THE FOLATE ANTAGONISTS 2.

Phthalysulfathiazole
* Topically use Sulfonamide – silver
Sulfonamides sulfadiazine,mafemide ,sulfacetamide= use as
Are synthetic anti-microbial agents derived from topical treatment for burns
sulfanilamide. * Sulfasalazine (A Sulfidine) – use in treatment of
They are structural analogs of para-aminobenzoic ulcerative colitis and rheumatoid arthritis.
acid (PABA), a factor required by bacteria for folic * For ocular infections =sulfacetamide – use in the
acid synthesis. treatment of trachoma ( chlamydia trachoma)

Mechanism of Action Untoward Effects:

Inhibit competitively with the conversion of PABA 1. 75% involves the skin with sensitization often
to folic acid mediated by the enzyme being responsible conditions prod. Include:
dihydropteroate synthetase a. Exfoliative Dermatitis, photosensitivity
b. Steven – Johnson syndrome (fever,
H2N
malaise and erythema multiforme).
COOH
2. Drug fever (due to sensitization)
p- Aminobenzoic acid (PABA) 3. Blood dyscrasias rare but can occur. But the drug
Pteridine precursor should be stopped if any of the following occurs:
a.Acute hemolytic anemia (seen in
- H2N S NHR patients with Glucose – 6 – Phosphate
Dihydropteroate dehydrogenase def.)
synthetase
Sulfanilamide
b.Aplastic anemia
c.Agranulocytosis
(and other sulfonamides)
d.Thrombocytopenia
e. Eosinophilia
Competitive inhibition of folic acid
Folic Acid synthesis by sulfonamides
4. Crystalluria (rare with sulfisoxazole- more
soluble) occurs with more newer agents,
Antibiotic Activity: Bacteriostatic Sulfamethaxazole and long acting agents especially
Antimicrobial Spectrum: in acidic urine.
a. Staph. Aureus 5. Hepatitis
b. Non enterococcal Streptococeus 6. Kernicterus in newborn
c. Listeria monocytogenes
d. Nocardia
Drug Interactions
e. Neisseria
f. H. influenza
Sulfonamides inhibit the metabolism of
g. E. coli a.Warfarin
h. Proteus mirabilis b.Phenytoin
c.Tolbutamide
Sulfonamides: For systemic use d.Chlorpropamide
1. Sulfamethizole – short acting
2. Sulfisoxazole – short acting STEVEN JOHNSON SYNDROME
3. Sulfadiazine – short acting
4. Sulfamerazine – short acting
5. Sulfamethazine - short acting
6. sulfacetamide - (ophthalmic infections)
7. Sulfisomidine
8. Sulfachloropyridazine - short acting Trimethoprim (TMP)
9. Sulfamethoxypyridazine Trimethoprim is a synthetic antimicrobial cpd.
10.Sulfamethoxazole - intermediate acting Which is available as a single agent and in a fixed
11. Sulfamethazine - short acting combination with sulfamethoxazole (TMP-SMX)
12. Sulfadoxine - long acting
Mechanism of Action
Combination of: It interferes with the action of dihydrofolate
1. Sulfadiazine reductase, the enzyme that reduces dihydrofolic to
2. Sulfamerazine Trisulfapyrimidine tetrahydrofolic acid. An essential step in purine and
ultimately DNA synthesis.
3. Sulfamethazine

Uses of Sulfonamides
* Sulfadiazine + Pyrimethamine – effective against
Toxoplasmosis
* Sulfadoxine + Pyrimethamine – (Fansidar)
effective for Chloroquine resistant P. Falcifarum.
* Sulfamethoxazole + Trimethoprim - produces
Synergistic action =useful in respiratory, urinary.
Ear and sinuses infection

[For instestinal Use: (Long acting)]

1. Succinylsulfathiazole
 (Dihydrofolic) (Tetrahydrofolic) Precursors
a.Listeria meningitis
folinic Acid
b.Legionella infection
PABA folic Acid CoF
c.Typhoid fever
Sulfonamide 4. Meningitis due to Acinetobacter ; Ps maltophila;
Adenine
competes with Dihydrofolate Guanine Enterobacter
PABA reductase Thymine
Mechanism of Bacterial Resistance
Trimethoprim
1 Inhibited by Sulfonamide
Trimethoprim
1. Over production 1. Inability of drug to
2
of PABA by penetrate cell
Sequential blockade - results in a higher degree of
synergistic activity against a wide spectrum of microorganisms (membrane) envelope
microorganism 2.Altered 2. Presence of
dihydropteroate unsusceptible
Antibiotic activity of Trimethoprim: synthetase dihydrofolate reductase
bacteriostatic 3. Plasmid that code 3. Over production of
Antibiotic activity of Trimethoprim + for the production of dihydrofolate reductase
Sulfamethoxazole = Broad spectrum , Bactericidal drug resistance 4. Mutation
due to synergistic action of the two drug.

Antimicrobial Spectrum of Trimethoprim THE BROAD SPECTRUM ANTIBIOTICS

1. Gram positive Aerobic Bacteria A. CHLORAMPHENICOL
a.S. aureus (including penicillin – resistant and First isolated from cultures of Streptomyces
some methicillin resistant strain) venezuelae
b.Staph. Epidermidis – Contains a nitrobenzene moiety and derivative of
c.Streptococcus dichloroacetic acid
d.Listeria monocytogenes
2. Gram (-) Aerobic Bacteria Mechanism of Action : inhibits protein synthesis –
a. E. coli binds to 50s ribosomal subunit and prevent peptide
b. Enterobacter bond formation by blocking the action of peptidyl
c. Klebsiella transferase.
d. Providencia (High conc. it will inhibit eukaryote protein
e. Morganella
synthesis and may affect mitochondrial protein
f. Serratia marcescens
g. Citrobacter synthesis).
h. Salmonella Antimicrobial spectrum – broad spectrum
i. Shigella
j. Yersinia Bactericidial against:
k. Acinetobacter 1.H. influenza
l. Vibrio 2.Strep. Pneumonia
m. Aeromonas 3. N. meningitides
n. Ps. maltophila
o. Ps cepacia (but not Ps. Aeruginasa- resistant) More commonly it is Bacteriostatic
p. H. influenzae (including ampicillin – resistant Highly active against
strains) 1.Methicillin – sensitive staph. Aureus
q. Neiseria (Meningococci and Gonococci) 2.Strep. Pneumoniae
r. Branhamella catarrhalis – sensitive to TMP- 3.Listeria monocytogenes
SMX combination 4.N. gonorrhea
5.H. influenza
TMP-SMX Combination – other Sensitive 6.Bordotella pertusis
organisms 7.Salmonella
1.Anaerobic organisms 8. Brucella
2.Pneumocytis carinii 9.E. Coli
10.Proteus mirabilis
Adverse Effects 11.Klebsiella
1.Nausea, diarrhea – most common adverse effect 12.Shigella
2.hypersensitivity 13.Anaerobic bacteria
a.Peptococcus, peptostreptococcus
3.Hematologic disorders in persons with
b.Clostridium
suboptional folate nutrition- c.Actinomyces
megaloblastic anemia d.Bacteroides
14.Spirochetes
Clinical Use: TMP-SMX ( Co-trimoxazole) 15.Mycoplasma
1.UTI; prostates; epididymo – orchitis 16. Chlamydia (effective only in vitro although not
2. Drug of choice for: clinically effective)
a.Nocardia asteroids infections 17.Rickettsia
b.Pneumocystis carinii
c.Shigellosis Pharmacokinetics:
d.Travelers diarrhea (E. coli) -well absorb from the GIT (can also be administered
e.Yersinia entercolitica IV -chloramphenicol succinate)
3.2nd line of choice for -it is lipid soluble and diffuses well into tissues and
body fluids, and it also crosses the placenta.
-It is metabolized in the liver by glucuronyl EXCEPT for Minocycline – enters the brain in the
transferase. Unmetabolized drug is cleared by absence of inflammation, and also appears in tears
glomerular filtration. Conjugates eliminated by and saliva , useful in eradicating meningoccal
tubular secretion. Only 10% of the parent carrier state.
compound is excreted by Glomerular filtration. Most Tetracycline are metabolized in the liver
and excreted into the bile, they undergo
Adverse Effects: enterophepatic circulation then they are excreted by
1.Dose-related bone marrow suppression – aplastic glomerular filtration EXCEPT Doxycycline in
anemia – irreversible which metabolite is excreted into the feces.
2.Gray baby syndrome – occurs in Neonates due to Therapeutic Applications of Tetracyclines
low capacity to glucoronidate the drug and 1.Rickettsia infections including Rocky mountain
underdeveloped renal function spotted fever, typhus, Q fever
2.Mycoplasma pneumonia
Drug interactions 3.Chlamydial infections – lymphogranaloma
Block metabolism of: venereum; psittacosis – hepatitis, myocarditis
1.Warfarin 4.Lyme disease – Borrelia burgdorferi
2. Phenytoin á conc. and potentiating 5.Syphillis – Trepanoma pallidum
their effects 6.H. influenza
7.Cholera – V. Cholera, V. Vulnifious
3.Tolbutamide
8.Inflammatory Acne Vulgaris – Corynebacterium
4.Chlorpropamide
acnes
Clinical Uses of Chloramphenicol
9.Lepotospirosis
1.Drug of first choice – Typhoid fever
10.Spirillum minor (Rat-bite fever)
2.Empiric therapy of bacterial meningitis in
11. Yersinia pestis, Y. enterolitica
children – use in combination with Ampicillin
12.Francisella tularancis
3.Alternative drug of:
13.Pasteurella multocida
a.Rickettsial infections
14.Minocycline (followed by doxycline) are also
b.Brucellosis
effective against staph. Aureus and streptococci
c.Meningitis cause by Strep pneumonia,
15.N. gonorrhea, N. meningitides
d.Meningitidis or H. influenza
16.Brucellosis, relapsing fevers
17.Granuloma inguinale (alymmabacterium
Bacterial Resistance to chloramphenicol
granulomatis)
1.R-factor – codes for an acetyl coenzyme a
18.Mycobacterium fortuitum – Doxycycline only
transferase that inactivates the drug
Adverse Effects:
B.TETRACYCLINE
1.Gastric discomfort: due to irritation of gastric
The first compounds, chlortetracycline was isolated
mucosa. Diarrhea – due to clostridium
from Streptomyces aureofaciens.
dificile colitis
– are a group of closely related compounds that
2.Effects on calcified tissues – deposition in the
consist of four fused rings with a system of
bone and primary dentition occurs during
conjugated double bonds.
calcification in growing children. This
results to discoloration, hypoplasia of the
Mechanism of Action: inhibit protein synthesis
teeth and temporary stunting of growth
binds to 30s subunit of bacterial ribosomes and
3.Fatal hepatotoxicity : occurs in pregnant women
prevent binding of aminoacyl tRNA.
whoreceived high doses of tetracyclines
Antibacterial Spectrum: Broad Spectrum
especially if they have pyelonephritis
Bacteriostatic
4.Minocycline – vestibular toxicity (dizziness,
tinnitus, vertigo)
Members:
5.Photosensitivity – more common with
a.Oxytetracycline – Streptomyces rimosos
demeclocycline
b.Demeclocycline
6.Superinfections – resistant staph, clostridia or
c.Methacycline
candida
d.Doxycycline
7.fanconi syndrome-renal tubular necrosis attributed
e.Minocycline
to the use of expired or outdated
tetracyclines.
Pharmacokinetics:
- Adequately but incompletely absorb from GIT
Bacterial Resistance to tetracycline
after oral adm.
-inability of the organism to accumulate the drug –
- Absorption is decrease by presence of milk and
R factor
antacids,as result of complex formation with
-any organism resistant to one tetracycline is
magnesium, Ca++, and Aluminum; iron.
resistant to all.
- Minocycline and Doxycycline which are highly
lipophilic are more better absorb even in the
presence of food.
- Are distributed throughout body fluids. Enters
CSF but Levels are insufficient to achieve
therapeutic efficacy