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:• Rapidly Absorbed from GIT:i) Sulfisoxazoleii) Sulfamethoxazoleiii) Sulfadiazine Poorly absorbed – Active in

Bowel:i) Sulfasalazine Topically used:i) Sulfacetamideii) Silver Sulphadiazineiii) Mafenide Long Acting:i) Sulfadoxine

Diaminopyrimidines:i) Trimethoprimii) Pyrimethamine

Folate Antagonists

• Inhibitors Of Folate synthesis:

i) Sulfisoxazoleii) Sulfamethoxazoleiii) Sulfadiazineiv) Sulfasalazinev) Sulfacetamidevi) Silver Sulphadiazinevii) Mafenideviii) Sulfadoxine• Inhibitors of Folate reductioni) Trimethoprimii) Pyrimethamine

• Inhibitors of Folate synthesis and reduction:

i) Co-trimoxazole

STRUCTURE OF SULFONAMIDESSTRUCTURE OF SULFONAMIDES

Folic Acid Folic Acid Synthesis in Synthesis in

BacteriaBacteria

Inhibited bySULFONAMIDES Dihydropteroat

e synthase

Effects of SulfonamidesEffects of Sulfonamides

ChemistryTerm 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 bacteriaResistant strains are producedBacteriostatic – Depend on host defence mechanism to eradicate infections.

Antibacterial Spectrum. (Sulfonamides)Resistance against the sulfonamides is an

increasing problem. The spectrum includes:Streptococcus pyogenesStreptococcus pneumoniaeHaemophilus influenzaHaemophilus ducreyiNocardiaActinomycesCalymmatobacterium granulomatisChlamydia 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

SulfonamidesDihydropteroate 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:

1. 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% patientsAplastic 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, diarrhea5. 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:

1. Urinary tract infections: ( Not treatment of choice due to resistant strains) usually combination “Co-trimoxazole” is used.

2. Nocardiosis3. Toxoplasmosis: Pyrimethamine + sulfadiazine is treatment of

choice. Patient should take atleast 2 liters of fluid to avoid UT complication.

Pyrimethamine: Loading dose 75 mg Followed by 25 mg orally/ daySulfadiazine: 1 g orally/ 6 hourly

3 – 6 weeks

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:a) Sulfapyridine (cause of adverse / toxic effects)b) 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. Hypersensitivity2. In patients with impaired renal functions3. In patients with impaired hepatic functions4. Pregnancy5. LactationDrug Interactions:1. Oral anticoagulants2. Sulfonylurea3. Hydantoin anticonvulsants( sulfonamides potentiate their effect) Therefore Dose adjustment is

required.

Diaminopyrimidines

• Ttimethoprim• Pyremethamine

1. 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

Dihydropteroic Acid

Dihydrofolic acid

Tetrahydrofolic Acid

glutamate

Blocked By Sulfonamides

Blocked By Trimethoprim

NADPHNADP

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

Dihydropteroic Acid

Dihydrofolic acid

Tetrahydrofolic Acid

glutamate

Blocked By Sulfamethoxazole

Blocked By Trimethoprim

NADPHNADP

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.