Pharm - Sulfonamides, Trimethoprim (Nuc. Acid. Synth. Inhibitors) Flashcards
what is the most COMMON bacterial cause of UTI
e. coli
protonsil was first discovered to work in a 10 month old infant with what infection
staphylococcal septicemia
name 3 “general purpose” sulfonamides
sulfamethoxazole
sulfadiazine
sulfisoxazole
name 3 sulfonamides for special applications
mafenide
silver sulfadiazine
sulfacetamide sodium (ophthalmic)
true or false
trimethoprim is available both on its own and as a combination with sulfamethoxazole
true
aside from sulfonamides and trimethoprim, name another chemical class that are nucleic acid synthesis inhibitors
pyrimethamine
how is pyrimethamine available
by itself and in combination with sulfadoxine
true or false
trimethoprim and pyrimethamine by themselves do not contain sulfa
true
all the sulfas are derived from what molecule and what molecule does this mimic
SULFANILAMIDE - which structurally mimics PABA — the starting point of nucleic acid synthesis
true or false
sulfa drugs are noncompetitive inhibitors of PAPA
FALSE - competitive
they are structurally similar - only diff is that the COOH in PABA has been chaned to sulfonamide in sulfanilamide
differentiate between what they inhibit:
sulfonamides vs trimethoprim and pyrimethamine
sulfonamides inhibit DHPS (dihydropteroate synthase)
trimethoprim and pyrimethamine inhibit DHFR (dihydrofolate reductase)
true or false
trimethoprim and pyrimethamine are competitive inhibitors
true - structually analgous to the substrate of DHFR
sulfonamides are structurally analagous to ______ and inhibit ______
PABA
inhibit dihydropteroate synthase
sulfonamides have synergy with……..
DHFR inhibitors
(trimethoprim and pyrimethamine)
bacteria need to synthesize _____ for nucleic acid biosynthesis
folate
explain the mechanism of purine (produces DNA) synthesis
include enzymes, cofactors, and which steps are inhibited
Pterdine + PABA gives dihydropteroic acid through dihydropteroate synthase
(THIS IS THE STEP THAT SULFONAMIDES INHIBIT)
dihydropteroic acid and glutamate as cofactor give dihydrofolic acid (enzyme = dihydrofolate synthase)
dihydrofolic acid with NADPH as cofactor (oxidized to NADH) and through DHFR produces THF (tetrahydrofolic acid)
THF produces purines and then DNA
of the 3 enzymes involved in bacterial DNA (nucleic acid) synthesis, which do humans have? explain
we have dihydrofolate synthase – that’s why it’s not a target for antibiotics
however, we also have DHFR, HOWEVER, this is still a target for trimethoprim!!!!! this is possible because trimethoprim and pyrimethamine have much higher affinity for the bacterial version of the enzyme rather than the human version
what does methotrexate inhibit
DHFR (OF HUMANS)
are sulfonamides bacteriostatic or cidal
static
true or false
sulfonamides are active against gram positive and gram negative bacteria
TRUE - but there are exceptions
not effective against the gram negative pseudomonas aeruginosa (resistant)
actually STIMULATES the growth of the gram positive - rickettsiae
true or false
sulfonamides have activity against anaerobes
FALSE - very poor activity
are sulfonamides active against enteric bacteria? how can you remember this?
YES
remember - can be used for UTI which is mainly due to e. coli
HOWEVER, some strains of e. coli, neisseria, and shigella are resistant - watch out
name 3 main infections that bactrim is used for
UTI
respiratory tract pathogens
ear infections
true or false
bactrim is effective against both MRSA and MSSA strains
true
are sulfonamides active against protozoa?
some
name 4 main mechanisms in which bacteria become resistant to sulfonamides
overproduce PABA - which competes with sulfa
overproduce dihydropteroate synthase
impair permeability, or actively efflux the sulfonamide
some bacteria use EXOGENEOUS folate - intrinsically resistant bc they don’t need that first step anymore that sulfonamides inhibit
4 methods of trimethoprim resistance
reduce cell permeability (gram -)
overproduce DHFR
produce an ALTERED reductase enzyme so the drug has reduced binding
by mutation or plasma-encoded trimethoprim resistant DHFR’s
bactrim is the drug of choice for which 3 infections??
why isn’t it used more?
UTI
MRSA
ear infections in kids
not used as much bc of development of resistance
sulfa______ and sulfamethoxazole are used almost exclusively to treat UTIS
sulfasoxazole
_________ is widely used in ulcerative colitis, enteritis, and other IBD’s, and rheumatoid arthritis
sulfasalazine
________ is used as ophthalmic solution or ointment for bacterial conjunctivitis and trachoma
sodium sulfacetamide
___ and ___ are used topically for burn wounds
silver sulfadiazine and mafenide acetate
sulfasalazine is oral, but is it absorbable or nonabsorbable
non
__+ ___ is first line therapy for acute toxoplasmosis
sulfadiazine + pyrimethamine
long acting oral absorbable sulfonamide and what used for
sulfadoxine
sulfadozine + pyimethamine used for malaria (NOT IN US)
how is trimethoprim excreted and why is this important
most is excreted unchanged in the urine (only 30% metabolized) – thus, kidney function is very important
if low function, need to decrease dose
explain how sulfonamides are distributed and excreted
widely distributed - CNS, placenta, fetus
excreted in the URINE in both free and acetylated forms
which sulfonamide has an EXTREMELY long half life of 4-10 days
the long acting - sulfadoxine
important adverse effects of sulfonamides
SJS (RARE)
mild rashes
photosensitivity
NVD
in pts with G6PDH deficiency - hemolytic anemia
CNS effects (headache, delirium)
UT - crystalluria and hematuria
name for sulfonamide metabolites
haptens
sulfa POTENTIATES these drugs……
explain
oral anticoagulants
sulfonylurea hypoglycemics
hydantoin anticonvulsants
displaces them from albumin and inhibits their metabolism, thus INCREASING their effect (potentiation)
trimethoprim AE
megaloblastic anemia
leukopenia
granulocytopenia
bone marrow suppression
in pts with AIDS and pneumocystic pneumonia, what toxicity can occur
liver
