Sulfonamides and Trimethoprim

Question 1

First effective chemotherapeutic agent employed systemically for the prevention and cure of bacterial infections in man?

Answer 1

Sulfonamides

Question 2

What are the important structural features of the sulfonamides?

Answer 2

Sulfamide (SO2) attached to a benzene ring and an amino group (NH2)

Question 3

What causes inactivation of the sulfonamide and how?

Answer 3

Hepatic metabolism of amino group

Question 4

Are sulfonamides broad spectrum or narrow spectrum?

Answer 4

Broad spectrum (both Gram + and -)

Question 5

Are sulfonamides bacteriostatic or bacteriocidal?

Answer 5

Bacteriostatic, so immune system is key for resolution

Question 6

Instance when a sulfonamide can be bacteriocidal?

Answer 6

High concentration achieved in urine to treat UTI

Question 7

On what part of the bacteria will sulfonamide work in treating the UTI?

Answer 7

Effect cell’s ability to replicate by starving it of thymine

Question 8

Sulfonamides are structural analogues to what compound?

Answer 8

Para aminobenzoic acid (PABA) so it’s a competitive inhibitor

Question 9

Why is PABA important to bacteria and why is its antagonism not toxic to humans?

Answer 9

Bacteria use PABA to make folic acid. We get our folic acid from our diet

Question 10

What is folic acid used for?

Answer 10

Synthesis of purines, pyrimidines, and proteins

Question 11

Is there a delay in the effect of sulfonamides and why?

Answer 11

Yes, bacteria can use up folate pools before taking up sulfonamide

Question 12

How can sulfonamide be bacteriocidal instead of its normal bacteristatic?

Answer 12

When it achieves high enough concentration to cause a thymine-less death by stopping DNA synthesis

Question 13

Sulfonamides are synergistic with what drug?

Answer 13

Trimethoprim

Question 14

Where does Trimethoprim work on the bacteria?

Answer 14

Still at folic acid, except it inhibits dihydrofolate reductase from transforming dihydrofolate to tetrahydrofolate, the carbon donor to proteins, DNA, & RNA.

Question 15

What does Sulfamethoxazole and Trimethoprim do (SMZ/TMP)?

Answer 15

Sequential blockade of folic acid in bacteria (PABA—SMZ—>Dihydrofolic acid–TMP–> Tetrahydrofolic acid—–>DNA helper

Question 16

How can bacteria gain resistance to sulfonamides (4)? Note the primary method.

Answer 16

1. Alter enzyme using PABA so it only uses PABA and not the sulfonamide
2. Increase capacity to inactivate or destroy sulfonamide
3. Alternative metabolic pathway for synthesis
   * 4. Increase PABA synthesis to outcompete the sulfonamide (primary)

Question 17

Are sulfonamides soluble or insoluble?

Answer 17

Insoluble; transformed to soluble salts.

Question 18

Character of gut absorption for Sulfonamide?

Answer 18

Rapid: 70-100% absorbed from oral

Question 19

Can Sulfonamides be given subcutaneously or intramuscular and why?

Answer 19

No, sulfonamide salts are highly alkaline

Question 20

2 specific uses of sulfonamides?

Answer 20

Opthalmic solutions/ointments due to good aqueous humor penetration
Meningitis (can cross BBB)

Question 21

How do sulfonamides travel in the blood and what does this mean for their activity?

Answer 21

Bound to plasma protein (displace bilirubin), only unbound drugs can enter the cell & act

Question 22

What is a toxicity that can occur with sulfonamide binding to plasma proteins?

Answer 22

They displace bilirubin that can then cross blood brain barrier and deposit in basal ganglion causing brain damage

Question 23

Distribution of Sulfonamides?

Answer 23

Uniform throughout body, crosses blood brain barrier and get into aqeous humor of eye

Question 24

How is Sulfonamide metabolized?

Answer 24

Hepatic at the amino group which eliminates the antibacterial, but keeps the toxicity

Question 25

How is Sulfonamide eliminated? What fluids have high and low concentrations?

Answer 25

In urine by filtration through the kidneys; has high concentration in intestinal juices (most reabsorbed) and low levels are in saliva, milk, and prostatic fluid

Question 26

Why is sulfonamide the drug of choice for a kidney infection?

Answer 26

Its excretion provides for levels 10-25 higher than that in serum

Question 27

Toxic effects from Sulfonamides?

Answer 27

GI intolerance, anorexia, nausea, vomiting

Question 28

2 major toxic effects of Sulfonamides

Answer 28

Hypersensitivity rash: Stevens-Johnson syndrome (loss of mucosal lining) in children could be fatal Crystallization in kidneys

Question 29

Two ways to prevent sulfonamide crystallization in kidneys?

Answer 29

Maintain high urine ph (alkaline w/ NaHCO3) and high urine flow via high fluid intake (1.5-2L/day)

Question 30

What genetic deficiency will react with sulfonamides? What does this cause?

Answer 30

Glucose-6-phosphate dehydrogenase deficiency; acute hemolytic anemia

Question 31

What is a toxic effect sulfonamides will have on newborns?

Answer 31

Sulfonamide displaces bilirubin causing its deposit in brain leading to brain damage

Question 32

Is sulfonamide prescribed for oral dental lesions?

Answer 32

No. Used in UTI, topical infections (burns, eyes)

Question 33

What are six therapeutic uses for sulfonamides?

Answer 33

Pulmonary lesions, brain abscesses, joint infections, urinary tract infections (often 1st agent tried), systemic infections, topical infections (burn wounds, eye infections)

Question 34

What is a characteristic of sulfonamides that even if put with other sulfonamides they act as if they are alone in solution?

Answer 34

Principle of Independent solubility

Question 35

What does principle of independent solubility help with in Sulfonamide treatment?

Answer 35

Decreases risk of urine crystallization

Question 36

What does treating with 3 sulfonamide cocktail allow?

Answer 36

Can get higher therapeutic dose, while avoiding precipitating out in urine

Question 37

How does trimethoprim work?

Answer 37

Selective inhibitor of dihydrofolate reducatase in lower organism (has a higher affinity for the bacterial version of this enzyme--> in humans, a 20-60kx greater needed)

Question 38

When is trimethoprim bacteriostatic? Bacteriocidal?

Answer 38

Bacteriostatic: absence of all products of one-carbon metabolism Bacteriocidal: Absence of thymine (but presence of purines and amino acids)

Question 39

Why does thymine play such a big role in trimethoprim?

Answer 39

"Thymineless death" causes unbalanced growth, killing the bacteria

Question 40

What two ways bacteria form resistance to trimethoprim?

Answer 40

1. Increased levels of enzyme, dihydrofolate reductase | 2. Reduced binding to trimethoprim to target enzyme

Question 41

What is one potential toxicity of trimethoprim?

Answer 41

To bone marrow progenitors causes suppression of blood cell production

Question 42

What is the half life of SMZ/TMP?

Answer 42

5-15 hours

Question 43

Where in the body is SMZ/TMP bacteriocidal?

Answer 43

Blood and urine due to low thymine [ ] (high amino acid content)