Antimetabolites

Question 1

Antimetabolites drugs?

Answer 1

1. Sulfonamides
2. Trimethoprim
3. Co-trimoxazole

Question 2

Antimetabolites Pathway MOA?

Answer 2

1. PABA is converted to dihydrofolate by the enzyme dihydropteroate synthetase
2. Dihydrofolate is converted to tetrahydrofolate by dihydrofolate reductase
3. Tetrahydrofolate is converted to synthesisof purines and then to DNA

Question 3

Which enzymes do which antimetoabolites act on?

Answer 3

Sulfonamides-dihydropteroate synthetase enzyme

Trimethoprim-dihydrofolate

Question 4

Sulfonamides parent drug?

Answer 4

Prontosil(parent drug)=Sulfanilamide(intialy produced) =Sulfonamides

Question 5

Sulfonamides and PABA?

Answer 5

Structural analogues of PABA

Question 6

Sulfonamides targets what type of bacteria?

Answer 6

Target both gram +ve and -ve bacteria

Question 7

Sulfonamides MOA for bacteria?

Answer 7

Bacteriostatic cell division but does not kill

Question 8

Sulfonamides and rickettsia?

Answer 8

Sulfonamides stimulate rickettsiae

Question 9

What affects the effects of sulfonamides?

Answer 9

1. Presence of pus
2. Tissue Fluid
3. PABA

Question 10

Sulfonamides CI

Answer 10

-Pregnancy

Question 11

Sulfonamides in clinical examples & their indications?

Answer 11

1. Silver Sulfadiazine(topical)

I: Infected leg ulcers, pressure sores and burn wounds

2. Sulfasalazine

-Spilt by intestinal microflora

Sulfapyridine + 5-aminosalicylaste

I: Rheumatoid arthrytis & colitis

3. Oral absorbable
   – Sulfamethoxazole
   
   • In combination with
     trimethoprim (co-
     trimoxazole)

Question 12

Trimethoprim

-Bacteria MOA
-Spectrum
-MOA

Answer 12

-Bacteriostatic
-Broad Spectrum
-Inhibits dihydrofolate reductase

Question 13

Co-trimoxazole?

Answer 13

A combination of sulfonamides and trimethroprim

Question 14

Co-trimoxazole composition?

Answer 14

Combination of trimethoprim and sulfamethoxazole

Ratio: 1: 5
T: S

Question 15

Co-trimoxazole bacteria MOA?

Answer 15

Bactericidal

Question 16

Co-trimoxazole I?

Answer 16

For use in HIV patients
-Pneumocystis jirovecii pnemonia
-Toxoplasmosis & Isospora belli diarrhea
-Nocardiosis (treatment of choice)

Question 17

Which condition does co-trimoxazole not treat and why?

Answer 17

Not used for rickettsiae ‘coz it causes rickettsiae

Question 18

Co-trimoxazole CI?

Answer 18

Pregnant woman

Question 19

Antimetabolites mechanisms of resistance-5?

Answer 19

1. Overproduction of PABA
2. Overproduction of dihydrofolate reductase
3. Production of altered reductase with decreased drug binding
4. Production of dihydropteroate synthetase with decreased affinity for sulfonamides
5. Loss of permeability to both drugs

Question 20

Sulfamethoxazole S/E-7?

Answer 20

-Kernicterus (Bilirubin displacement)-toxic encephalopathy

-Allergy: Rash, SJS, Drug fever

-Decreased efficacy of oral contraceptives

-Nausea, vomiting and headache

-Agranulocytosis & thrombocytopenia

-Precipitation of acetylated metabolites in the
urine (crystalluria) → drink lots of water and
make urine more alkaline

-Cross-sensitivity with other sulfanilamide
derivatives

Question 21

Trimethoprim S/E-5?

Answer 21

-Tetraogenic
-Megaloblastic anemia
-Myelosuppression-Bone marrow depression
-Skin rashes, pruritis, glossitis, epigastric pain
-Reduced efficacy of combined oral conceptives

Question 22

Co-trimoxazole S/E-4?

Answer 22

-Thrombocytopenia (when used with diuretics)

-Fever & Myelosuprresion (In AIDS patients)

-Megaloblastic anemia(long term use)

-Nausea, vomitting, skin rashes and anemia

Question 23

Antimetabolites CI-4?

Answer 23

1. Pregnancy
2. Porphyria
3. G6PD Deficiency
4. Allergy

Question 24

Which adverse effect is CI for antimetabolites and is rare for drugs to treat?

Answer 24

Porphyria

Question 25

Action of antimetabolites?

Answer 25

• As antibiotics: inhibit DNA, RNA & protein
  synthesis by blocking the folate pathway
• Tetrahydrofolate leads to the synthesis of
  nucleotides and ultimately DNA

Question 26

Why are so many organisms resistant to Sulfonamide?

Answer 26

Due to widespread use=many organisms became resistant

Question 27

Sulfonamide broad spectrum bacteria?

Answer 27

ANC

Actinomyces
Nocardia
Chlamydia trachomatis Plasmodia

Question 27

Sulfonamide enteric bacteria?

Answer 27

KEESS

klebsiella
E coli
Enterobacter
salmonella
shigella

Question 28

What are the line of treatment for sulfonamides and why?

Answer 28

Sulfonamides are NOT the drugs of 1st choice.

Reasons:
– Bacterial resistance → use of combinations &
more effective antibiotics
– Toxicity (hypersensitivity)

Question 29

Sulfonamide Pharmacokinetics:

-Absorption
-Distribution
-Administration and least likely
-Protein binding and consequences
-Metabolism
-Excretion

Answer 29

-Absorption:
Well absorbed from the GIT

-Distribution:
Wide distribution to tissues and body fluids (incl. CNS, cerebrospinal fluid), placenta & foetus

-Administration and least likely:
Usually not topically administered → cause
allergic reactions

-Protein binding and consequences:
Protein binding (20 – 90%)=Increased protein binding and thus causes varying drug interactions

-Metabolism:
* Metabolised in the liver

-Excretion:
* Acetylated and glucuronidated before being
excreted in the urine

Question 30

Sulfonamide DI-4?

Answer 30

Potentiate effects of:
1. Oral anticoagulants (warfarin)-Increased risk of bleeding

2. Sulfonylureas (e.g. glibenclamide)-Increase hypoglycaemia in type 2 diabetes
3. Phenytoin-Sulfonamide inhibit metabolism
4. Methotrexate-can cause myelosuppression

Question 30

Why should water be taken with Sulfonamide?

Answer 30

Precipitation of acetylated metabolites in the
urine (crystalluria) → drink lots of water and
make urine more alkaline

Question 30

What do susceptible organisms require?

Answer 30

Extracellular PABA to form dihydrofolic acid and essential step in the production of nucleotide and nucleic acids

Question 30

Sulfamethoxazole type of therapy

Answer 30

Never used in monotherapy because of the resistance. It is used in combination with trimethoprim (co-trimoxazole)