Folate Antagonists, Quinolones, and UTI Agents Flashcards
2 types of folate antagonist drugs
Sulfonamides and trimethoprim/pyrimethamine
Sulfonamides MOA
Inhibit dihydrofolate synthesis (specifically dihydropteroate synthetase)
Trimethoprim and pyrimethamine MOA
Inhibitors of folate reduction (inhibit dihydrofolate reductase)
How do humans obtain folate?
Obtain reduced folate in diet
This is an example of selective toxicity for many drugs
Sulfonamides compete with this for folate synthesis pathway
PABA (p-aminobenzoic acid)
Sulfonamides are a ______ inhibitor of nucleic acid synthesis
Indirect
Sulfonamides are a _______ inhibitor dihyropteroate synthase which prevents PABA incorporation into folic acid
Competitive
Spectrum for sulfonamides
Broad spectrum
But resistance severely limits actual clinical spectrum
4 adverse effects of sulfonamides
Crystal formation in urine
Blood problems (esp. with G6P dehydrogenase deficiency)
Hypersensitivity
Kernicterus in infants
Glucose-6-P dehydrogenase deficiency is most commonly seen in people from this descent
Mediterranean and African origin
Highest risk of acute hemolysis as a result of sulfonamide use is in patients with this
Genetic deficiency in RBC glucose-6-phosphate dehydrogenase (FAVism)
Crystal formation in urine, blood problems, hypersensitivity, and kernicterus in infants are adverse effects of this
Sulfonamides
Rare medical emergency affecting skin and mucous membranes that can be triggered by sulfonamides
Fever, malaise, erythema multiforme, ulceration of mucous membranes
Stevens-Johnson syndrome
What is Stevens-Johnson syndrome?
Rare medical emergency affecting skin and mucous membranes that can be triggered by sulfonamides
2 Adverse effects of trimethoprim and pyrimethamine
Skin rashes
Major bone marrow toxicity potential when used chronically but can be reduced with folic acid supplementation (Megaloblastic anemia, Leukopenia, Granulocytopenia)
Skin rashes and bone marrow toxicity (megaloblastic anemia, leukopenia, granulocytopenia) are adverse effects to this
Trimethoprim and Pyrimethamine
Bone marrow toxicity when trimethoprim and pyrimethamine are used chronically can be reduced with this
Folic acid supplementation
Optimal ratio for Trimethoprim-Sulfamethoxazole combination therapy
Produce sequential blockage of folate synthesis; super additive drug interaction
20 parts Sulfa to 1 part Trimethoprim
Spectrum of quinolones
Broad spectrum (block DNA synthesis and function)
Effective for gram negative rods in UTIs and GI infections, and some gram positive
MOA of quinolones
Inhibit topoisomerase II (DNA gyrase) and IV
Quinolones inhibition of this is the primary drug target in gram negative bacteria
DNA gyrase (topoisomerase II)
Quinolones inhibition of this is the primary drug target in gram positive bacteria
Topoisomerase IV
Quinolones inhibition of DNA gyrase (topoisomerase II) is the primary drug target for this type of bacteria
Gram negative
Quinolones inhibition of topoisomerase IV is the primary drug target for this type of bacteria
Gram positive
Drugs that chelates with some metals (e.g. antacids containing aluminum hydroxide or magnesium hydroxide: Maalox, Mylanta)
Quinolones
Quinolones chelates with this
Some metals
(e.g. antacids containing aluminum hydroxide or magnesium hydroxide: Maalox, Mylanta)
4 Common problems with quinolone use
Nauseua, vomiting, diarrhea
Nephrotoxicity
Avoid use with antacids
3 C’s
Quinolones should avoid use with these
Antacids
Drug that should avoid use with antacids
Quinolones
3 C’s of quinolones
Central nervous system (headaches, malaise, depression, psychosis, hallucinations)
Cartilage (ruptured tendons, avoid use in pregnancy and children)
Cardiac toxicity (QT prolongation)
The 3 C’s (central, cartilage, cardiac) describe the adverse effects of this drug
quinolones
Quinolones black box (3)
Avoid use in myasthenia gravis
Discontinue at first sign of tendon inflammation or pain
Tendon rupture
Tendon most vulnerable to rupture with quinolone use
(all tendons are vulnerable)
Achilles tendon
Tendon rupture can occur as early as _____ hours following first dose, and last ______ after last dose
Early as 48 hours
Last months after last dose
Primary elimination of quinolones
Tubular secretion
Blocked by probenecid resulting in longer durations of serum antibacterial action
Tubular secretion of quinolones is blocked by this, resulting in longer durations of serum antibacterial action
Probenecid
Tubular secretion of this drug is blocked by probenecid, resulting in longer durations of serum antibacterial action
Quinolones
2 antiseptic agents used to treat UTIs
Nitrofurans
Methenamine
MOA of nitrofurans
Form reactive intermediates that damaged nucleic acid
Requires bacterial reduction enzymes (nitroreductases) for activation
Nitrofurans require these for activation
Bacterial reduction enzymes (nitroreductases)
This limits mammalian toxicity of nitrofurans (selectively toxic)
High biotransformation potential with rapid renal excretion keeps serum levels low
Spectrum of nitrofurans
Mainly used as gram negative agent (narrow spectrum), but some important activity in gram positive (extended spectrum)
This keeps serum levels of nitrofurans very low
First pass effect
5 adverse effects of Nitrofurans
Nausea/vomiting
Hypersensitivity
Pulmonary reactions (acute pneumonia, interstitial fibrosis)
Peripheral neuropathy
Hemolytic anemia with RBC G6PD deficiency
Avoid use in late pregnancy
2 pulmonary reactions with nitrofurans
Acute pneumonia
Interstitial fibrosis
MOA of methenamine
Prodrug that is converted to formaldehyde in acid pH of 5.5 or less in urine, denaturing proteins and is toxic to most bacteria
Methenamine is converted to this in acid pH of 5.5 or less in urine
Formaldehyde
Spectrum of methenamine
Broad spectrum
Is converted to formaldehyde, which is toxic to most bacteria
Bacteria that alkalize urine and disrupt methenamine mechanism
Proteus bacteria
Proteus bacteria disrupt methenamine mechanism by doing this
Alkalize urine
Methenamine is often combined with this to optimize activity
Urine acidifier mandelic acid
2 contraindications of methenamine
Elevated ammonia levels make this contraindicated in hepatic dysfunction patients
Mandelic acid form contrainidicated in renal dysfunction patients to avoid acid crystallization
Elevated ammonia levels (contraindicated in hepatic dysfunction patients) and mandelic acid form (contraindicated in renal dysfunction patients) are effects of this drug
Methenamine
Urinary analgesic that alleviates symptoms of UTIs
Phenazopyridine (Azo)
Phenazopyridine (Azo) is a minor metabolite of this
Acetaminophen
This drug is a minor metabolite of acetaminophen
Phenazopyridine (Azo)
Adverse effects of Phenazopyridine (Azo)
Body fluid discoloration
Not to be used in renal failure
Drug that inhibits dihydropteroate synthase, preventing PABA incorporation into folic acid
Sulfonamides
Blood problems (acute hemolysis in G6PD deficiency), hypersensitivity and Stevens-Johnson syndrome, and kernicterus in infants are adverse effects of this drug
Sulfonamides
Drugs that inhibit dihydrofolate reductase
Trimethoprim and Pyrimethamine
Skin rashes and bone marrow toxicity (megaloblastic anemia, leukopenia, granulocytopenia) are adverse effects of this
Trimethoprim and Pyrimethamine
Drugs that inhibit topoisomerase II (DNA gyrase) and IV
Quinolones
Part of quinolones black box indicates use should be avoided in this
Myasthenia gravis
Tendon rupture is a characteristic adverse effect / warning of this drug
quinolones
Drug that forms reactive intermediates and damaged nucleic acids
Nitrofurans
Nausea/vomiting, hypersensitivity, pulmonary reactions (acute pneumonia, interstitial fibrosis), peripheral neuropathy, hemolytic anemia with RBC G6PD deficiency, and avoid use in late pregnancy are adverse effects of this
Nitrofurns
