Cell metabolism/DNA Replication inhibitorsTB/Misc

Sulphanilamide

Sulfonamides; Discovered by Gerard Domagk

• Studied a bright red dye, Prontosil, which was metabolized in vivo to —

Inhibits dihydropteroate synthetase, thus preventing folic acid synthesis.

What is the mechanism of action (MOA) of sulfonamides?

Ionized.

What is the active form of sulfonamides?

The para-amino group must be unsublstituted.

What is essential for the activity of sulfonamides?

The aromatic ring and the sulfonamide functional groups are both required.

What functional groups are required for sulfonamides?

Both must be directly attached to the aromatic ring.

How must the sulfonamide and amino groups be positioned?

The aromatic ring must be para-substituted only.

What should the substitution on the aromatic ring be?

The sulfonamide nitrogen must be primary or secondary.

What must the sulfonamide nitrogen be?

Yes, R2 can be modified.

Can R2 be modified in sulfonamides?

True

True or false

• Discovered by Gerard Domagk ‡ Studied a bright red dye, Prontosil, which was metabolized in

  vivo to sulfanilamide

Bacterial dihydrofolate reductase inhibitor.

What is the mechanism of action (MOA) of Trimethoprim?

Protozoal dihydrofolate reductase inhibitor.

What is the mechanism of action (MOA) of Pyrimethamine?

Prodrug of 5-aminosalicylic acid.

What is Sulfalazine?

Sulfamethoxazole + Trimethoprim (synergistic combination).

What drugs are combined in Co-trimoxazole?

1st attack of UTI, P. carinii pneumonia (DOC).

What conditions is Co-trimoxazole used for?

Sulfadiazine + Trimethoprim.

What is Co-trimazine composed of?

Used in Toxoplasmosis.

What is the primary use of Sulfadiazine + Pyrimethamine?

Used in Malaria.

What is Sulfadoxine + Pyrimethamine used for?

Used in Burns.

What is the use of Silver sulfadiazine + Mafenide?

Inhibit dihydropteroate synthetase.

What is the mechanism of action (MOA) of sulfones?

Used in leprosy.

What is Dapsone used for?

Contraindicated in G6PD deficiency.

What is a contraindication for Dapsone?

May cause hemolytic anemia.

What potential side effect can Dapsone cause?

QUINOLONES

patterned after Nalidixic acid (NegGram) o synthetic antibacterial agent

inhibits DNA Gyrase/Topoisomerase IV

Quinolone MOA

Recall

Recall

1,4 dihydro-4-oxo-3 pyridine carboxylic acid.

What is the nucleus of fluoroquinolones?

It greatly reduces or abolishes activity.

What effect does the addition of groups at position 2 have on activity?

It increases antibacterial activity.

What is the effect of adding a fluorine atom at position 6?

It provides activity against Pseudomonas aeruginosa when added at position 7.

What role does piperazine play in fluoroquinolones?

Small alkyl substitution.

What substitution provides greater potency at position 1?

Photosensitivity.

What is the side effect of adding a halogen at position 8?

Lomefloxacin.

Which fluoroquinolone has the highest activity?

Sparfloxacin.

Which fluoroquinolone has the lowest activity?

Enzyme inhibitor.

What type of inhibitor are fluoroquinolones?

They interact with fluoroquinolones.

What do products containing divalent and trivalent metals affect?

Inhibit nucleic acid synthesis

What is the mechanism of action (MOA) of nitrofurans?

Nitro at 5th position

What structural feature at the 5th position provides antibacterial activity?

Nitrofurantoin

What nitrofuran is used in UTI?

Nitrofurazone

Which nitrofuran is used topically in burns?

Furazolidone

What is the nitrofuran used in bacterial or protozoal diarrhea?

Metronidazole

What nitrofuran is effective against trichomonas, amoeba, giardia, and anaerobic bacteria?

C. difficile induced pseudomembranous colitis

What is the DOC for metronidazole?

Methenamine (Urotropin)

What is a urinary antiseptic used in UTI?

Formaldehyde release in low pH

What is required for the antibacterial effect of Methenamine?

Given with acidifying agents (NH4Cl)

How is the effect of Methenamine optimized?

Acetohydroxamic acid (Lithostat)

What is given to counteract urease produced by certain bacteria?

Fusidic acid

An antibiotic obtained from Fusidium coccineum with a CPPP structure

Streptomyces meditirranei

What is the source of this Rifampicin?

Inhibits RNA polymerase

What is the mechanism of action (MOA) of Rifampicin?

Most active agent in clinical use for TB patients

What is the significance of Rifampicin in tuberculosis treatment?

Red-orange secretions, hepatotoxicity, enzyme inducer

What are the side effects and interactions of Rifampicin?

Isoniazid (H)

What is aka Isonicotinic acid hydrazine?

Inhibit synthesis of mycolic acid

What is the mechanism of action (MOA) of Isoniazid?

Peripheral neuropathy, hepatotoxicity

What are the side effects of Isoniazid?

Give pyridoxine/vitamin B6

What should be administered alongside Isoniazid?

Pyrazinamide (Z)

What is aka Pyrazinecarboxamine?

Unclear (Fatty acid synthesis (FAS-1) Inhibitor)

What is the mechanism of action (MOA) of Pyrazinamide?

First line drug for short-term treatment

What is the significance of Pyrazinamide in tuberculosis treatment?

Prodrug of pyrazinoic acid

What is the relationship between Pyrazinamide and pyrazinoic acid?

Hyperuricemia, hepatotoxicity

What are the side effects of Pyrazinamide?

Ethambutol (E)

What is the mechanism of action (MOA) of Ethambutol?

Inhibits arabinosyl transferase

How does Ethambutol affect the mycobacterial cell wall?

Optic neuritis (blue-green vision)

What is a side effect of Ethambutol?

Streptomycin

What is the first and oldest antibiotic effective in the treatment of tuberculosis?

Streptomyces capreolus

What is the source of this second-line Capreomycin?

Ototoxicity, nephrotoxicity

What are the side effects of Capreomycin?

Para-aminosalicylic acid (PAS)

What is the mechanism of action (MOA) of Aminosalicylic acid?

Inhibits dihydropteroate synthetase

How does Aminosalicylic acid contribute to tuberculosis treatment?

One of the very first drugs used for tuberculosis

What is the historical significance of Aminosalicylic acid?

Ethionamide

Analog of isoniazid ‡ s/e: hepatotoxicity

Clofazimine (Lamprene

• Tuberculoid

• Lepromatous

For — leprosy (mild), dapsone + rifampicin is given. However, for — leprosy (severe), clofazimine is added to the regimen