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39 Cards in this Set

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Sulfonamide MOA & resistance
-block dihydropterate synthetase.

-mimic PABA

--| purine & pyrimidine synthesis

--| cell division

BACTERIOSTATIC (not cidal)

Resistance by synthesizing 70x more PABA (precursor to dihydrofolate), to become competitive enough to bind dihydropterate synthetase (1000x affinity for sulfonamide)

Resistance 2: change dihydropterate synthetase structure

Resistance 3: bypass 1-carbon transfer step by "salvage" pathway
List of sulfonamides
sulfamethoxazole
sulfisoxazole
sulfadiazine
sulfasalazine
sulfacetamide
sulfadoxine
(Trimethoprim) - works synergistically
Trimethoprim MOA
Inhibits bacterial Dihydrofolate reductase.

Synergism with sulfonamides:
cotrimoxazole (1 trimeth:5sulfamethoxazole)
cotrimazine (1 trimeth:5sulfadiazine)
Sulfonamide bacterial toxicity, absorption & distribution
Toxicity: selectively toxic to bacteria b/c folate synthesis = obligatory

Absorption: oral or topical (soluble solts given parenterally)

Readily absorbed w/ peak [drug]blood in 30 min

Plasma protein bound (displaces other drugs & biliruben --> neonatal jaundice when given late term)

Distribution: total body water, readily enters CNS, synovial & ocular fluid, fetal circulation, milk
Sulfonamide metabolism, elimination, & toxicity
Metabolism: 1. Acetylation at free-amino group (rendered inactive) 2. Some oxygenation of aeromatic ring or side chain.

Elimination: majority eliminated unchanged. Concentrated in urine (useful for UTI). Older types form crystals in tubules and ureter.

Toxicity: low CTI (theraputic index), toxicity in 5% of patients:
1) renal tox (crystalized in urine, 8-10g/day, give water)
2) blood dyscrasias (hemolytic anemia, agranulocytosis, aplastic anemia, thrombocytopenia. immune response to sulfonamide hapten?)
3) Dermal toxicity (rashes, pruritus, erythema, exfoliative dermatitis, stevens-johnson syndrome ~fatal)
4) rare - hepatitis, fever
5) less serious - headache, gi discomfort
Trimethoprim/sulfonamide drugs
cotrimoxazole-aka bactrim/septra (1 trimeth:5sulfamethoxazole)
cotrimazine (1 trimeth:5sulfadiazine)
Trimethoprim synergism
with sulfanomides

--| dihydrofolate reductase
--| NT synthesis later in pathway than sulfonamides

100,000x higher affinity for bacterial enzyme

decrease risk of resistance when used with sulfonamide
Sulfonamide structural site of difference
substituents on N1 nitrogen.

substitution on N4 nitrogen terminates activity (acetylation)
Sulfisoxazole, Sulfamethoxazole, sulfadiazine
short acting, rapidl abs/exc.

3 most common prescribed

last 2 in combo with Trimethoprim
Sulfadimethoxine
long acting sulfonamide, poor exc, useful in protozoal infections (AIDS patients)

toxic
Sulfadiazine
silver salt of drug --> topical use in burns
Sulfacetamide
topical use in eye, low irritation
Poorly absorbed sulfonamides
(pthalylsulfathiazole)

used to sterilize gut pre-bowel-surgery (but prefered drug is aminoglycosides).

Non absorbed

Gut flora cleaves N4 group.
Dapsone
Sulfone drug (not sulfonamide)

Antileprosy

MOA: similar to sulfonamides
Clinical use: sulfonamides
against most Gram+ and many Gram-

lower UTI (cotrimoxazole) from E. coli & prostatitis

combo w/ trimeth --> bacterial dysentery

sometimes --> meningococcal infection (other Ab's prefered)

Topical --> eyes (conjunctivitis) or prophylactic for burns

Protozoal infections (respond poorly to Ab's):
Chlamydia, nocardia, toxoplasma
Chloroquine resistant plasmodium falciparum
Pneumocystis carinii (or trimeth alone) high toxicity in AIDS.
Quinolone list
Nalidixic acid
norfloxacin (fluoroquinolone)
ciprofloxacin (fluoroquinolone)
Quinolone MOA/selective tox/resistance
--| DNA gyrase (bacterial topoisomerase)

Sel Tox: much less inhibition to mammalian topoisomerase

Resistance: Altered DNA gyrase/drug transport properties. R-plasmids ID'd. not wide spread, not understood.
Quinolone Toxicity/clinical uses
Toxicity: rare. GI distubrances, CNS effects, allergic skin reaction.

Clinical use:
UTI (nalidixic acid limited, newer quin's used).
Gonorrhea (* beta-lactam resistant strains)
Diarrhea (shigella, toxigenic e. coli, salmonella, typhoid)
Respiratory Infections: bacterial (hemophilus, streptococcus, pseudomonas) & nonbacterial (chlamydia, mycoplasma, legionella)
Osteomyelitis - potential not yet tapped.
Drugs for uncomplicated UTI (by enterobacteria)
cotrimoxazole

newer quinolones

(nalidixic acid, limited use)
Penicillins
Penicillin G
Penicillin V

nafcillin
methicillin
oxacillin
cloxacillin
dicloxacillin
flucoxacillin

ampicillin
amoxacillin

carbenicillin
ticarcillin

azocillin
mezlocillin
pipericillin
Cephalosporins
cephalothin
cefazolin
cefalexin

cefurixime
cefamandole
cefoxitin
cefaclor

moxalactam
cefaperazone
ceftazidime
ceftriaxone
Other beta-lactams
clavulanic acid
sulbactam
imipenem
aztreonam
Aminoglycosides
neomycin
gentamycin
streptomycin
amikacin
tobramycin
kanamycin
Tetracyclines
tetracycline
doxycycline
Misc
bacitracin
vancomycin
polymyxin
chloramphenicol
erythromycin
clindamycin
clarithromycin
azithromycin
Anti-tuberculosis drugs
isoniazid
pyrazinamide
rifampin
ethionamide
ethambutol
aminosalicylic acid (PAS)
streptomycin
cycloserine
Antifungal drugs
nystatin
amphotericinB
itraconazole
griseofulvin
ketoconazole
flucytosin
miconazole
clotrimazole
fluconazole
Antiprotozoal drugs
metronidazole
primaquine
mefloquine
chloroquine
haloxatrine
quinine
pyrimethamine
doxycycline
artimisinin
proguanil
dapsone
sulfadoxine
Antihelmintics
niridazole
ivermectin
mebendazole
metronidazole
thiabendazole
diloxanide fluorate
niclosamide
iodoquinol
praziquantel
pyrantel pamoate
albendazole
piperazine
diethylcarbamazepine
Antineoplastic Groups
alkylating agents
antimetabolites
natural products
Alkylating agents
mechlorethamine
cycloposphamide
melphalan
chlorambucil
bis-chlorethyl nitrosourea (BCNU)
hydroxyurea
Antimetabolites
methotrexate
fluorouracil
cytarabine
mercaptopurine
Natural products
vincristine
actinomycin D
L-asparaginase
daunorubicin
doxorubicin
bleomycin
vinblastine
Immunosuppressant groups
1) corticosteroids
2) cytotoxic agents
3) T-cell suppressants
4) antibodies

1) prednisone, prednisolone
2) cyclophosphamide, azathioprine
3) cyclosporine, tacrolimus
4) antithymocyte globulin, muromonoab - CD3
Antiviral agents
amantadine
rimantadine
acyclovir
valcyclovir
famciclovir
penciclovir
ganciclovir
foscamet
sorivudine
idoxuridine
vidarabine
trifluridine
ribavarine

& Anti-HIV agents
Anti-HIV agents
lamivudine
abacavar
tonofovir
emtricitabine
nevirapine
delaviridine
efavirenz
saquinavir
ritonovir
indiavir
nelfinavir
amprenavir
NRTIs
retrovir
didanosine
zalcitabine
stavudine
inverase
lamivudine
abacavar
tonofovir
emtricitabine
NNRTIs
nevirapine
delaviridine
efavirenz
Protease inhibitors
invirase
saquinavir
ritonovir
indiavir
nelfinavir
amprenavir