Synthetic Antimicrobial Agents - 15Qs Flashcards
List synthetic Antimicrobial agents
Sulfonamides
Sulfones
Quinolones
They are non-natural in origin
MOA of Sulfonamides
Bacteriostatic antimetabolite
What are Sulfonamides analogs of?
P-aminobenzenesulfonamide
What enzyme catalyses Dihydropteroate diphosphate to Dihydropteroic acid
Dihydropteroate synthase (inhibits the above conversion)
Are Sulfonamides used orally?
First safe and effective oral anti-infective agent
Name other MOA of Sulfonamides in other bacteria
Sulfonamides also block the biosynthesis of dihydrofolic acid by acting as a FALSE METABOLITE
Role of Dihydropteroate synthase here
The false metabolizes are converted by Dihydropteroate synthase to a more advanced intermediate which can’t continue down normal pathway
Which bacteria are intrinsically resistant to Sulfonamides
Bacteria capable of taking up pre-formed Folic acid (Vit B9)
Why are humans immune to the anti-metabolite effect of Sulfonamides
Humans do not have the necessary enzymes needed to biosynthesize Folic acid
What does the Sulfonamide moiety mimic?
Carboxyl group of PABA
What is the PKa of Carboxyl group of PABA
6.5
What’s the relationship btw the acidity of the NH group on the sulfonamide and it’s inhibition?
The more acidic the NH on Sulfonamides is, the better the inhibition and and the more water soluble the drug is at physiological PH.
For example, Sulfanilamide Pka = 10.4
What’s the role of resonance in stability of the Sulfonamides?
The ability of the NH group to undergo resonance leads to stability of the molecule.
List other factors that enhance stability in Sulfonamides.
Acidity is enhanced by substitution of a heterocyclic ring for ONE of the HYDROGENS of the sulfonamide moiety.
List primary uses of Sulfonamides (becuz of their broad spectrum)
A. Uncomplicated UTI cuzed by E. coli
B. Pneumocystis carinii infections in immune compromised pts e.g. AIDS and organ transplant pt
C. As 2nd or 3rd choice for most other susceptible bacteria
Are Sulfonamides orally active?
How are they excreted?
Yes.
They are excreted in active form in urine
How are Sulfonamides metabolized?
Partially deactivated in the LIVER by
A. N-4 acetylation (MAIN)
B. by glucoronidation
Are Sulfonamides protein bound?
Yes.
Intermediate (30- 70 %)
MOA of plasmid resistance (which is very common in Sulfonamides)
Altered Dihydropteroate synthase
What’s the main AE of Sulfonamides?
Allergy (rash, photosensitivity and drug fever. SJS can happen, but is rare)
What AE was common?
What advise would be given to pts to combat this?
Crystalurea, which led to Nephritis
Patients advised to drink lots of water
Are Sulfonamides cross allergen with penicillin
No
What enhances acidity?
Heterocyclic rings
Name specific-use sulfa drug.
What’s it used for?
Sulfasalazine
Prodrug for ulcerative colitis and crohns dx (anti-inflammatory)
What are the metabolizes of sulfasalazine?
Which is the active one?
Metabolized by gut flora to
Sulfapyridine and MAS
MAS- is the active one, but is a GUT irritant, so can’t be admin directly
What is the function of MAS
MAS is the active ingredient that treats both ulcerative colitis and crohn’s dx due to its anti-inflammatory activity
What’s the diff btw Sulfone and Sulfonamide?
Sulfone central sulfur atom is attached to 2 carbons
Sulfonamides central sulfur atom is attached to 1 carbon and 1 Nitrogen
What’s Sulfone used for?
Special utility in treating Hansen’s dx (leprosy) caused by Mycobacterium leprae.
How’s tx regime for leprosy
Prolonged tx, but doesn’t replace lost tissue
Sulfone is used in combo with Rifampicin
Role of Trimethoprim
Target similar pathway as sulfur drug, but they target diff enzymes, but final outcome is still prevention of folate therefore preventing DNA/RNA synthesis
What does trimethoprim inhibit
Dihydrofolate reductase
Inh Dihydrofolic acid from converting to Tetrahydofolic acid
How does Trimethoprim differentiate btw human cells and bacteria?
Selective toxicity
DFHR in humans is 20,000-40,000 times less sensitive than bacterial enzyme
How’s trimethoprim used?
It’s MOA?
PO
Bacteriostatic
When is the Parenteral form used?
In AIDS pt
Is trimethoprim synergistic with Sulfonamides
Yes.
How’s the combo of trimethoprim/sulfonamide used?
1:5 ratio
Can trimethoprim be used as an individual agent?
Yes.
It’s increasingly used as a single therapeutic agent
Describe the spectrum of trimethoprim?
Intrinsically broad spectrum
What are trimethoprim/sulfonamide used?
Primarily against UTI
Significant use against Shigelliosis, otitis media, traveller’s diarrhea, and bronchitis
How does resistance dev in trimethoprim
Resistance dev fast via alteration in the structure of DHFR
Because of R-factor plasmid transfer
List the most common SEs
Rash, nausea and vomiting
Name rare SEs of trimethoprim
Blood dysuriasias and PMC due to superinfection by C. Diff
Name the Quinolones
Nalidixic acid
Oxolinic acid
Cinnoxacin
Enoxacin
Does resistance dev to Quinolones?
Yes.
Very quickly
Uses of Quinolones
Primarily for UTI
Quinolones wrt
A. Absorption
B. Protein binding
C. SEs
A. Well absorbed
B. high protein binding
C. GI upset, rashes, photosensitivity, visual disturbances, convulsion
Fluoroquinolones.
What’s the effect of the addition of F to the quinolone structure?
F at C-6 Increases gram tve activity => broader spectrum
What’s the effect of piperazine attached to C-7 of Fluoroquinolones
Increases anti-psuedomonas activity
What decreases the potency of Fluoroquinolones
Antacid
Hematinics
Tonics
Diary products
What’s the effect of methoxy added to C-8 of Fluoroquinolones
In 3rd gen?
Increases anti-gram positive effect
MOA of Fluoroquinolones
Bactericidal
How does Fluoroquinolones carry out it bactericidal action
Inh bacterial DNA GYRASE and Topoislmerase IV(but nor mammalian Topoislmerase II)
How does resistance dev to Fluoroquinolones
Decreased uptake
Altered DNA gyrase or topoiosomerase
List SE Of Ciprofloxacin (covers Fluoroquinolones in gen)
Pro-convulsant Occasional Hallucination GIT (diarrhea, vomiting, abdominal pain, anorexia) Insomnia Visual disturbance
Can epileptics use Ciprofloxacin?
Not recommended
It’s pro-convulsant esp I. Epileptics
Counseling pt for insomnia using Fluoroquinolones
Pt to avoid caffeine, as this may potentiate insomnia
Why is Ciprofloxacin not given b4 puberty or to women of child-bearing age?
Erosion of (wt-bearing) joints
What’s the concern of people with cardiovascular issues about Fluoroquinolones?
Prolongation of QT interval which may lead to Arrythmias
Effect on NSAIDS on Ciprofloxacin
NSAIDs may exacerbate the CNS and convulsive SEs
Effect of the C-8 methoxy on Fluoroquinolones
They have lowered/ no liver metabolism
Have increased activity against topoiosomerase IV(becuz gram tve hv more topoiosomerase than gyrase)
Is Ciprofloxacin broad-spectrum?
Yes.
And used for many infections including UTI
Nitroimidazoles
Name the main agent here
Metronidazole
Uses of Metronidazole
Amoebal vaginitis (main use)
Also used for
Trichomoniasis, Giardiasis and Gardnerella vaginitis
What m.o. does metronidazole target?
Protozoa (not bacteria)
What’s the MOA metronidazole?
Bactericidal
How does metronidazole carry out its action?
By partial reduction of the NITRO group to poorly characterized product.
What’s the effect of the poorly characterized pdts?
Bind with critical cysteine-containing enzyme, which leads to the death of m.o.
List miscellaneous UTI drugs
Macrodantin/Nitrofurantoins
Phosphomycin
Methenamine/Hexamethylenetetramine
What are Macrodantin/Nitrofurantoin used for?
UTI prophylaxis
MOA of Macrodantin/Nitrofurantoin
Inh DNA/RNA fxns
Bactericidal
What happens as a result of rapid absorption of Macrodantin/Nitrofurantoin?
Nausea and vomiting
MOA of phosphomycin
BcteriCIDAL
Inh cell wall synthesis at an early phase
Primary uses of Phosphomycin
E. coli
Enterobacter faecalis
What happens to Methenamine/Hexamethylenetetramine in acid?
It depolarizes resulting in liberated formaldehyde
What’s the effect of the liberated formaldehyde (from Methenamine/Hexamethylenetetramine)
Non-specific bactericide
Whats Methenamine/Hexamethylenetetramine used for?
Recurrent UTI inf
