SULFONAMIDES,

TRIMETHOPRIM AND
QUINOLONES
Inhibitor of Nucleic Acid Synthesis

Overview
Nucleic acid synthesis:
NA of the cells are DNA and RNA
RNA (mRNA, tRNA, rRNA)
DNA double helix (2 chain of a linear polymer of
nucleotides) and supercoil with the core
Nucleotide consists of
base (purine (A ,G) and pyrimidine (T, C)
precursor: folate

sulfonamides

sugar (deoxyribose) + P

Overview
Nucleic acid synthesis (cont):
synthesis needs enzymes
to separate supercoil: DNA gyrase (topoisomerase II)
to replicate DNA: DNA polymerase

rifampicin

quinolones

Overview
Folate:
without FA cell cant growth or divide
sulfa: D acts as inhibitor for FA synthesis
cheap and effective
BUT: D-resistance, allergics
Sulfa + trimethoprim co-trimoxazole

SULFONAMIDES &
TRIMETHOPRIM

Folate antagonists
a. Inhibitors of folate synthesis (= SULFONAMIDES)

Sulfacetamide eyes infection

Sulfadiazine skin infection

Sulfasalazine collitis ulcerative, crohns disease (colon inf)

Sulfamethoxazole gram (-) enteric rods

b. Inhibitors of folate reduction

Trimethoprim = sulfamethoxazole

Pyrimethamine -- toxoplasmosis

c. Both

Co-trimoxazole

Sulfonamides
M.O.A and spectrum:
sulfanilamides is a structural analogue of PABA
(precursor of FA in bacteria)
bacteria has to synthesis FA (but we get it from food)
soonly inhibit growth, NOT to kill (bacteriostatic)
spectrum: enterobacteria, chlamidia, toxoplasma (sulfadiazine, pyrimethamine)

Sulfonamides
Resistance:
Random mutations
Plasmids
Irreversible
Mechanism:
a. Altered enzyme ( affinity to sulfa)
uptake of sulfa
PABA synthesis (overcome
inhibition enzymes by sulfa)

Sulfonamides
PK:

A : oral , supp (for crohns disease), iv (p.o is not

possible), NOT topical (allergic)

D: can cross P-BB and B-BB (in non-inflammed

condition)

M: liver inactive excreted through kidney

(crystalluria)

AEs:

Mild moderate (nausea, vomiting)

Met-Hb-emia cyanosis

Serious SE: hepatitis (Kern icterus in the babysulfa displaces bilirubin from albumin),
hypersensitivity, BM depression, crystalluria

Trimethoprim
MOA:

Inhibitor of dihydrofolate reductase (folate 4-h-folate)

So..inhibit growth (bacteriostatic)

More potent than sulfamethoxazole

Trimethoprim
PK:

= sulfamethoxazole

A: oral , supp (for crohns disease), iv (p.o is not possible)

D: can cross P-BB and B-BB (in non-inflammed condition)

M: liver inactive excreted through kidney (crystalluria)

AEs:

Mild moderate (nausea, vomiting)

Anemia megaloblastic

Co-trimoxazole
MOA:

Sulfamethoxazole + trimethoprim

Still bacteriostatic, but more potent and wider spectra

Clinical use:

UTI (incl. prostate & vaginal infection), RTI

Pneumocystis carinii (in HIV) prophylaxis (high dose)

GI inf. (Typhus abdominalis, shigellosis)

Resistance:

Need 2 simultaneous processes to become resistant

So, less frequent

Co-trimoxazole
PK:

A: oral , supp (for crohns disease), iv (severe cases)

D: high conc. in lung and kidney

M: liver inactive excreted through kidney

AEs:

Rash, GI upset (nausea, vomit)

Anemia megaloblastic

DI with warfarin, phenitoin

QUINOLONES

Quinolones
MOA:

Enter the cells through porins

Bind to enzyme AND DNA

Inhibit action of topoisomerase II (a DNA gyrase)

So, supercoil in DNA cant be open cant be transcript

and there will be a cleavage of the DNA cell death

Quinolones
PK:

A: well absorbed p.o

Al, Mg, Fe, Zn /antacida/sucralfate inhibit absorption

D: well distributed (to joint, sof tissue, lung, etc)

Concentrated in phagocyte

Not cross BBB

M: hepatic (CYP-450)

E: through kidney

Quinolones
AM spectra + clinical use:

Bactericid

Broad spectrum Gram (+) and (-)

Indication:

Complicated UTI

Respiratory Tract Infection

STI (GO)

Soft tissue, bone, skin infection

TB infection (second line drug)

Quinolones
Resistance:

Chromosom mutations

Spreading through plasmid

Cross-resistance among quinolones

How?

Altered target (enzyme) affinity

porins and efflux

Quinolones
AEs:

GI problem (nausea, vomit, diarrhea)

CNS disturbance (headache, dizziness, lightheadedness)

!! Epilepsy

Nephrotoxic, photosensitivity

DI:

Quinolone: CYP inhibitor

plasma conc. of some drugs (theophylin)

Quinolone is metabolised by CYP

Cimetidine will plasma conc. of quinolones

Quinolones
CI:

Pregnancy and lactation

Children < 18 y-o

Renal insufficiency