Cushman - Sulfonamides Flashcards
Mechanism of Action
The incorporation of ___ into the ___ acid nucleus is inhibited competitively by the sulfonamides, which are bioisosteres of PABA
- The sulfonamides inhibit ___ synthase. Since mammalian cells utilize preformed folates in the diet and some bacterial cells are required to make their own folic acid, the sulfonamides have ___ toxicity
for bacterial cells as opposed to mammalian cells.
- PABA
- folic
- dihydropteroate
- selective
Structure-Activity Relationships
The structure of sulfanilamide resembles that of ___
- However, there is a significant difference in the acidity of PABA (pKa 4.9) vs. sulfanilamide (pKa 10.4). PABA is mainly ___ at physiological pH, whereas sulfanilamide is a weak ___
- PABA
- anionic
acid
Early work on the synthesis of sulfanilamide derivatives established that the attachment of electron-withdrawing heteroaromatic rings ___ the sulfonamide nitrogen and ___ the potency. For example, the pKa of sulfadiazine is 6.36.
- The increase in acidity is due to the ___ of the aromatic substituent as well as ___ stabilization of the anion
- acidified, enhanced
- electronegativity
- resonance
The increase in acidity also ___ the incidence of crystalluria (crystallization of the sulfonamide in the urine, resulting in ___ damage), although it is still recommended to drink large quantities of water with some sulfonamides in order to avoid crystalluria
- decreased
- kidney
Sulfacetamide
Sulfadiazine
Sulfamethoxazole
Sulfasalazine
Sulfonamides in general inhibit both Gram positive and negative bacteria
- nocardia
- ___ trachomatis
- and some protozoa and fungi
- Enteric bacteria such as ___ , ___ , ___ , ___ , and ___ are inhibited (EEKSS)
- Chlamydia
- E. coli, klebsiella, salmonella, shigella, and enterobacter
Sulfonamides are usually used in ___
- The resistance factors are too widespread for these drugs to be used in a single drug therapy
The antifungal activity of trimethoprim-
sulfamethoxazole has become important for treatment of AIDS-infected patients that have developed infections caused by Pneumocystis jiroveci.
Trimethoprim inhibits ___ reductase, so the combination inhibits sequential steps in the biosynthesis of tetrahydrofolic acid
combination
dihydrofolate
Sulfasalazine is a ___ that is not absorbed well from the ___ tract. Bacteria in the GI tract metabolize it to sulfapyridine and 5 aminosalicylic acid, which has ___ activity.
- Sulfasalizine is used to treat ulcerative colitis and Crohn’s disease. Direct administration of salicylates, including 5 aminosalicylic acid, is irritating to the gastric mucosa.
Note: Ulcerative colitis causes inflammation and ulcers in the top layer of the lining of the large intestine. In
Crohn’s disease, all layers of the intestine may be involved
- prodrug
- GI
- antiinflammatory
___ in combination with pyrimethamine (DHFR inh) is used for first-line chemotherapy to treat acute ___
- Toxoplasma gondii is similar to the pathogen that causes malaria, and infections are common and usually, but not always, subclinical
- Sulfadiazine
- toxoplasmosis
Adverse Reactions
- All sulfonamides and their derivatives are ___
- Sulfonamide derivatives in use include carbonic anhydrase inhibitors (e.g. acetazolamide), thiazides (e.g. HCTZ), furosemide, sulfonylurea hypoglycemic agents (e.g. glyburide), and others
Allergic reactions
- rash
- photosensitivity
- drug fever
- SJS
Other adverse reactions include
- ___
- hematopoietic disturbances including hemolytic or aplastic ___ , granulocytopenia, and ___
Anorexia, nausea, vomiting occurs in 1%-2% of patients
- cross-reactive
- crystalluria
- anemia, thrombocytopenia
Resistance
1) Mutations that cause overproduction of ___
2) Mutations in the target enzyme ( ___ synthase) that decrease its affinity for the sulfonamides
3) Mutations that result in a decrease in cell ___ to the sulfonamides
resistance is very common - largely ↓ effectiveness as single-use
- PABA
- dihydropteroate
- permeability
BACTRIM PK
400 mg sulfamethoxazole (SMX) and 80 mg trimethoprim (TMP)
- TMP is absorbed (85-90%) and distributed more ___ than sulfonamides
- SMX is widely distributed in the body including the ___ and is also rapidly eliminated
- rapidly
CSF
Metabolism
The sulfonamides are generally metabolized by N-4 N ___ and in some cases N-1 ___
- The metabolites have no antibiotic activity. Hydroxylamine and nitroso metabolites are ___
population divided into rapid /slow acetylators. Affects rate of metab
- acetylation
- glucuronidation
- toxic
Miscellaneous Drugs
Colistin
- Polymyxin antibiotic metabolite of Bacillus polymyxa. It is a ___ drug that is used as a last resort for treatment of multidrug-resistant ___ , Acinetobacter, and Klebsiella pneumoniae
MOA: ___ that has ___ regions, so the overall structure resembles that of a cationic detergent that is able to solubilize bacterial ___ . The ammonium cations are able to displace cations in the bacterial cell membrane (Mg++ and Ca++) and facilitate binding of the antibiotic to anionic lipopolysaccharides in the cell membrane.
- nephrotoxic
- P. aeruginosa
- polycation, lipophilic, membranes
Metronidazole
Metronidazole
useful for treatment of ___ bacteria and protozoa. It is the drug of choice for treatment of first episodes of mild to moderate ___ infections
MOA: partial reduction of the nitro group in anaerobic bacteria leads to a ___ anion that degrades bacterial ___
- Since this happens only in anaerobic cells and not human cells, metronidazole has selective cytotoxicity for anaerobes
- anaerobic
- C. diff
- radical
- DNA
Recently Approved Drugs
___ Acetate (Xenleta)
Indication: Community-acquired bacterial pneumonia
Mechanism: Selective binding to the peptidyl transferase center (PTC) of the ___ ribosomal subunit to prevent bacterial protein synthesis.
- Lefamulin
- 50S
Recently Approved Drugs
___ (Pretomanid)
Indication: Treatment-resistant ___
Mechanism: Inhibits ___ acid biosynthesis through an unknown mechanism, and poisons respiration ( ___ ) through generation of nitric oxide
- Pretomanid
- mycolic
- mitochondria
