sulfas and diaminopyrimidines
-optimizing sulfa:TMP is hard
-elimination rates very different (ex. TMP quick, sulfa slow)

Means that adverse events are likely due to sulfa not TMP

Question 17

Sulfonamide dosing

Answer 17

Labels often say once daily, but recommended to use BID

**sulfas are time dependent

Question 18

Sulfonimide adverse events

Answer 18

1. hypersensitivity rxns
2. keratoconjunctivitis sicca
3. REnal damage
   4.

Question 19

hypersensitivity rxns

Answer 19

-occurs in 3-6% of people
-different rxns based off of side chains
-N1 position: associated with type I hypersensitivity rxn
-N4 position: forms reactive metabolites that can cause direct cytotoxicity or stimulate an immunologic response

**typically due to antimicrobial sulfas, not other sulfa drugs

Question 20

Hypersensitivity rxn cinical signs

Answer 20

-blood dyscrasias
*IM hemolytic anemia in horses
*thrombocytopenia and epistaxis

• non-septic arthritis

-skin eruptions (Dobermans)

-hepatic necrosis

Question 21

Keratoconjunctivitis sicca (KCS)
**KNOW THIS

Answer 21

Dry eye due to decreased tear production
-sulfa component toxic to lacrimal acinar cells
-easy to confirm with Schirmer tear test

**more common in smaller dogs?; occur in 15% of dogs

Typically resolves when sulfa therapy stops (but not always)

Question 22

Renal damage from sulfonamides

Answer 22

-poorly soluble so can precipitate in urine
*especially when decreased tubular flow (dehydration) or acidic urine (decreased sulfa solubility)

-can lead to crystalluria, hematuria, tubule block

Question 23

Why is renal damage less of an issue with sulfonamides now?

Answer 23

Because sulfa drugs often used with TMS and therefore lower doses of sulfa are needed
**remember that they will still be dehydrated!!

Question 24

Why does Sulectim contain 4 different sulfas?

Answer 24

Each sulfa has a different solubility
*4x of one sulfa= increased chance of precipitation in renal tubules
*1x of 4 sulfas= same antimicrobial effect but less likely to precipitate at once

Question 25

Hypothyroidism for sulfonamides

Answer 25

-inhibition of thyroid enzyme activity
*generally reversible

**issue in rodents= thyroid carcinomas

Question 26

GI issues with sulfonamides

Answer 26

-diarrhea, vomiting, salivation

Question 27

Anemia from sulfonamides

Answer 27

-Rare
-from chronic use
-related to reduced folate production from intestinal bacteria
**can supplement folic acid (Vit B9)

Question 28

Injection and drug reactions with sulfonamides

Answer 28

Injections
-lesions after IM
-Rapid IV= thrombophlebitis or anaphylaxis in horses

Drug interactions
-no relevance
-can interact with procaine (PPG) because it is also a PABA analogue