Folic Acid Synthesis Inhibitors

Folic acid enzymes are necessary for the

synthesis of Amino acids, hence necessary for
bacterial protein synthesis. We shall be
discussing some drugs which interfere with the
synthesis of folic acid at different levels and
prevent / inhibit growth of micro-organisms.
 Classification:
• Sulfonamides: Diaminopyrimidines:
• Rapidly Absorbed from GIT: ii) Trimethoprim
iii) Sulfisoxazole iii) Pyrimethamine
iv) Sulfamethoxazole
v) Sulfadiazine
 Poorly absorbed – Active in
Bowel:
vii) Sulfasalazine
 Topically used:
ix) Sulfacetamide
x) Silver Sulphadiazine
xi) Mafenide
 Long Acting:
xiii) Sulfadoxine
 Folate Antagonists

• Inhibitors Of Folate • Inhibitors of Folate

synthesis: synthesis and reduction:
 Sulfisoxazole ii) Co-trimoxazole
 Sulfamethoxazole
 Sulfadiazine
 Sulfasalazine
 Sulfacetamide
 Silver Sulphadiazine
 Mafenide
 Sulfadoxine
• Inhibitors of Folate reduction
xi) Trimethoprim
xii) Pyrimethamine
STRUCTURE OF SULFONAMIDES
 Inhibited by Dihydropteroat
SULFONAMIDES e synthase

Folic Acid
Synthesis in
Bacteria
 Effects of Sulfonamides

Chemistry
Term sulfonamide is employed herein as generic name of
derivatives of para-aminobenzenesulfonamide

Effects on Microbial agents:

Wide range of antimicrobial activity against both Gram +ve and
Gram –ve bacteria
Resistant strains are produced
Bacteriostatic – Depend on host defence mechanism to eradicate
infections.
Antibacterial Spectrum. (Sulfonamides)

Resistance against the sulfonamides is an increasing

problem. The spectrum includes:
Streptococcus pyogenes
Streptococcus pneumoniae
Haemophilus influenza
Haemophilus ducreyi
Nocardia
Actinomyces
Calymmatobacterium granulomatis
Chlamydia trachomatis
MIC:
0.1 µg / ml for Chlaymdia trachomatis, 4 – 6 µg / ml for E. Coli. Peak
plasma drug concentration achievable in vivo 100 – 200µg / ml
Resistant Strains:
Although the drug was very active against majority of N.
meningitidis but now in USA N.M serogroups B & C
and serogroup A in other countries are resistant to it.
(Shigella, E.Coli – Isolated from community acquired UTI)
 Mechanism Of Action of
Sulfonamides
Competitive antagonists of PABA. Hence they interfere and
prevent the normal utilization of PABA for the synthesis of
Folic Acid (Pteroylglutamic Acid).

More Specific: Pteridine + PABA

Dihydropteroate Sulfonamides
Synthetase

Dihydropteroic Acid
 Important Considerations
• Sensitive organisms are those which synthesize their own folic
acid
• Some micro-organisms may utilize PREFORMED folic acid and
thus not effected by these drugs – Sulfonamide Insensitive
micro organisms.
• Mammalian cells are not affected as they require preformed
Folic acid as they can not synthesize it. So they are comparable
to sulfonamides – insensitive organisms.
• Acquired bacterial Resistance:
• Usually by random mutation.
• By transfer through plasmids
Pharmacokinetics of Sulfonamides

• All sulfonamides EXCEPT specially designed for their local action in

the bowel (Sulfasalazine) are rapidly absorbed from G.I Tract.
• 70% to 100% dose is absorbed – 30 minutes found in urine
• Peak plasma levels – 2 – 6 hrs ..
• Small intestine is the place of absorption, some portion may be
absorbed from stomach as well.
• Absorption from other routes: Vagina, respiratory tractor abraded skin
is variable & unreliable but the drug absorbed is sufficient to produce
hypersensitivity reaction in susceptible individuals.
• Distributed uniformly – all tissues. Exceptions: Sulfadiazine –
throughout total body water. Sulfisoxazole – confined largely to
intracellular spaces.
• Readily pass through placenta, enters fetal circulation – sufficient to
exert antimicrobial as well as toxic effects
• Elimination:
• Kidneys – unchanged + metabolic products i.e. good clearance
depends upon renal functions. In acid urine older drugs may
precipitate and form crystals – cause urinary retention.
• Small amounts – feces, milk, bile and other secretions.
Untoward reactions of sulfonamides

The adverse effects of ‘Sulfonamides’ are numerous and

varied, certain forms of toxicity may be related to
individual drugs.
The adverse effects common to most of the sulfonamides
are as follows:
• Disturbance of the urinary tract.
Crystallurea is common with the use of less soluble and
older sulfonamides but less common with rapidly
soluble drugs e.g Sulfisoxazole.
{Adequate amount of water (1200 ml) adults. With
sulfonamides to reduce this complication}
Urinary Obstruction
2. Disorder of the hematopoietic:

Acute hemolytic anemia:

Due to sensitization phenomenon Or due to erythrocytic
deficiency of G6PD activity.
This is a rare condition usually with use of sulfadiazine
(.5%)
Agranulocytosis: Only in 0.1% patients
Aplastic Anemia: very rare.
3. Hypersensitivity reaction:

Skin Rashes, mucous membrane rashes. Erythema nodosum, erythema

multiforme of the Steven Johnson syndrome, exfoliative dermatitis,
photosensitivity.
Fever, malaise and pruritis often present simultaneously.
4. G.I Tract:
Nausea, vomiting, diarrhea
5. In New Born:
• Kernicterus (encephalopathy, displacement of bilirubin from
plasma albumin), due to deposition of bilirubin in basal ganglia and
substantia nigra.
• Should not be given to pregnant ladies as they cross placental
barrier.
6. Rare:
Focal or diffuse hepatic necrosis (.1%) due to drug sensitization.
Steven Johnson Syndrome
Indications of sulfonamides:
• Sulfonamides are not usually prescribed alone, mostly
combination therapy is preferred, however, the indications are:
• Urinary tract infections: ( Not treatment of choice due to
resistant strains) usually combination “Co-trimoxazole” is used.
• Nocardiosis
• Toxoplasmosis: Pyrimethamine + sulfadiazine is treatment of
choice. Patient should take atleast 2 liters of fluid to avoid UT
complication.
Pyrimethamine: Loading dose 75 mg 3 – 6 weeks
Followed by 25 mg orally/ day
Sulfadiazine: 1 g orally/ 6 hourly
4. For Prophylaxis:
• Effective equal to oral penicillins to prevent
streptococcal infections and recurrence of rheumatic
fever – in susceptible persons.
• Due to toxicity drug resistance makes them less
desirable but could be given to penicillin allergic
patients.
• Its adverse effects occur within 8 weeks after the
administration, past 8 weeks the untoward effects are not
so serious. Therefore WBC count should be done once a
week for 1st eight weeks.
 Some Sulfonamides used alone:
• Sulfasalazine:
This drug is poorly absorbed from GIT, hence used in treatment of
IBD ( Ulcerative Colitis) and regional enteritis. But there is a
considerable chance of relapse even in patients who initially
respond well. Corticosteroids are better for T/T but
sulfasalazine is preferred in patients with mild infection.
Mechanism Of Action:
Sulfasalazine is broken down by the GI bacteria into two compounds:
e) Sulfapyridine (cause of adverse / toxic effects)
f) 5-aminosalicylate ( Active agent against IBD)

Note: sulfasalazine can cause reversible infertility in males due to

change in sperm number and morphology.
• Sulfacetamide:
This drug is usually used in ophthalmic preparations. Its water
solubility is very good and hence very high aqueous
concentrations are less irritant than other sulfonamides. But risk
of sensitization is present although very less but known sensitive
patients should not be prescribed.
• Silver sulfadiazine:
This drug in vitro inhibits nearly all pathogenic bacteria and fungi
including some resistant to sulfonamides.
Indications: used topically to reduce microbial colonization and
incidence of infections of wounds from burns.
Contraindication: Should not be used in established deep infection
and known hypersensitivity.
Mafenide: also used for burns, superinfection with Candida
occasionally may be a problem.
Contraindications of Sulfonamides
1. Hypersensitivity
2. In patients with impaired renal functions
3. In patients with impaired hepatic functions
4. Pregnancy
5. Lactation
Drug Interactions:
• Oral anticoagulants
• Sulfonylurea
• Hydantoin anticonvulsants
( sulfonamides potentiate their effect) Therefore Dose adjustment is
required.
 Diaminopyrimidines

• Ttimethoprim
• Pyremethamine

4. Trimethoprim:
Spectrum:
Same as that of sulfonamides – but 20 to 100 times more
potent. Resistance can develop with frequent use
alone.
Mechanism Of Action of trimethoprim

Pteridine + PABA
Blocked By
Sulfonamides
Dihydropteroic Acid
glutamate

Dihydrofolic acid
NADPH
NADP Blocked By
Trimethoprim
Tetrahydrofolic Acid
 The Combinations

• Inhibitors of Folate synthesis and reduction:

• Sulfamethoxazole + Trimethoprim = Co-
Trimoxazole
The introduction of trimethoprim with
combination of sulfamethoxazole is a clinically
effective antimicrobial agent. The combination is
SYNERGISTIC and the drug becomes Bactericidal.
Mechanism Of Action of Co-Trimoxazole

Pteridine + PABA
Blocked By
Sulfamethoxazole
Dihydropteroic Acid
glutamate

Dihydrofolic acid
NADPH
NADP Blocked By
Trimethoprim
Tetrahydrofolic Acid
 Antibacterial Spectrum of Co-trimoxazole

The Spectrum Includes:

 Chlamydia diphtheria
 N. Meningitidis
 S. Pneumoniae (but there is disturbing incidence of resistance)
From 50% to 95%
 Staphylococcus aureus
 Staphylococcus epidermidis
 S. pyogenes
 Viridans group of streptococci
 E.Coli
 Proteus mirabilis
 Proteus morganii
 Proteus rettgeri
 Enterobacter species
 Salmonella
 Shigella
 Pseudomonas pseudomallei
 Serratia
 Alcalgenes
 Klebsiella species
 Brucella abortus
 Pasturella haemolytica
 Yersinia pseudotuberculosis
 Yersinia enterocolitica
 Nocardia asteriodes
 Methicillin-resistant
strains of S. Aureus
(although resistant to
drugs alone but are
sensitive to combo.)
 Adverse effects of Co-trimoxazole

• Permanent impairment of renal function (crystal urea, urinary

obstruction)
• In recommended doses the combination does not induce folic acid
deficiency in normal persons, but margin of safety may be narrow
in individuals with cells deficient in folate, therefore in such cases
may cause or precipitate megaloblastosis, leukopenia or
thrombocytopenia
• In routine 75% of adverse effects involve skin as described in
sulfonamides. ( SJ syndrome is rare and is in older individuals)
• GIT – mostly nausea and vomiting – diarrhea is rare.
• Mild jaundice (transient)
• CNS reactions consist of headache, depression and
hallucinations. (sulfonamides)
• Various types of anemia (aplastic, hemolytic,
macrocytic), coagulation disorders, granulocytopenia,
agranulocytosis, Henoch-Schölein purpura,
Sulfhemoglobinemia.
• AIDS patients more susceptible to adverse effects.
Therapeutic uses of Co-Trimoxazole.
• Urinary Tract Infections:
Treatment of uncomplicated lower urinary tract infections

• Bacterial Respiratory tract infections:

• Gastrointestinal infections
• Infections by Pneumocytis carinii (an opportunistic infection in
patients with AIDS)
• Prophylaxis in Neutropenic patients.
• Successfully used in treatment of whipples disease
• Dosage depends on individual infection.