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The Folate

The Folate

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Published by: dhainey on Jan 26, 2009
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09/29/2012

THE FOLATE ANTAGONISTS Sulfonamides Are synthetic anti-microbial agents derived from sulfanilamide.

They are structural analogs of para-aminobenzoic acid (PABA), a factor required by bacteria for folic acid synthesis. Mechanism of Action Inhibit competitively with the conversion of PABA to folic acid mediated by the enzyme dihydropteroate synthetase
H2N COOH

2. Phthalysulfathiazole * Topically use Sulfonamide – silver sulfadiazine,mafemide ,sulfacetamide= use as topical treatment for burns * Sulfasalazine (A Sulfidine) – use in treatment of ulcerative colitis and rheumatoid arthritis. * For ocular infections =sulfacetamide – use in the treatment of trachoma ( chlamydia trachoma) Untoward Effects: 1. 75% involves the skin with sensitization often being responsible conditions prod. Include: a. Exfoliative Dermatitis, photosensitivity b. Steven – Johnson syndrome (fever, malaise and erythema multiforme). 2. Drug fever (due to sensitization) 3. Blood dyscrasias rare but can occur. But the drug should be stopped if any of the following occurs: a.Acute hemolytic anemia (seen in patients with Glucose – 6 – Phosphate dehydrogenase def.) b.Aplastic anemia c.Agranulocytosis d.Thrombocytopenia e. Eosinophilia 4. Crystalluria (rare with sulfisoxazole- more soluble) occurs with more newer agents, Sulfamethaxazole and long acting agents especially in acidic urine. 5. Hepatitis 6. Kernicterus in newborn Drug Interactions Sulfonamides inhibit the metabolism of a.Warfarin b.Phenytoin c.Tolbutamide d.Chlorpropamide STEVEN JOHNSON SYNDROME

p- Aminobenzoic acid (PABA) Pteridine precursor H2N S NHR

Dihydropteroate synthetase

Sulfanilamide (and other sulfonamides)

Folic Acid

Competitive inhibition of folic acid synthesis by sulfonamides

Antibiotic Activity: Bacteriostatic Antimicrobial Spectrum:
a. b. c. d. e. f. g. h. Staph. Aureus Non enterococcal Streptococeus Listeria monocytogenes Nocardia Neisseria H. influenza E. coli Proteus mirabilis

Sulfonamides: For systemic use 1. Sulfamethizole – short acting 2. Sulfisoxazole – short acting 3. Sulfadiazine – short acting 4. Sulfamerazine – short acting 5. Sulfamethazine - short acting 6. sulfacetamide - (ophthalmic infections) 7. Sulfisomidine 8. Sulfachloropyridazine - short acting 9. Sulfamethoxypyridazine 10.Sulfamethoxazole - intermediate acting 11. Sulfamethazine - short acting 12. Sulfadoxine - long acting Combination of: 1. Sulfadiazine 2. Sulfamerazine 3. Sulfamethazine

Trimethoprim (TMP) Trimethoprim is a synthetic antimicrobial cpd. Which is available as a single agent and in a fixed combination with sulfamethoxazole (TMP-SMX) Mechanism of Action It interferes with the action of dihydrofolate reductase, the enzyme that reduces dihydrofolic to tetrahydrofolic acid. An essential step in purine and ultimately DNA synthesis.

Trisulfapyrimidine

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) PABA folic Acid

(Tetrahydrofolic) folinic Acid

Precursors CoF Adenine Guanine Thymine

Sulfonamide competes with PABA Dihydrofolate reductase

a.Listeria meningitis b.Legionella infection c.Typhoid fever 4. Meningitis due to Acinetobacter ; Ps maltophila; Enterobacter Mechanism of Bacterial Resistance Trimethoprim Sulfonamide 1. Over production 1. Inability of drug to of PABA by penetrate cell microorganisms (membrane) envelope 2.Altered 2. Presence of dihydropteroate unsusceptible synthetase dihydrofolate reductase 3. Plasmid that code 3. Over production of for the production of dihydrofolate reductase drug resistance 4. Mutation THE BROAD SPECTRUM ANTIBIOTICS A. CHLORAMPHENICOL First isolated from cultures of Streptomyces venezuelae – Contains a nitrobenzene moiety and derivative of dichloroacetic acid Mechanism of Action : inhibits protein synthesis – binds to 50s ribosomal subunit and prevent peptide bond formation by blocking the action of peptidyl transferase. (High conc. it will inhibit eukaryote protein synthesis and may affect mitochondrial protein synthesis). Antimicrobial spectrum – broad spectrum Bactericidial against: 1.H. influenza 2.Strep. Pneumonia 3. N. meningitides More commonly it is Bacteriostatic Highly active against
1.Methicillin – sensitive staph. Aureus 2.Strep. Pneumoniae 3.Listeria monocytogenes 4.N. gonorrhea 5.H. influenza 6.Bordotella pertusis 7.Salmonella 8. Brucella 9.E. Coli 10.Proteus mirabilis 11.Klebsiella 12.Shigella 13.Anaerobic bacteria a.Peptococcus, peptostreptococcus b.Clostridium c.Actinomyces d.Bacteroides 14.Spirochetes 15.Mycoplasma 16. Chlamydia (effective only in vitro although not clinically effective) 17.Rickettsia

1

Inhibited by Trimethoprim 2

Sequential blockade - results in a higher degree of synergistic activity against a wide spectrum of microorganism

Antibiotic activity of Trimethoprim: bacteriostatic Antibiotic activity of Trimethoprim + Sulfamethoxazole = Broad spectrum , Bactericidal due to synergistic action of the two drug. Antimicrobial Spectrum of Trimethoprim 1. Gram positive Aerobic Bacteria a.S. aureus (including penicillin – resistant and some methicillin resistant strain) b.Staph. Epidermidis c.Streptococcus d.Listeria monocytogenes 2. Gram (-) Aerobic Bacteria
a. E. coli b. Enterobacter c. Klebsiella d. Providencia e. Morganella f. Serratia marcescens g. Citrobacter h. Salmonella i. Shigella j. Yersinia k. Acinetobacter l. Vibrio m. Aeromonas n. Ps. maltophila o. Ps cepacia (but not Ps. Aeruginasa- resistant) p. H. influenzae (including ampicillin – resistant strains) q. Neiseria (Meningococci and Gonococci) r. Branhamella catarrhalis – sensitive to TMPSMX combination

TMP-SMX Combination – other Sensitive organisms 1.Anaerobic organisms 2.Pneumocytis carinii Adverse Effects 1.Nausea, diarrhea – most common adverse effect 2.hypersensitivity 3.Hematologic disorders in persons with suboptional folate nutritionmegaloblastic anemia Clinical Use: TMP-SMX ( Co-trimoxazole) 1.UTI; prostates; epididymo – orchitis 2. Drug of choice for: a.Nocardia asteroids infections b.Pneumocystis carinii c.Shigellosis d.Travelers diarrhea (E. coli) e.Yersinia entercolitica 3.2nd line of choice for

Pharmacokinetics: -well absorb from the GIT (can also be administered IV -chloramphenicol succinate) -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 transferase. Unmetabolized drug is cleared by glomerular filtration. Conjugates eliminated by tubular secretion. Only 10% of the parent compound is excreted by Glomerular filtration. Adverse Effects: 1.Dose-related bone marrow suppression – aplastic anemia – irreversible 2.Gray baby syndrome – occurs in Neonates due to low capacity to glucoronidate the drug and underdeveloped renal function Drug interactions Block metabolism of: 1.Warfarin 2. Phenytoin á conc. and potentiating their effects 3.Tolbutamide 4.Chlorpropamide Clinical Uses of Chloramphenicol 1.Drug of first choice – Typhoid fever 2.Empiric therapy of bacterial meningitis in children – use in combination with Ampicillin 3.Alternative drug of: a.Rickettsial infections b.Brucellosis c.Meningitis cause by Strep pneumonia, d.Meningitidis or H. influenza Bacterial Resistance to chloramphenicol 1.R-factor – codes for an acetyl coenzyme a transferase that inactivates the drug B.TETRACYCLINE The first compounds, chlortetracycline was isolated from Streptomyces aureofaciens. – are a group of closely related compounds that consist of four fused rings with a system of conjugated double bonds. Mechanism of Action: inhibit protein synthesis binds to 30s subunit of bacterial ribosomes and prevent binding of aminoacyl tRNA. Antibacterial Spectrum: Broad Spectrum Bacteriostatic Members: a.Oxytetracycline – Streptomyces rimosos b.Demeclocycline c.Methacycline d.Doxycycline e.Minocycline Pharmacokinetics: - Adequately but incompletely absorb from GIT after oral adm. - Absorption is decrease by presence of milk and antacids,as result of complex formation with magnesium, Ca++, and Aluminum; iron. - 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

EXCEPT for Minocycline – enters the brain in the absence of inflammation, and also appears in tears and saliva , useful in eradicating meningoccal carrier state. Most Tetracycline are metabolized in the liver and excreted into the bile, they undergo enterophepatic circulation then they are excreted by glomerular filtration EXCEPT Doxycycline in which metabolite is excreted into the feces. Therapeutic Applications of Tetracyclines 1.Rickettsia infections including Rocky mountain spotted fever, typhus, Q fever 2.Mycoplasma pneumonia 3.Chlamydial infections – lymphogranaloma venereum; psittacosis – hepatitis, myocarditis 4.Lyme disease – Borrelia burgdorferi 5.Syphillis – Trepanoma pallidum 6.H. influenza 7.Cholera – V. Cholera, V. Vulnifious 8.Inflammatory Acne Vulgaris – Corynebacterium acnes 9.Lepotospirosis 10.Spirillum minor (Rat-bite fever) 11. Yersinia pestis, Y. enterolitica 12.Francisella tularancis 13.Pasteurella multocida 14.Minocycline (followed by doxycline) are also effective against staph. Aureus and streptococci 15.N. gonorrhea, N. meningitides 16.Brucellosis, relapsing fevers 17.Granuloma inguinale (alymmabacterium granulomatis) 18.Mycobacterium fortuitum – Doxycycline only Adverse Effects: 1.Gastric discomfort: due to irritation of gastric mucosa. Diarrhea – due to clostridium dificile colitis 2.Effects on calcified tissues – deposition in the bone and primary dentition occurs during calcification in growing children. This results to discoloration, hypoplasia of the teeth and temporary stunting of growth 3.Fatal hepatotoxicity : occurs in pregnant women whoreceived high doses of tetracyclines especially if they have pyelonephritis 4.Minocycline – vestibular toxicity (dizziness, tinnitus, vertigo) 5.Photosensitivity – more common with demeclocycline 6.Superinfections – resistant staph, clostridia or candida 7.fanconi syndrome-renal tubular necrosis attributed to the use of expired or outdated tetracyclines. Bacterial Resistance to tetracycline -inability of the organism to accumulate the drug – R factor -any organism resistant to one tetracycline is resistant to all.

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