Lec #5 (Wk 2): DNA/Nucleic Acid Synthesis Inhibitors (PHARMACOLOGY)

Question 1

What are examples of folic acid synthesis inhibitors / antifolates / folate antagonists?

Answer 1

1- Sulfonamides
2- Trimethoprim

(Commonly used in combination to give you TMP/SMX or Co-trimoxazole).

Think of you going on a hike and see 2 pathways with a signpost in between, on 1 side we have a spring lake made of sulfur (Sulfonamides) and on the other side we have a temple (Trimethoprim), the signpost says TMP/SMX which is a combination of both.

Question 2

Provide examples of sulfonamides & is it a bacteriostatic or bactericidal?

Answer 2

Think of you going on a hike and see 2 pathways with a signpost in between, on 1 side we have a spring lake made of sulfur (Sulfonamides) and on the other side we have a temple (Trimethoprim), the signpost says TMP/SMX which is a combination of both.

So now, in this sulfur spring lake we have a pair of socks, 1 pair has the letter M to show sulfamethoxazole the other is a simple socks to show sulfasoxazole. We have a giant diamond in this lake to show sulfadiazine, and another silver sulfadiazine. (slide gives an extra one: sulfacetamide).
It is a bacteriostatic (both drugs independently are bacteriostatic but when combined; bactericidal).

Question 3

What is the MoA for sulfonamides?

Answer 3

The folic acid synthesis pathway, it will competitively inhibit the first enzyme of that pathway.

PABA + Pteridine –> Dihydropteroate (Enzyme = Dihydropteroate synthase).
So it inhibits this enzyme.

Question 4

Route of administration, metabolism, & excretion of sulfonamides?

Answer 4

• Rapidly absorbed after oral administration.
• Must be metabolized in the liver in order to be active.
• Excreted in the unchanged & metabolized form through the kidneys.
  It distributes into most body tissues & fluids.

Question 5

What is the spectrum of activity of sulfonamides, potent against what bacteria, and what bacteria are commonly resistant to sulfonamides?

Answer 5

• Broad activity; against gram + & -.
• Potent against Ducreyi, chlamydia, nocardia (no heart), & granulomatis.
• Bacteria which developed resistance are: S. pneumoniae, S. pyogenes, S. aureus, H. Influenzae, E. coli, N. meningitidis, & Shigella.

Question 6

What are the therapeutic uses of sulfonamides?

Answer 6

• UTI
• Otitis media
• Ocular (eye) infection.
• Burns

Question 7

What are the side effects of sulfonamides?

Answer 7

Think of you going on a hike and see 2 pathways with a signpost in between, on 1 side we have a spring lake made of sulfur (Sulfonamides) and on the other side we have a temple (Trimethoprim), the signpost says TMP/SMX which is a combination of both.

Now in this sulfur spring lake, it is quite dirty and a person who went swimming there developed rashes to show (1) hypersensitivity reactions, and a 2-headed zombie one called Steven the other Johnson to show (2) Stevens-Johnson syndrome, Steven is holding sunscreen to show (3) photosensitivity and Johnson is gobbling on liver to show (4) Hepatotoxicity. In this lake there was a kidney containing crystals to represent (5) Crystalluria. In this dirty lake, there was some blood and flags saying ‘G6PD’ to represent that those with (6) Glucose-6-phosphate deficiency could develop hemolytic anemia upon taking sulfonamides.

Question 8

How do some bacteria develop resistance to sulfonamides?

Answer 8

1- Random mutation.
2- Transfer through plasmids.
3- Permeability barrier.
4- Efflux pumps.

Question 9

What is trimethoprim & its MoA?

Answer 9

Trimethoprim is an antifolate which affects the 3rd and last enzyme of the folic acid synthesis pathway.
Dihydrofolic acid –> Tetrahydrofolic acid
(Enzyme = Dihydrofolate reductase, and we have NADPH –> NADP+)
So the enzyme being inhibited by trimethoprim is dihydrofolate reductase.

It is 20-100 times more potent than the other antifolate (Sulfonamide) and just like sulfonamide, also has broad spectrum activity against both gram + & -.

Question 10

What bacterias developed resistance to trimethoprim?

Answer 10

1- Pseudomonas Aeruginosa.
2- B. Fragilis.
3- Enterococci.

Question 11

What are the therapeutic uses of trimethoprim?

Answer 11

1- UTIs
2- Bacterial Prostatitis (BUT fluroquinolones is preferred to treat this).

Used in treating those conditions because they reach a higher concentration in the acidic prostatic & vaginal fluids.

Question 12

What are the adverse effects seen in trimethoprim?

Answer 12

1- Produces effects of folic acid deficiency like megaloblastic anemia, leukopenia, and granulocytopenia, this can be combatted by giving folinic acid (5-formyl tetrahydrofolate).
2- It is teratogenic where it can cause neural tube defects if taken during pregnancy thus it is contraindicated in pregnancy.

think of that temple in the pathway, it has bones all around it to represent bone marrow suppression (1), and a pregnant woman came to pray bs found it old looking so got angry (Contraindicated).

Question 13

Why do we combine sulfamethoxazole with trimethoprim?

Answer 13

This is called TMP/SMX or Co-trimoxazole.
The drugs individually are bacteriostatic bs together are bactericidal where they are synergistic and can block 2 enzymes at once. The ratio in body fluids & tissue is 20 (sulfa): 1 (trimethoprim).

Question 14

Can TMP/XMS or co-trimoxazole cross the BBB?

Answer 14

Yes - thus can treat meningitis.

Question 15

What are the therapeutic uses of TMP/XMS or co-trimoxazole?

Answer 15

In the signpost present between the temple (trimethoprim) & the sulfa lake (sulfonamides), we have a urinal to represent it is used for;
- UTI
- Traveller’s diarrhea
And there is a traveller on MARS rover to show it is effective against;
- MRSA
And this traveller is holding a balloon in the shape of lungs, 1 lung has cysts & the other is in the shape of a nose;
- Pneumocystitis jirovecii
- Pneumonia
- Sinus infections

Question 16

What is the first line therapy for pneumocystitis jirovecii?

Answer 16

TMP/XMS or AKA Co-trimoxazole.

Question 17

What is the mechanism of Action for fluoroquinolone?

Answer 17

Inhibits bacterial DNA gyrase (topoisomerase II) & topoisomerase IV. This consequently inhibits replication of DNA thus leading to bacterial cell death.

Question 18

Are fluoroquinolones bacteriostatic or bactericidal? Do they exert Post-Antibiotic Effects (PAE)?

Answer 18

Bactericidal.
They exhibit concentration dependent killing (just like ahminoglycosides) and exert post-antibiotic effect (PAE).

Question 19

In gram positive & gram negative, do we target topoisomerase II or topoisomerase IV?

Answer 19

Gram + bacteria = topoisomerase IV.
Gram - bacteria = topoisomerase II (DNA Gyrase).

Question 20

What are examples of medications which belong to the fluoroquinolones class?

Answer 20

All drugs from this class end in ‘floxacin’. We will represent them as a flock of seagulls. We will have an old-aged seagull sipping on a discarded cup to show (Ciprofloxacin). There are YOUNG (new fluoroquinolones) hippie seagulls 1 wearing a Levis shirt (Levofloxacin), a moxi shirt (Moxifloxacin) and the last one is wearing a gem-studded jacket (Gemifloxacin). all the new fluoroquinolones (the last 3) are all smoking to show that they are ‘respiratory fluoroquinolones’ which are used for hospital acquired pneumonia.
Ciprofloxacin is a classy seagull that is admiring the Mona Lisa painting to show how effective it is against pseudomonas.

Question 21

Side effects of fluoroquinolones?

Answer 21

A jogger is coming out of the restaurant & kneeling down & holding onto his ankle since his achilles tendon got ruptured to represent;
- Tendonitis.
His legs are covered in bandages to represent;
- Peripheral neuropathy.
When he was falling, he accidentally hit a kid & slammed his nose causing the little child to cry since nose is made of cartilage which tells us;
- Fluoroquinolones are contraindicated for growing children since they are harmful to the cartilage.
A cute mean squirrel is laughing at this crying child to represent;
- A long QT interval.
The child’s pregnant mother is comforting him to show him it is contraindicated during pregnancy.
During this incident, a chrome colored cell got squished to represent that they inhibit CYP450 enzymes.

Question 22

Fill in the gap:
__________ are a class of antibiotics that can possibly cause tendonitis, tendon rupture, leg cramps, & myalgia.

Answer 22

Fluoroquinolones.

Question 23

_______ is a possible connective tissue complication of fluoroquinolones administration in patients >60 years old.

Answer 23

Tendonitis.

Question 24

Fluoroquinolones can be divided into generations, give a drug example for each & their spectrum.

Answer 24

1st generation:
Nalidixic acid (quinolone).
Spectrum: gram - organism NOT pseudomonas.

2nd generation:
Ciprofloxacin
Norfloxacin
Ofloxacin
Spectrum: improved activity against gram - including pseudomonas. They have activity against aerobic bacteria with some activity against gram + bacteria.

3rd generation:
Levofloxacin.
Spectrum: improved activity against gram + bacteria.

4th generation:
Moxifloxacin
Gemifloxacin
Spectrum: Increased activity against gram + organisms, & broad anaerobic coverage.

Question 25

How can bacteria develop resistance against fluoroquinolones?

Answer 25

1- Altered target; like a mutation to the topoisomerase.

2- Reduced expression porin channels.

3- Increased expression of efflux pumps.

Question 26

Route of administration for fluoroquinolones?

Answer 26

Oral
IV

IF TAKEN ORALLY SHOULD NEVER BE TAKEN WITH A SUPPLEMENT LIKE CALCIUM, IRON, ZINC, ANTACIDS (CONTAIN ALUMINUM SALTS) AS FLUOROQUINOLONES CONTAIN METAL IONS THUS CAN BIND TO THAT & INHIBIT GIT ABSORPTION.

Question 27

Can fluoroquinolones cross the BBB?

Answer 27

No but they can slowly penetrate the BBB during INFLAMMATION.

Question 28

Can fluoroquinolones be detected in breast milk?

Answer 28

Ciprofloxacin
Ofloxacin
Levofloxacin
all those can be detected in human breast milk.

Question 29

What is the first line drug treatment for tuberculosis?

Answer 29

Rifampicin.

Question 30

Is rifampicin bacteriostatic or bactericidal? MoA?

Answer 30

Bactericidal.
Interferes with the DNA-dependent RNA polymerase thus blocking RNA synthesis.

Question 31

What is the spectrum for rifampicin?

Answer 31

Intracellular & extracellular mycobacteria including:
- Tuberculosis.
- M. Kansasii
- M. Avium Complex (MAC).
- M. Leprae.

Question 32

what are the pharmacokinetics of rifampicin?

Answer 32

• Induces hepatic CYP450 enzymes which can lead to potential drug interactions.
• Half life of the drug is reduced in the first 2 weeks due to auto-induction.
• Eliminated thro the bile, feaces, urine.
• Causes urine, faeces, and tears to be orange-red in color.

Question 33

Adverse effects of rifampicin?

Answer 33

1- Hepatitis.
2- Intermittent dosing or higher doses can cause flu like symptoms.

Question 34

what drug causes the urine, feces, and tears to be red-orange?

Answer 34

Rifampicin thus warn patients so that they don’t get scared.