Diforin - General Information
Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [PubChem]
Pharmacology of Diforin
Diforin is a bactericidal agent active against organisms of the genus Mycobacterium, specifically M. tuberculosis, M. bovis and M. kansasii. It is a highly specific agent, ineffective against other microorganisms. Diforin is bactericidal to rapidly-dividing mycobacteria, but is bacteriostatic if the mycobacterium is slow-growing.
Diforin for patients
Food: Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food.
Acetaminophen: A report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted In induction of P-450IIE1 in the patients liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates a cetaminophen hepatoxicity in rats.
Carbamazepine: Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made.
Ketoconazole: Potential interaction of Ketoconazole and Isoniazid may exist. When Ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88% after 5 months of concurrent Isoniazid and Rifampin therapy.
Phenytoin: Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made.
Therophylline: A recent study has shown that concomitan administration of isoniazid and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow theophylline serum levels should be monitored closely, and appropriate dosage adjustments of theophylline should be made.
Valproate: A recent case study has shown a possible increase in the plasma level of valproate when co administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co administered, and appropriate dosage adjustments of valproate should be made.
Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug -induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid such as drug fever, chills, arthritis; and acute liver disease of any etiology.
Additional information about Diforin
Diforin Indication: For the treatment of all forms of tuberculosis in which organisms are susceptible.
Mechanism Of Action: Diforin is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.
Drug Interactions: Acetaminophen Risk of hepatotoxicity
Aminophylline Increases the effect and toxicity of theophylline
Dyphylline Increases the effect and toxicity of theophylline
Oxtriphylline Increases the effect and toxicity of theophylline
Theophylline Increases the effect and toxicity of theophylline
Phenytoin Diforin increases the effect of phenytoin in 20% of patients
Mephenytoin Diforin increases the effect of phenytoin in 20% of patients
Fosphenytoin Diforin increases the effect of phenytoin in 20% of patients
Ethotoin Diforin increases the effect of phenytoin in 20% of patients
Meperidine Possible episodes of hypotension
Ketoconazole Diforin decreases the effect of ketoconazole
Warfarin The agent increases the effect of anticoagulant
Acenocoumarol The agent increases the effect of anticoagulant
Dicumarol The agent increases the effect of anticoagulant
Anisindione The agent increases the effect of anticoagulant
Carbamazepine Carbamazepine effect is increased as is isoniazid toxicity
Disulfiram Increased risk of CNS adverse effects
Food Interactions: Avoid aged foods (cheese, red wine), pickled foods, cured foods (bacon/ham), chocolate, fava beans, beer, unless approved by your physician.
Take on empty stomach: 1 hour before or 2 hours after meals.
Take with a full glass of water.
Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
Increase dietary intake of magnesium, folate, vitamin B6, B12, and/or consider taking a multivitamin.
Generic Name: Isoniazid
Synonyms: Isonicotinhydrazid; Isonicotinic acid hydrazide; Isonicotinic hydrazide; Isonicotinohydrazide; Isonicotinoyl hydrazide; Isonicotinyl hydrazide; Isonicotinylhydrazine; Isohydrazide; Isonicotinyl hydrazine; INH; Hydrazide; Hydrazid; HIA
Drug Category: Antitubercular Agents
Drug Type: Small Molecule; Approved
Other Brand Names containing Isoniazid: Andrazide; Antimicina; Antituberkulosum; Armacide; Armazid; Armazide; Atcotibine; Azuren; Bacillin; Cedin; Cemidon; Chemiazid; Chemidon; Cortinazine; Cotinazin; Cotinizin; Defonin; Dibutin; Diforin; Dinacrin; Ditubin; Ebidene; Eralon; Ertuban; Eutizon; Evalon; FSR 3; Fimalene; GINK; Hidranizil; Hidrasonil; Hidrulta; Hidrun; Hycozid; Hyozid; Hyzyd; Ido-tebin; Idrazil; Inah; Inizid; Iscotin; Isidrina; Ismazide; Isobicina; Isocid; Isocidene; Isocotin; Isolyn; Isonerit; Isonex; Isoniacid; Isoniazid SA; Isoniazide; Isonicazide; Isonicid; Isonico; Isonicotan; Isonicotil; Isonide; Isonidrin; Isonikazid; Isonilex; Isonin; Isonindon; Isonirit; Isoniton; Isonizide; Isopyrin; Isotamine; Isotebe; Isotebezid; Isotinyl; Isozide; Isozyd; Laniazid; Laniozid; Mybasan; Neo-Tizide; Neoteben; Neoxin; Neumandin; Nevin; Niadrin; Nicazide; Nicetal; Nicizina; Niconyl; Nicotibina; Nicotibine; Nicotisan; Nicozide; Nidaton; Nidrazid; Nikozid; Niplen; Nitadon; Nydrazid; Nyscozid; Pelazid; Percin; Phthisen; Pycazide; Pyreazid; Pyricidin; Pyridicin; Pyrizidin; Raumanon; Razide; Retozide; Rifamate; Rimicid; Rimifon; Rimiphone; Rimitsid; Robiselin; Robisellin; Roxifen; Sanohidrazina; Sauterazid; Sauterzid; Stanozide; TB-Phlogin; TB-Razide; TB-Vis; Tebecid; Tebenic; Tebexin; Tebilon; Tebos; Teebaconin; Tekazin; Tibazide; Tibemid; Tibison; Tibivis; Tibusan; Tubazid; Tubazide; Tubeco; Tubecotubercid; Tuberian; Tubicon; Tubilysin; Tubomel; Tyvid; Unicocyde; Unicozyde; Vazadrine; Vederon; Zidafimia; Zinadon; Zonazide;
Absorption: Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.
Toxicity (Overdose): LD50 100 mg/kg (Human, oral). Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects. In vivo, Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits generation of pyridoxal phosphate. Isoniazid also combines with pyridoxal phosphate; high doses interfere with the coenzyme function of the latter.
Protein Binding: Very low (0-10%)
Biotransformation: Primarily hepatic. Isoniazid is acetylated by N -acetyl transferase to N -acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system. The rate of acetylation is genetically determined. Slow acetylators are characterized by a relative lack of hepatic N -acetyltransferase.
Half Life: Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.
Dosage Forms of Diforin: Tablet Oral
Chemical IUPAC Name: pyridine-4-carbohydrazide
Chemical Formula: C6H7N3O
Isoniazid on Wikipedia: https://en.wikipedia.org/wiki/Isoniazid
Organisms Affected: Mycobacteria