Synthetic Antimicrobial Agents - 15Qs Flashcards by Renny Oye

List synthetic Antimicrobial agents

Sulfonamides
Sulfones
Quinolones

They are non-natural in origin

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MOA of Sulfonamides

Bacteriostatic antimetabolite

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What are Sulfonamides analogs of?

P-aminobenzenesulfonamide

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What enzyme catalyses Dihydropteroate diphosphate to Dihydropteroic acid

Dihydropteroate synthase (inhibits the above conversion)

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Are Sulfonamides used orally?

First safe and effective oral anti-infective agent

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Name other MOA of Sulfonamides in other bacteria

Sulfonamides also block the biosynthesis of dihydrofolic acid by acting as a FALSE METABOLITE

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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

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Which bacteria are intrinsically resistant to Sulfonamides

Bacteria capable of taking up pre-formed Folic acid (Vit B9)

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Why are humans immune to the anti-metabolite effect of Sulfonamides

Humans do not have the necessary enzymes needed to biosynthesize Folic acid

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What does the Sulfonamide moiety mimic?

Carboxyl group of PABA

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What is the PKa of Carboxyl group of PABA

6.5

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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

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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.

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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.

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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

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Are Sulfonamides orally active?

How are they excreted?

Yes.

They are excreted in active form in urine

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How are Sulfonamides metabolized?

Partially deactivated in the LIVER by

A. N-4 acetylation (MAIN)

B. by glucoronidation

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Are Sulfonamides protein bound?

Yes.

Intermediate (30- 70 %)

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MOA of plasmid resistance (which is very common in Sulfonamides)

Altered Dihydropteroate synthase

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What’s the main AE of Sulfonamides?

Allergy (rash, photosensitivity and drug fever. SJS can happen, but is rare)

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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

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Are Sulfonamides cross allergen with penicillin

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What enhances acidity?

Heterocyclic rings

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Name specific-use sulfa drug.

What’s it used for?

Sulfasalazine

Prodrug for ulcerative colitis and crohns dx (anti-inflammatory)

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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