Folic Acid Antagonists

Question 1

Name the three classes of folic acid antagonists

Answer 1

Sulfonamides, Trimethoprim, Co-trimoxazole

Question 2

Describe the biosynthesis pathway of folic acid, which steps occur in microorganisms and humans, and explain its importance

Answer 2

Biosynthesis Pathway:

Microbes
1. Dihydropteroate Synthase:
Pteridine + PABA => Dihydropteroic acid

2. Dihydrofolate Synthase:
   Dihydropteroic acid + Glutamate => Dihydrofolic acid

Microbes and Humans
1. Dihydrofolate reductase:
Dihydrofolic acid + NADPH => Tetrahydrofolate

2. Tetrahydrofolate cofactors / precursors are needed for the synthesis of amino acids, purines and thymidine in DNA, RNA and protein synthesis

Question 3

Combination therapy of cotrimoxazole exerts what kind of effect?

Answer 3

Synergistic bactericidal effect

Question 4

Sulfonamide mechanism of action - Which step of the pathway does it inhibit?

Answer 4

Competitively inhibit the action of dihydropteroate synthase

Question 5

What makes a bacteria sensitive to the inhibitory effect of sulfonamides?

Answer 5

A bacteria is sensitive to sulfonamide action only if it is necessary for the bacteria to synthesise its own folic acid.

Bacteria that can use preformed folates are not affected. Hence, sulfonamides are sufficient but not necessary.

Question 6

Why does sulfonamides alone exert bacteriostatic effect?

Answer 6

It is sufficient to compete with PABA for dihydropteroate synthase.

Sulfonamide action can be counteracted by higher PABA concentrations

Question 7

Why are mammalian cells insensitive to sulfonamides?

Answer 7

Mammalian cells require preformed folic acid and cannot synthesise it

Question 8

How are sulfonamides administered?

Answer 8

Oral - Well absorbed (Except sulfasalazine)

Question 9

Sulfonamide distribution

Answer 9

Serum albumin bound

Distributed throughout bodily fluids including cerebrospinal fluid, placental barrier and fetal tissue

Question 10

How are sulfonamides cleared and why are they nephrotoxic?

Answer 10

Hepatic acetylation and conjugation of sulfonamides retain the toxic potential to precipitate at neutral or acidic pH causing crystalluria

Eliminated by glomerular filtration and secretion in kidneys and in breast milk

Question 11

4 Adverse Drug Events caused by sulfonamides and explain how the pharmacokinetic properties can lead to them

Answer 11

1. Crystalluria (Nephrotoxicity) - Resolve by hydration: Due to hepatic acetylation retaining toxic potential to precipitate in neutral or acidic pH
2. Hypersensitivity - Rash, SJS, angioedema: Due to presence of sulfur
3. Hematopoietic disturbances - Hemolytic anemia in G6PD deficiency: G6PD enzyme has antioxidant properties by maintaining high levels of GSH and NADPH which protect cells from oxidative damage
4. Kernicterus - Newborns with bilirubin entering CNS: Bilirubin displacement from serum albumin which becomes free to pass into the CNS

Question 12

Sulfonamides can potentiate the effect of which drug

Answer 12

Warfarin

Question 13

What patient population are sulfonamides contraindicated in?

Answer 13

Newborns, infants, pregnant women, breastfeeding

Question 14

What does trimethoprim inhibit?

Answer 14

Dihydrofolate reductase

Question 15

Trimethoprim MOA

Answer 15

Inhibit dihydrofolic acid reduction to tetrahydrofolate (active form) required for purine, pyrimidine and amino acid synthesis

Question 16

Spectrum activity of Trimethoprim

Answer 16

Enterobacter spp, E coli, Klebsiella

Question 17

How do bacteria become resistant to trimethoprim?

Answer 17

Reduced affinity for trimethoprim through alteration of dihydrofolate reductase in Gram negative bacteria

Question 18

Trimethoprim is administered ________

Answer 18

Orally (Rapid)

Question 19

What is an advantage of trimethoprim as a weak base?

Answer 19

It can achieve higher concentrations in relatively acidic prostatic and vaginal fluids

Question 20

What does trimethoprim basicity mean for drug distribution?

Answer 20

Wide distribution into body tissues and fluids including CSF

Question 21

Trimethoprim is eliminated by ________

Answer 21

renal excretion unchanged

Question 22

Why is trimethoprim avoided in pregnancy?

Answer 22

Its adverse effect is that it causes folic deficiency affecting red blood cell synthesis, leading to megaloblastic anemia, leukopenia and granulocytopenia in pregnant patients having poor diets

Question 23

How can folic acid deficiency be managed?

Answer 23

Administer folinic acid, a 5 formyl derivative of tetrahydrofolate that can readily convert to tetrahydrofolate without the need for reduction

Question 24

Ratio of Cotrimoxazole

Answer 24

Trimethoprim:Sulfamethoxazole = 1:5

Question 25

Cotrimoxazole trade name

Answer 25

Bactrim and Septra

Question 26

Cotrimoxazole MOA

Answer 26

Inhibit two sequential steps in the synthesis of tetrahydrofolate

Question 27

Cotrimoxazole is administered ____

Answer 27

Commonly oral but can be used IV in severe pneumonia and UTI when cannot take by mouth

Question 28

Cotrimoxazole drug distrbution

Answer 28

Throughout the body

Acidic prostatic and vaginal fluids

Good CSF penetration and readily crosses BBB

Question 29

Cotrimoxazole clearance

Answer 29

Parent and metabolites renally excreted

Question 30

5 Clinical uses of Cotrimoxazole

Answer 30

1. UTI (E coli) 1st line prophylaxis in recurrent UTI in women and penicillin allergies
2. RTI (Haemophilus, Klebsiella)
3. Toxoplasmosis
4. MRSA skin and soft tissue infection (community-acquired)
5. Pneumocystis Pneumonia (Pneumocystis jiroveci) in immunocompromised patients

Question 31

Which trimesters of pregnancy should cotrimoxazole be avoided?

Answer 31

1st trimester in case of folate deficiency and last trimester in case of G6PD deficiency

Question 32

6 Adverse Effects of Cotrimoxazole

Answer 32

Presence of Sulfur:
1. Skin reactions - Rash (Common)
2. Photosensitivity
3. Nausea and vomiting (Common)
4. Glossitis and Stomatitis

In G6PD deficiency:
5. Hemolytic anemia

Folic acid deficiency due to Trimethoprim:
6. Megaloblastic anemia, leukopenia, thrombocytopenia

Question 33

Cotrimoxazole drug interactions

Answer 33

Phenytoin half-life increases

Warfarin effect enhanced