General Description
Odorless lemon yellow crystals or fine yellow powder. Bitter taste.
Reactivity Profile
NITROFURANTOIN(67-20-9) is sensitive to light. This chemical is incompatible with alkalis. NITROFURANTOIN(67-20-9) is also incompatible with strong oxidizers and strong acids. NITROFURANTOIN(67-20-9) decomposes on contact with metals other than stainless steel and aluminum.
Air & Water Reactions
Insoluble in water.
Hazard
Questionable carcinogen.
Fire Hazard
Flash point data for this chemical are not available; however, NITROFURANTOIN is probably combustible.
Chemical Properties
lemon yellow crystalline powder
Originator
Furadantin,Norwich Eaton ,US,1953
Uses
A nitrofuran antibiotic with low resistance potential that is rapidly metabolized by mammals. Active against both Gram-positive and Gram-negative bacteria. Nitrofurantoin is also a prooxidant that is
cytotoxic due to the generation of intracellular H2O2. Antibacterial.
Definition
ChEBI: An imidazolidine-2,4-dione that is hydantoin substituted at position 1 by a [(5-nitro-2-furyl)methylene]amino group. An antibiotic that damages bacterial DNA.
Indications
Like nitrofurazone, nitrofurantoin is an effective drug that acts on a number of Grampositive and Gram-negative microorganisms (staphylococci, streptococci, dysentery bacillus, colon bacillus, paratyphoid bacillus, and others). It is primarily used for treating infectious diseases of the urinary tract (pyelitis, pyelonephritis, cystitis, urethritis). Synonyms of
this drug are furadonin, ituran, phenurin, urolong, cistofuran, nitrofurin, and many others.
Manufacturing Process
To a solution of 18.9 grams (0.166 mol) n-heptaldehyde in 25 ml of isopropanol is added, with stirring, a solution of 19.1 grams (0.166 mol) of 1aminohydantoin in 110 ml water acidified with concentrated HCl. The heavy white precipitate formed is filtered and washed, until acid free, with small amounts of water and ether. The yield of N-(n-heptylidene)-1-aminohydantoin is 14 grams of MP 150°C (with decomposition). This may be recrystallized from dimethylformamide.
A mixture of 2.5 grams (0.016 mol) of 5-nitro-2-furaldoxime, 3.9 grams (0.018 mol) of N-(n-heptylidene)-1-aminohydantoin and 5 cc of sulfuric acid (density 1.84) is placed in a 250 cc beaker. It is heated with stirring at steam bath temperature for about 1.5 hours. Upon cooling, a solid precipitates which is collected by filtration, washed with water, isopropanol and ether in turn and dried at 110°C for 4 hours. There is obtained N-(5-nitro-2-furfurylidene)-1aminohydantoin in 96 to 98% yield, according to US Patent 2,927,110.
Brand name
Ivadantin (Procter & Gamble);Furan;Nitrofan.
Therapeutic Function
Antibacterial (urinary)
Antimicrobial activity
It is active against almost all the common urinary
pathogens, except Proteus mirabilis. It is bactericidal.
It antagonizes the activity of nalidixic acid and other quinolones
in vitro, but this combination is unlikely to be used
clinically.
Acquired resistance
Surprisingly for an agent that has been used for so long, resistance
remains uncommon. R-factor-mediated resistance has
been reported, but this appears to be very unusual. The mechanism
of resistance seems to be a decreased nitroreductase
activity in the target organism.
There is cross-resistance within the nitrofuran group, but
none with antibiotics of other chemical classes.
Pharmaceutical Applications
A synthetic compound available only for oral administration.
There are three formulations, differing in their crystalline
nature: microcrystalline, macrocrystalline, and a delayedrelease
preparation containing a combination of the two. The
macrocrystalline form is said to be less liable to give rise to
the most common adverse event, nausea. However, pharmacokinetic
and clinical trial evidence for this assertion is not
very strong.
It is slightly soluble in water (c. 200 mg/L) but more so
in dilute alkali. Solubility in ethanol is modest (500 mg/L),
but the compound dissolves very well in dimethylformamide
(80 g/L). If packaged in light-resistant containers and kept at
room temperature, it is stable for more than 5 years. The yellow
solution should be kept in the dark.
Biochem/physiol Actions
Nitrofurantoin is an antibactericidal compound that has been historically prepared by the reaction of 1-aminohydantoin sulfate and 5-nitro-2-furaldehyde diacetate. It shows activity against many Gram-positive and Gram-negative bacteria. Nitrofurantoin is effective against enterococci, staphylococci, streptococci, corneybacteria, many strains of Escherichia coli. Most strains of Proteus spp. and Pseudomonas aeurginosa are more resistant to this compound. Nitrofurantoin is activated by bacterial flavoproteins (nitrofuran reductase) to actively reduce reactive intermediates that modulate and damage ribosomal proteins or other macromolecules, such as DNA. This inhibits DNA, RNA, protein, and cell wall synthesis which causes cell death. Nitrofurantoin has a low resistance potential that is rapidly metabolized by mammals and is active against both Gram-positive and Gram-negative bacteria. It is also a pro-oxidant that is cytotoxic due to the generation of intracellular H 2O2. It is an inhibitor of glutathione reductase. Nitrofurantoin produces hepatotoxicity caused by the redox cycling of the nitro group and its radical anion which leads to oxidative stress.
Pharmacokinetics
Oral absorption:>95%
Cmax 100 mg oral: <2 mg/L after 1–4 h
Plasma half-life:0.5–1 h
Volume of distribution: 0.6 L/kg
Plasma protein binding: 60–70%
Absorption
It is absorbed mainly from the proximal small intestine and
the plasma peak concentration may not be achieved for as
long as 4 h. The recommendation to take the drug with food
may be motivated by reducing the incidence of nausea rather
than increasing bioavailability.
Bioavailability varies widely between different brands and
this may not be apparent from results of standard in-vitro
pharmaceutical tests. Therefore, different brands should not
be substituted unless therapeutic equivalence has been formally
established.
Distribution
Serum levels are low, owing to extensive metabolism and the
short plasma half-life. Tissue concentrations are too low for
adequate treatment of systemic infection, including pyelonephritis.
Negligible concentrations are found in breast milk
and only a small amount crosses the placenta.
Metabolism and excretion
About 20% of the dose is excreted in microbiologically
active form in the urine, sufficient to give inhibitory concentrations
against urinary pathogens for up to 6 h. With
reduced renal function (creatinine clearance <60 mL/min),
urinary excretion falls, and virtually ceases when creatinine
clearance is below 20 mL/min. This gives rise to the risk of
accumulation in the blood and inadequate urine levels. With
this proviso, it can be given to elderly patients. Infants over
the age of 3 months may also be treated, but in the absence
of a suitable suspension, and at the recommended dosage, a
6-month baby would need to be given one-tenth of a standard
50 mg tablet.
Clinical Use
Acute dysuria and frequency
Bacteriuria in pregnancy
Prophylaxis of recurrent cystitis (reduced dosage)
Synthesis
Nitrofurantoin, 1-(5-nitrofurfurylidenamino)hydantoin (33.3.5), is synthesized from hydrazinoacetic acid (33.3.2), which is synthesized by reacting chloroacetic
acid with hydrazine. Reacting hydrazinoacetic acid with potassium cyanate gives the semicarbazidoacetic acid (33.3.3), which upon heating cyclizes into 1-aminoidantoin (33.3.4).
Reacting this with diacetylacetal of 5-nitrofurfurol gives the desired nitrofurantoin.
Veterinary Drugs and Treatments
Considered a urinary tract antiseptic, nitrofurantoin is used primarily
in small animals, but also occasionally in horses in the treatment
of lower urinary tract infections caused by susceptible bacteria. It
is not effective in treating renal cortical or perinephric abscesses or
other systemic infections.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
Nitrofurantoin is metabolised in the liver and most body
tissues, while about 30-40% of a dose is excreted rapidly
in the urine as unchanged nitrofurantoin. Some tubular
reabsorption may occur in acid urine.
