Sulphonimides Flashcards
Potentiated sulfa drugs
-sulfadiazine (with trimethoprim; TMS)
-sulfadimethoxine (with ormetoprim)
-sulfadoxine (with TMS)
**different sulfonamides used in different formulations depending on the situation with a diaminopyrimidines
Non-potentiated sulfa drugs
-sulfa on their own without trimethoprim or ormetoprim
-used for scour boluses, gi/resp infections, medicated waters
Borgal and Trimidox
-potentiated products (sulfa +trimethoprim)
-IM or SC; some extralabel IV
Sulfonamide mechanism of action
-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
Diaminopyrimidines mechanism of action
-includes trimethoprim, ormetoprim, pyrimethamine
-inhibits dihydrofolate reductactase therefore preventing tetrahydrofolic acid formation and therefore purines and thymidine
**Bactericidal when added to sulfa
Do sulfonimides impact mammal folate synthesis?
Bacteria must make their own folate BUT mammals utilize dietary folate (Vit B9)
Sulfonamide implications from competitive inhibition of PABA
-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
Sulfonamide spectrum of activity
-some gram + isolates
-some gram - isolates
-many anaerobes
-some protozoa and coccidia
What do sulfonimides not work well against?
-pseudomonas
-enterococcus
-resistance emerging rapidly in many bacterial species (strep equi. e coli, salmonella)
Sulfonimides synergism
Potentiated drugs- combination of sulfonimides with Diamuopurimidines (trimethoprim) resulted in a lower MIC and better effect!
Sulfonimide variability
-often labelled for various infectious conditions but highly variability among individual isolates
Sulfonimides resistance
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
Does cross resistance exist between sulfas?
Yes
-means that if resistance to one sulfa than resistant to other sulfas
-emerges more slowly with potentiated sulfas than with sulfas alone
Sulfonimide PK
**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
Elimination of sulfonimides
-hepatic metabolism (to inactive metabolites)
-renal excretion (glomerular filtration)
Sulfa vs potentiated component PK
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
Sulfonamide dosing
Labels often say once daily, but recommended to use BID
**sulfas are time dependent
Sulfonimide adverse events
- hypersensitivity rxns
- keratoconjunctivitis sicca
- REnal damage
4.hypothyroidism - GI issues
- Injection site rxns
- Anemia
hypersensitivity rxns
-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
Hypersensitivity rxn cinical signs
-blood dyscrasias
*IM hemolytic anemia in horses
*thrombocytopenia and epistaxis
- non-septic arthritis
-skin eruptions (Dobermans)
-hepatic necrosis
Keratoconjunctivitis sicca (KCS)
**KNOW THIS
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)
Renal damage from sulfonamides
-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
Why is renal damage less of an issue with sulfonamides now?
Because sulfa drugs often used with TMS and therefore lower doses of sulfa are needed
**remember that they will still be dehydrated!!
Why does Sulectim contain 4 different sulfas?
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
Hypothyroidism for sulfonamides
-inhibition of thyroid enzyme activity
*generally reversible
**issue in rodents= thyroid carcinomas
GI issues with sulfonamides
-diarrhea, vomiting, salivation
Anemia from sulfonamides
-Rare
-from chronic use
-related to reduced folate production from intestinal bacteria
**can supplement folic acid (Vit B9)
Injection and drug reactions with sulfonamides
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
