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Isoniazid structure
Isoniazid structure

Isoniazid

Iupac Name:pyridine-4-carbohydrazide
CAS No.: 54-85-3
Molecular Weight:137.14
Modify Date.: 2022-04-21 20:27
Introduction: antibacterial, tuberculostatic View more+
1. Names and Identifiers
1.1 Name
Isoniazid
1.2 Synonyms

4-PYRIDINECARBOHYDRAZIDE 4-pyridine-carbonic acid hydrazide 4-PYRIDINECARBOXYLIC ACID HYDRAZIDE 4-PYRIDINECARBOXYLIC ACID HYDRAZIDE FOR 4-Pyridinecarboxylic acid, hydrazide AKOS BBS-00004103 Cedin EINECS 200-214-6 fsr3 GINK HIA HYCOZID Hyzyd In-73 INAH INH Isoniazide Isonicotinate hydrazide isonicotinic acid hydrazid Isonicotinic acid hydrazide Isonicotinohydrazide isonicotinoyl hydrazide Isonicotinyl hydrazid Isonicotinyl hydrazide Isoteb LANIAZID MFCD00006426 NYDRAZID pyridine-4-carbohydrazide pyridine-4-carboxylic acid hydrazide Pyridine-4-carboxylic hydrazide RIMIFON

1.3 CAS No.
54-85-3
1.4 CID
3767
1.5 EINECS(EC#)
200-214-6
1.6 Molecular Formula
C6H7N3O (isomer)
1.7 Inchi
InChI=1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)
1.8 InChkey
QRXWMOHMRWLFEY-UHFFFAOYSA-N
1.9 Canonical Smiles
C1=CN=CC=C1C(=O)NN
1.10 Isomers Smiles
C1=CN=CC=C1C(=O)NN
2. Properties
3.1 Density
1.2620 (rough estimate)
3.1 Melting point
171-173 °C(lit.)
3.1 Boiling point
251.97°C (rough estimate)
3.1 Refractive index
1.6910 (estimate)
3.1 Flash Point
>250°C
3.1 Vapour pressure
Negligible (NTP, 1992)
3.1 Precise Quality
137.05900
3.1 PSA
68.01000
3.1 logP
0.77630
3.1 Solubility
125g/l
3.2 AnalyticLaboratory Methods
Many methods for the quantitative estimation of INH; are known including iodometric, bromometric and argentometric methods, a vanadametric method, a potentiometric determination, a chromatographic determination, a gas chromatographic determination, color reactions and using chloramine-T;.
3.3 Appearance
white crystalline powder
3.4 Storage
Air Sensitive. Store under Argon. Ambient temperatures.
3.5 Chemical Properties
white crystalline powder
3.6 Color/Form
White or colorless
3.7 Decomposition
When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
3.8 Odor
Odorless
3.9 PH
pH of a 1% aqueous solution 5.5 to 6.5
3.10 Physical
PHYSICAL DESCRIPTION: Odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8. (NTP, 1992)
3.11 pKa
pKa 2.00/3.60/10.8(H2O) (Uncertain)
3.12 Water Solubility
14 g/100 mL (25 oC)
3.13 Spectral Properties
MAX ABSORPTION (ALCOHOL): 263 NM (LOG E= 3.6)
IR: 7547 (Sadtler Research Laboratories Prism Collection)
UV: 8-45 (Organic Electronic Spectral Data, Phillips et al, John Wiley & Sons, New York)
MASS: 65072 (NIST/EPA/MSDC Mass Spectral Database, 1990 version); 322 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63)
Intense mass spectral peaks: 78 m/z, 106 m/z, 137 m/z
UV max (water): 266 nm (E(1%)(1 cm) 378); (0.01N HCl): 265 nm (E(1%)(1 cm) approx 420).
3.14 Stability
Stability Stable, but may be air or light sensitive. Combustible. Incompatible with strong oxidizing agents, chloral, aldehydes, iodine, ferric salts, hypochlorites.
3.15 StorageTemp
2-8°C
3. Use and Manufacturing
4.1 Definition
ChEBI: A carbohydrazide obtained by formal condensation between pyridine-4-carboxylic acid and hydrazine.
4.2 General Description
Odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8.
4.3 GHS Classification
Signal: Warning
GHS Hazard Statements
Aggregated GHS information provided by 212 companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (98.11%): Harmful if swallowed [Warning Acute toxicity, oral]
H315 (88.21%): Causes skin irritation [Warning Skin corrosion/irritation]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P264, P270, P280, P301+P312, P302+P352, P321, P330, P332+P313, P362, and P501
4.4 Methods of Manufacturing
OXIDATION OF 4-METHYLPYRIDINE; OR 4-ETHYLPYRIDINE; TO ISONICOTINIC ACID;, WHICH IS REACTED AS THE METHYL OR ETHYL ESTER WITH HYDRAZINE; OR HYDRAZINE HYDRATE;
4.5 Purification Methods
Crystallise isoniazide from 95% EtOH and dry it in a vacuum. [Beilstein 22 III/IV 545, 22/2 V 219.]
4.6 Usage
antibacterial, tuberculostatic
4. Safety and Handling
5.1 Symbol
GHS07
5.1 Hazard Codes
Xn
5.1 Signal Word
Warning
5.1 Risk Statements
22-38-40-36/37/38
5.1 Safety Statements
37-36/37/39-26
5.1 Exposure Standards and Regulations
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl isoniazid, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
5.2 Packing Group
III
5.2 Octanol/Water Partition Coefficient
log Kow = -0.70
5.3 Fire Hazard
Isoniazid is combustible.
5.4 Hazard Declaration
H302-H315
5.4 DisposalMethods
SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.
5.5 RIDADR
2811
5.5 Caution Statement
P301 + P312 + P330
5.5 Formulations/Preparations
... INH IS AVAILABLE IN A USP GRADE CONTAINING A MIN OF 98% OF ACTIVE INGREDIENT. SMALL AMT OF ISOMERIC COMPD AND HYDRAZINE MAY BE PRESENT.
Rifampicin is also supplied in combination with isoniazid...this combination is known as Rifamate (Merrell Dow), Rifinah (Merrell Dow), and Rimactazid (CIBA).
Powder: Oral: Solution: 50 mg/5 mL, Isoniazid Syrup (with sorbitol 70%), (Allscripts, Carolina Medical, Versa); Tablets: 100 mg, 300 mg. Parenteral: Injection: 100 mg/mL, Nydrazid (with chlorobutanol 0.25%), (Sandoz).
5.6 WGK Germany
3
5.6 RTECS
NS1751850
5.6 Sensitive
Air Sensitive
5.7 Toxicity

CHEMICAL IDENTIFICATION

RTECS NUMBER :
NS1751850
CHEMICAL NAME :
Isonicotinic acid hydrazide
CAS REGISTRY NUMBER :
54-85-3
LAST UPDATED :
199712
DATA ITEMS CITED :
119
MOLECULAR FORMULA :
C6-H7-N3-O
MOLECULAR WEIGHT :
137.16
WISWESSER LINE NOTATION :
T6NJ DVMZ

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :
Standard Draize test
ROUTE OF EXPOSURE :
Administration onto the skin
SPECIES OBSERVED :
Rodent - rabbit
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - woman
DOSE/DURATION :
90200 ug/kg/7D-I
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity) Behavioral - headache Cardiac - EKG changes not diagnostic of specified effects
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - woman
DOSE/DURATION :
99300 ug/kg
TOXIC EFFECTS :
Behavioral - hallucinations, distorted perceptions Behavioral - convulsions or effect on seizure threshold Gastrointestinal - nausea or vomiting
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - child
DOSE/DURATION :
3600 mg/kg/43W-I
TOXIC EFFECTS :
Sense Organs and Special Senses (Eye) - effect, not otherwise specified Behavioral - tremor Behavioral - ataxia
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - infant
DOSE/DURATION :
91 mg/kg
TOXIC EFFECTS :
Behavioral - tremor Behavioral - convulsions or effect on seizure threshold
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - child
DOSE/DURATION :
125 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - coma Nutritional and Gross Metabolic - metabolic acidosis
TYPE OF TEST :
LDLo - Lowest published lethal dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - man
DOSE/DURATION :
523 mg/kg/17W-I
TOXIC EFFECTS :
Liver - hepatitis (hepatocellular necrosis), diffuse Liver - hepatitis, fibrous (cirrhosis, post-necrotic scarring)
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - woman
DOSE/DURATION :
12 mg/kg/2D-I
TOXIC EFFECTS :
Behavioral - toxic psychosis Behavioral - ataxia
TYPE OF TEST :
LDLo - Lowest published lethal dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human
DOSE/DURATION :
100 mg/kg
TOXIC EFFECTS :
Peripheral Nerve and Sensation - structural change in nerve or sheath
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - man
DOSE/DURATION :
430 mg/kg
TOXIC EFFECTS :
Behavioral - general anesthetic Behavioral - convulsions or effect on seizure threshold
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - man
DOSE/DURATION :
39 mg/kg/9D-I
TOXIC EFFECTS :
Skin and Appendages - dermatitis, other (after systemic exposure)
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - man
DOSE/DURATION :
100 mg/kg/3W-C
TOXIC EFFECTS :
Behavioral - anorexia (human) Skin and Appendages - sweating Kidney, Ureter, Bladder - other changes
TYPE OF TEST :
LDLo - Lowest published lethal dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Human - man
DOSE/DURATION :
116 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Cardiac - other changes Lungs, Thorax, or Respiration - emphysema
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
1250 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
335 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
329 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intravenous
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
365 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intramuscular
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
400 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
133 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - dyspnea
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
100 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
125 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intravenous
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
149 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intramuscular
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
137 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - dyspnea
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Mammal - dog
DOSE/DURATION :
50 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Mammal - cat
DOSE/DURATION :
325 mg/kg
TOXIC EFFECTS :
Peripheral Nerve and Sensation - spastic paralysis with or without sensory change Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - dyspnea
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rabbit
DOSE/DURATION :
250 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - rabbit
DOSE/DURATION :
147 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - rabbit
DOSE/DURATION :
135 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intravenous
SPECIES OBSERVED :
Rodent - rabbit
DOSE/DURATION :
94 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intramuscular
SPECIES OBSERVED :
Rodent - rabbit
DOSE/DURATION :
155 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intracerebral
SPECIES OBSERVED :
Rodent - rabbit
DOSE/DURATION :
>12 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - guinea pig
DOSE/DURATION :
255 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - guinea pig
DOSE/DURATION :
195 mg/kg
TOXIC EFFECTS :
Peripheral Nerve and Sensation - spastic paralysis with or without sensory change Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - dyspnea
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - guinea pig
DOSE/DURATION :
195 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intravenous
SPECIES OBSERVED :
Rodent - guinea pig
DOSE/DURATION :
220 mg/kg
TOXIC EFFECTS :
Gastrointestinal - hypermotility, diarrhea
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intramuscular
SPECIES OBSERVED :
Rodent - guinea pig
DOSE/DURATION :
255 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
45 gm/kg/52W-C
TOXIC EFFECTS :
Nutritional and Gross Metabolic - weight loss or decreased weight gain
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
166 gm/kg/26W-I
TOXIC EFFECTS :
Peripheral Nerve and Sensation - structural change in nerve or sheath Blood - changes in platelet count Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - other transferases
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
280 mg/kg/14D-I
TOXIC EFFECTS :
Liver - change in gall bladder structure or function Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Mammal - dog
DOSE/DURATION :
2300 mg/kg/17W-I
TOXIC EFFECTS :
Brain and Coverings - other degenerative changes
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Mammal - dog
DOSE/DURATION :
577 mg/kg/33D-I
TOXIC EFFECTS :
Liver - hepatitis, fibrous (cirrhosis, post-necrotic scarring) Liver - other changes Related to Chronic Data - death
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Mammal - dog
DOSE/DURATION :
325 mg/kg/13W-I
TOXIC EFFECTS :
Liver - other changes
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
55 gm/kg/45W-C
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Skin and Appendages - tumors
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
1892 mg/kg multigenerations
TOXIC EFFECTS :
Tumorigenic - Carcinogenic by RTECS criteria Reproductive - Tumorigenic effects - transplacental tumorigenesis Lungs, Thorax, or Respiration - tumors
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
18524 mg/kg/84W-I
TOXIC EFFECTS :
Tumorigenic - Carcinogenic by RTECS criteria Lungs, Thorax, or Respiration - tumors
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
2200 mg/kg/8W-I
TOXIC EFFECTS :
Tumorigenic - Carcinogenic by RTECS criteria Blood - leukemia Blood - lymphoma, including Hodgkin's disease
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
5040 mg/kg/18W-C
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Unreported
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
27400 mg/kg/39W-C
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - bronchiogenic carcinoma
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
93 gm/kg/70W-C
TOXIC EFFECTS :
Tumorigenic - Carcinogenic by RTECS criteria Lungs, Thorax, or Respiration - tumors Liver - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
15 gm/kg/30W-C
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
27 gm/kg/49W-C
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Liver - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
79576 mg/kg/98W-C
TOXIC EFFECTS :
Tumorigenic - Carcinogenic by RTECS criteria Lungs, Thorax, or Respiration - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
8880 mg/kg/19W-C
TOXIC EFFECTS :
Tumorigenic - equivocal tumorigenic agent by RTECS criteria Lungs, Thorax, or Respiration - tumors Nutritional and Gross Metabolic - weight loss or decreased weight gain
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
269 mg/kg/21D-I
TOXIC EFFECTS :
Tumorigenic - equivocal tumorigenic agent by RTECS criteria Lungs, Thorax, or Respiration - bronchiogenic carcinoma Liver - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
9 gm/kg/17W-I
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Liver - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
2240 mg/kg/4W-I
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Liver - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
6720 mg/kg/32W-C
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors
TYPE OF TEST :
TD - Toxic dose (other than lowest)
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
2240 mg/kg/32W-C
TOXIC EFFECTS :
Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Subcutaneous
DOSE :
2790 ug/kg
SEX/DURATION :
female 6-14 day(s) after conception
TOXIC EFFECTS :
Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Subcutaneous
DOSE :
27900 ug/kg
SEX/DURATION :
female 6-14 day(s) after conception
TOXIC EFFECTS :
Reproductive - Specific Developmental Abnormalities - Central Nervous System Reproductive - Specific Developmental Abnormalities - musculoskeletal system
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
1848 mg/kg
SEX/DURATION :
female 1-21 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Embryo or Fetus - fetal death Reproductive - Effects on Newborn - delayed effects
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Subcutaneous
DOSE :
160 mg/kg
SEX/DURATION :
female 6-13 day(s) after conception
TOXIC EFFECTS :
Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Specific Developmental Abnormalities - musculoskeletal system
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
40 mg/kg
SEX/DURATION :
female 7-14 day(s) after conception
TOXIC EFFECTS :
Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)
TYPE OF TEST :
Cytogenetic analysis
TYPE OF TEST :
Cytogenetic analysis
TYPE OF TEST :
Specific locus test
TYPE OF TEST :
DNA damage
TYPE OF TEST :
DNA adduct
TYPE OF TEST :
DNA inhibition
TYPE OF TEST :
Mutation test systems - not otherwise specified
TYPE OF TEST :
Cytogenetic analysis
TYPE OF TEST :
Cytogenetic analysis
TYPE OF TEST :
Sperm Morphology
TYPE OF TEST :
Cytogenetic analysis

MUTATION DATA

TYPE OF TEST :
Host-mediated assay
TEST SYSTEM :
Rodent - guinea pig Bacteria - Salmonella typhimurium
DOSE/DURATION :
150 mg/kg
REFERENCE :
MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 41,89,1976 *** REVIEWS *** IARC Cancer Review:Animal Limited Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 4,159,1974 IARC Cancer Review:Human Inadequate Evidence IMSUDL IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- Volume(issue)/page/year: 7,227,1987 IARC Cancer Review:Group 3 IMSUDL IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- Volume(issue)/page/year: 7,227,1987 TOXICOLOGY REVIEW AJHPA9 American Journal of Hospital Pharmacy. (American Soc. of Hospital Pharmacists, 4630 Montgomery Ave., Bethesda, MD 20814) V.15- 1958- Volume(issue)/page/year: 32,202,1975 TOXICOLOGY REVIEW CRTXB2 CRC Critical Reviews in Toxicology. (CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- Volume(issue)/page/year: 2,365,1973 TOXICOLOGY REVIEW MMWOAU Muenchener Medicinische Wochenschrift. (Munich, Fed. Rep. Ger.) V.33-115, 1886-1973. Volume(issue)/page/year: 115,1685,1973 TOXICOLOGY REVIEW MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 39,111,1977 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOHS - National Occupational Hazard Survey (1974) NOHS Hazard Code - A1139 No. of Facilities: 33 (estimated) No. of Industries: 1 No. of Occupations: 1 No. of Employees: 297 (estimated) NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - A1139 No. of Facilities: 79 (estimated) No. of Industries: 2 No. of Occupations: 4 No. of Employees: 2924 (estimated) No. of Female Employees: 1480 (estimated)
5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Skin irritation, Category 2

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word

Warning

Hazard statement(s)

H302 Harmful if swallowed

H315 Causes skin irritation

Precautionary statement(s)
Prevention

P264 Wash ... thoroughly after handling.

P270 Do not eat, drink or smoke when using this product.

P280 Wear protective gloves/protective clothing/eye protection/face protection.

Response

P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell.

P330 Rinse mouth.

P302+P352 IF ON SKIN: Wash with plenty of water/...

P321 Specific treatment (see ... on this label).

P332+P313 If skin irritation occurs: Get medical advice/attention.

P362+P364 Take off contaminated clothing and wash it before reuse.

Storage

none

Disposal

P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

9. Other Information
9.0 Merck
14,5186
9.1 BRN
119374
9.2 Description
Isoniazid, the hydrazide of isonicotinic acid was introduced into medical practice for treating tuberculosis in 1953. Isoniazid exhibits bactericidal action on Mycobacterium tuberculosis. It inhibits the synthesis of mycolic acid, an important component of the cell membrane of mycobacteria. Mycolic acid is specific only to mycobacteria, and it is the cause of the selective toxicity of the drug with respect to these microorganisms.
Mutants that are resistant to isoniazid are rarely seen in nature, and in a spontaneously growing population of tuberculous bacillus there is approximately one mutant in every 105 –106 organisms. Large populations of microorganisms of the order 109 –1010 bacilli in the pulmonary cavities contain a significant number of resistant mutants. If only isoniazid is taken during treatment, an increased number of mutants will be observed and they will eventually become the dominant phenotype. The transformation from sensitive to nonsensitive microorganisms during treatment is called secondary or acquired resistance, which can originate over the course of a few weeks. Isoniazid is the most important drug for treating pulmonary and nonpulmonary forms of tuberculosis. It is active against both intracellular and extracellular organisms. In order to prevent secondary resistance, isoniazid should be used with other effective drugs (usually rifampin). Synonyms of this drug are tubazid, andrazide, niazid, piridizin, and many others.
9.3 Description
Isoniazid is an antibiotic that acts as a prodrug, being converted by bacterial catalase-peroxidases to form isonicotinic acyl-NADH complex, which inhibits mycolic acid biosynthesis. It is effective against several species of Mycobacterium, including M. tuberculosis.
9.4 Chemical Properties
white crystalline powder
9.5 Originator
Nyrazid,Squibb,US,1952
9.6 Uses
Isoniazid is an antimicrobial used for the prevention of tuberculosis infection or used concurrently with another agent for the treatment of tuberculosis infection. Rifampin, pyrazinamide, or both of these agents are commonly used with isoniazid. Isoniazid is the only Food and Drug Administration approved drug to treat latent tuberculosis in order to prevent it from becoming active.
9.7 Uses
antibacterial, tuberculostatic
9.8 Uses
Antibiotic for treatment of Mycobacterium tuberculosis, inhibits mycolic acid biosynthesis. Metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. Sele ctively induces expression of CYP2E1. Reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 at clinically relevant concentrations. Antib acterial (tuberculostatic).
9.9 Uses
For the treatment of all forms of tuberculosis in which organisms are susceptible.
9.10 Definition
ChEBI: A carbohydrazide obtained by formal condensation between pyridine-4-carboxylic acid and hydrazine.
9.11 Indications
Isoniazid (isonicotinic acid hydrazide, or INH) is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is a synthetic agent with a structural similarity to that of pyridoxine.
9.12 Manufacturing Process
4 parts of 4-cyanopyridine in 12 parts of water were reacted with 4 parts of hydrazine hydrate in the presence of 0.08 part of sodium hydroxide at 100°C under reflux for 7 hours. The product, after filtration and evaporation to dryness, was crystallized from ethanol. The yield of isonicotinyl hydrazide amounted to 3.27 parts which is 62% of the theoretical.
9.13 Brand name
Inh (Novartis); Nydrazid (Bristol-Myers Squibb); Nydrazid (Sandoz); Rimifon (Roche).
9.14 Therapeutic Function
Antitubercular
9.15 Biological Functions
Its action is bactericidal against replicating organisms, but it appears to be only bacteriostatic at best against semidormant and dormant populations. After treatment with INH, M . tuberculosis loses its acid fastness, which may be interpreted as indicating that the drug interferes with cell wall development.
9.16 Synthesis Reference(s)
The Journal of Organic Chemistry, 20, p. 412, 1955 DOI: 10.1021/jo01122a002
9.17 Antimicrobial activity
Susceptibility to isoniazid is virtually restricted to the M. tuberculosis complex (MIC 0.01–0.2 mg/L). It is highly bactericidal against actively replicating M. tuberculosis. Other mycobacteria are resistant, except for some strains of M. xenopi (MIC 0.2 mg/L) and a few strains of M. kansasii (MIC 1 mg/L).
9.18 Acquired resistance
Mutations in the katG gene, the inhA gene or its promoter region, and in the intergenic region of the oxyR–ahpC locus confer resistance to isoniazid. The relative proportions of such mutations vary geographically and are related to the distribution of the various lineages or superfamilies of M. tuberculosis.
Isoniazid resistance is the commonest form of drug resistance worldwide and the great majority of strains resistant to another agent are also resistant to isoniazid.
9.19 General Description
Odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8.
9.20 Air & Water Reactions
Sensitive to air and light. Absorbs insignificant amounts of moisture at 77°F at relative humidities up to approximately 90%. Water soluble. Dust can be explosive when suspended in air at specific concentrations.
9.21 Reactivity Profile
Isoniazid is incompatible with chloral, aldehydes, iodine, hypochlorites and ferric salts. Isoniazid is also incompatible with oxidizers. Isoniazid may react with sugars and ketones. Isoniazid can react as a weak acid or a weak base. Isoniazid can be decomposed by oxidative and reductive reactions.
9.22 Fire Hazard
Isoniazid is combustible.
9.23 Pharmaceutical Applications
One of a number of nicotinamide analogs found to have antituberculosis activity, following the observation that nicotinamide inhibited the replication of M. tuberculosis. It is soluble in water. The dry powder is stable if protected from light. It is a prodrug requiring oxidative activation by KatG, a mycobacterial catalase–peroxidase enzyme.
9.24 Mechanism of action
Isoniazid is active against susceptible bacteria only when they are undergoing cell division. Susceptible bacteria may continue to undergo one or two divisions before multiplication is arrested. Isoniazid can inhibit the synthesis of mycolic acids, which are essential components of mycobacterial cell walls.The mycobacterial enzyme catalase– peroxidase KatG activates the administered isoniazid to its biologically active form.The target sites for the activated isoniazid action are acyl carrier protein AcpM and Kas A, a β-ketoaceyl carrier protein synthetase that blocks mycolic acid synthesis. Isoniazid exerts its lethal effects at the target sites by forming covalent complexes.
9.25 Pharmacology
Isoniazid is water soluble and is well absorbed when administered either orally or parenterally. Oral absorption is decreased by concurrent administration of aluminum-containing antacids.
Isoniazid does not bind to serum proteins; it diffuses readily into all body fluids and cells, including the caseous tuberculous lesions. The drug is detectable in significant quantities in pleural and ascitic fluids, as well as in saliva and skin. The concentrations in the central nervous system (CNS) and cerebrospinal fluid are generally about 20% of plasma levels but may reach close to 100% in the presence of meningeal inflammation.
Isoniazid is acetylated to acetyl isoniazid by N-acetyltransferase, an enzyme in liver, bowel, and kidney. Individuals who are genetically rapid acetylators will have a higher ratio of acetyl isoniazid to isoniazid than will slow acetylators. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this is not proved. The slow or rapid acetylation of isoniazid is rarely important clinically, although slow inactivators tend to develop peripheral neuropathy more readily. Metabolites of isoniazid and small amounts of unaltered drug are excreted in the urine within 24 hours of administration.
9.26 Pharmacokinetics
Oral absorption: >95%
Cmax 300 mg oral: 3–5 mg/L after 1–2 h
Plasma half-life: 0.5–1.5 h (rapid acetylators)
: 2–4 h (slow acetylators)
Volume of distribution: 0.6–0.8 L/kg
Plasma protein binding: Very low
Absorption and distribution
Isoniazid is almost completely absorbed from the gut and is well distributed. Absorption is impaired by aluminum hydroxide. Therapeutic concentrations are achieved in sputum and CSF. It crosses the placenta and is found in breast milk.
Metabolism
Isoniazid is extensively metabolized to a variety of pharmacologically inactive derivatives, predominantly by acetylation. As a result of genetic polymorphism, patients are divisible into rapid and slow acetylators. About 50% of Caucasians and Blacks, but 80–90% of Chinese and Japanese, are rapid acetylators. Acetylation status does not affect the efficacy of daily administered therapy. The rate of acetylation is reduced in chronic renal failure.
Excretion
Nearly all the dose is excreted in the urine within 24 h, as unchanged drug and metabolic products.
9.27 Clinical Use
Isonicotinic acid hydrazide, isonicotinyl hydrazide, or INH(Nydrazid) occurs as a nearly colorless crystalline solid thatis very soluble in water. It is prepared by reacting the methylester of isonicotinic acid with hydrazine.
Isoniazid is a remarkably effective agent and continuesto be one of the primary drugs (along with rifampin, pyrazinamide,and ethambutol) for the treatment of tuberculosis.It is not, however, uniformly effective against all formsof the disease. The frequent emergence of strains of the tuberclebacillus resistant to isoniazid during therapy wasseen as the major shortcoming of the drug. This problemhas been largely, but not entirely, overcome with the use ofcombinations.
The activity of isoniazid is manifested on the growing tuberclebacilli and not on resting forms. Its action, which isconsidered bactericidal, is to cause the bacilli to lose lipidcontent by a mechanism that has not been fully elucidated.The most generally accepted theory suggests that the principaleffect of isoniazid is to inhibit the synthesis of mycolicacids, high–molecular-weight, branched β-hydroxyfatty acids that constitute important components of the cellwalls of mycobacteria.
9.28 Clinical Use
Isoniazid is among the safest and most active mycobactericidal agents. It is considered the primary drug for use in all therapeutic and prophylactic regimens for susceptible tuberculosis infections. It is also included in the first-line drug combinations for use in all types of tuberculous infections. Isoniazid is preferred as a single agent in the treatment of latent tuberculosis infections in high-risk persons having a positive tuberculin skin reaction with no radiological or other clinical evidence of tuberculosis. Mycobacterium kansasii is usually susceptible to isoniazid, and it is included in the standard multidrug treatment regimen.
9.29 Clinical Use
Tuberculosis (intensive and continuation phases)
Prevention of primary tuberculosis in close contacts and reactivation disease in infected but healthy persons (monotherapy)
9.30 Side effects
The incidence and severity of adverse reactions to isoniazid are related to dosage and duration of therapy. Isoniazid-induced hepatitis and peripheral neuropathy are two major untoward effects.
9.31 Side effects
Toxic effects are unusual on recommended doses and are more frequent in slow acetylators. Many side effects are neurological, including restlessness, insomnia, muscle twitching and difficulty in starting micturition. More serious but less common neurological side effects include peripheral neuropathy, optic neuritis, encephalopathy and a range of psychiatric disorders, including anxiety, depression and paranoia.
Neurotoxicity is usually preventable by giving pyridoxine (vitamin B6) 10 mg per day. Pyridoxine should be given to patients with liver disease, pregnant women, alcoholics, renal dialysis patients, HIV-positive patients, the malnourished and the elderly. Encephalopathy, which has been reported in patients on renal dialysis, may not be prevented by, or respond to, pyridoxine, but usually resolves on withdrawal of isoniazid.
Isoniazid-related hepatitis occurs in about 1% of patients receiving standard short-course chemotherapy. The incidence is unaffected by acetylator status. It is more common in those aged over 35 years and preventive isoniazid monotherapy should be used with care in older people.
Less common side effects include arthralgia, a ‘flu’-like syndrome, hypersensitivity reactions with fever, rashes and, rarely, eosinophilia, sideroblastic anemia, pellagra (which responds to treatment with nicotinic acid) and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. It exacerbates acute porphyria and induces antinuclear antibodies, but overt systemic lupus erythematosus is rare.
9.32 Chemical Synthesis
Isoniazid, isonicotinic acid hydrazide (34.1.1), is synthesized by reacting ethyl ester of isonicotinic acid with hydrazine.
isoniazid.jpg
9.33 Veterinary Drugs and Treatments
Isoniazid (INH) is sometimes used for chemoprophylaxis in small animals in households having a human with tuberculosis. It potentially can be used in combination with other antimycobacterial drugs to treat infections of M. bovis or M. tuberculosis in dogs or cats. But because of the public health risks, particularly in the face of increased populations of immunocompromised people, treatment of mycobacterial (M. bovis, M. tuberculosis) infections in domestic or captive animals is controversial. In addition, INH has a narrow therapeutic index and toxicity is a concern (see Adverse Effects).
In humans, isoniazid (INH) is routinely used alone to treat latent tuberculosis infections (positive tuberculin skin test) and in combination with other antimycobacterial agents to treat active disease.
9.34 Environmental Fate
Isoniazid is a colorless, odorless, white crystalline powder that is slowly oxidized by exposure to air. It undergoes degradation upon prolonged exposure to light. Isoniazid has a solubility of 1 g per 8 ml water, 1 g per 50 ml ethanol, and it is slightly soluble in chloroform and very slightly soluble in ether. A 10% solution of isoniazid has a pH of 6.0–8.0.
9.35 Metabolism
Isoniazid is extensively metabolized to inactive metabolites. The major metabolite is N-acetylisoniazid. The enzyme responsible for acetylation, cytosolic N-acetyltransferase, is produced under genetic control in an inherited autosomal fashion. Individuals who possess high concentrations of the enzyme are referred to as rapid acetylators, whereas those with low concentrations are slow acetylators. This may result in a need to adjust the dosage for fast acetylators. The N-acetyltransferase is located primarily in the liver and small intestine. Other metabolites include isonicotinic acid, which is found in the urine as a glycine conjugate, and hydrazine. Isonicotinic acid also may result from hydrolysis of acetylisoniazid, but in this case, the second product of hydrolysis is acetylhydrazine. Acetylhydrazine is acetylated by N-acetyltransferase to the inactive diacetyl product. This reaction occurs more rapidly in rapid acetylators. The formation of acetylhydrazine is significant in that this compound has been associated with the hepatotoxicity, which may occur during INH therapy.
9.36 Purification Methods
Crystallise isoniazide from 95% EtOH and dry it in a vacuum. [Beilstein 22 III/IV 545, 22/2 V 219.]
9.37 Toxicity evaluation
Isoniazid causes toxicity by altering the metabolism of pyridoxine and creating a functional deficiency. Pyridoxine is needed for transamination, transketolization, decarboxylation, and biotransformation reactions. This occurs through three processes: (1) isoniazid metabolites form complexes with pyridoxine increasing its urinary excretion with increasing doses; (2) isoniazid metabolites disrupt the conversion of pyridoxine to its active form, pyridoxine-50-phosphokinase; and (3) metabolites directly inactivate pyridoxal-50-phosphate.
Isoniazid-induced seizures are thought to be caused by the depletion of gamma-aminobutyric acid (GABA). GABA is the primary inhibitory neurotransmitter in the central nervous system that requires the cofactor pyridoxal-50-phosphate for its synthesis from glutamate. Prolonged seizures commonly result in plasma lactic acid accumulation that can lead to an anion gap metabolic acidosis. Isoniazid may worsen the severity of acidosis by inhibiting the production of nicotinamideadensosine dinucleotide (NAD), a cofactor necessary for the conversion of lactate to pyruvate. Long-term exposure to isoniazid therapy commonly causes peripheral neuropathy due to pyridoxine deficiency, and may induce pellagra, a niacin deficiency disorder. Niacin requires the cofactor pyridoxal-50- phosphate for its production from tryptophan.
The exact mechanism of isoniazid-induced hepatotoxicity is unknown. However, it is thought to involve an idiopathic autoimmune mechanism or result from direct hepatic injury from isoniazid or its metabolites. The metabolite thought to be responsible is acetyl hydrazine, produced from isoniazid hydrolysis via cytochrome P450 (CYP)2E1. Persons with the CYP2E1c1/c1 genotype may be more susceptible to hepatotoxicity. The role acetylator status plays in hepatotoxicity continues to be debated, but it is currently thought that slow acetylators are at greater risk. Other risk factors include increasing age, chronic isoniazid overdose, comorbid conditions such as malnutrition, pregnancy, diabetes, HIV, renal dysfunction, hepatic dysfunction, alcoholism, and concomitant use of enzyme inducing drugs.
Other enzymes inhibited by isoniazid include the cytochrome P450 mixed function oxidases, monoamine oxidase, glutamate decarboxylase, and histaminase. The consequences of these extensive enzymatic disturbances are mood elevation, decreased central nervous system GABA levels, depressed catecholamine synthesis, defects in glucose and fatty acid oxidation, and impaired metabolism of other drugs. Important drug interactions include those with carbamazepine, phenytoin, rifampin, theophylline, valproate, and warfarin. Isoniazid is also a weak monoamine oxidase inhibitor, and serotonin syndrome and tyramine reactions to foods causing flushing, tachycardia, and hypertension are reported.
Isoniazid does cross the placenta and enters the fetal compartment; however, it has been determined to not be a human teratogen in studies. In acute toxicity, fetal deformities have been reported.
9.38 Precautions
High isoniazid plasma levels inhibit phenytoin metabolismand potentiate phenytoin toxicity when the twodrugs are coadministered. The serum concentrations ofphenytoin should be monitored, and the dose should beadjusted if necessary.
9.39 Usage
Used for fluorescent HPLC detection of delta 4-3-ketosteroids
10. Computational chemical data
  • Molecular Weight: 137.14g/mol
  • Molecular Formula: C6H7N3O
  • Compound Is Canonicalized: True
  • XLogP3-AA: null
  • Exact Mass: 137.058911855
  • Monoisotopic Mass: 137.058911855
  • Complexity: 120
  • Rotatable Bond Count: 1
  • Hydrogen Bond Donor Count: 2
  • Hydrogen Bond Acceptor Count: 3
  • Topological Polar Surface Area: 68
  • Heavy Atom Count: 10
  • Defined Atom Stereocenter Count: 0
  • Undefined Atom Stereocenter Count: 0
  • Defined Bond Stereocenter Count: 0
  • Undefined Bond Stereocenter Count: 0
  • Isotope Atom Count: 0
  • Covalently-Bonded Unit Count: 1
  • CACTVS Substructure Key Fingerprint: AAADcYBjIAAAAAAAAAAAAAAAAAAAAAAAAAAsAAAAAAAAAAABgAAAHgAYAAAADADBmgQ8gJJqEACoAjF3VACCgCA1AiIa+CE4ZNgIIHLAlZGEIQhggADIyYYUAAAKAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==
11. Question & Answer
  • I have to identify delocalized electron pairs in Isoniazid (pairs not shown in the image below): I know the nitrogen in the ring has a localized electron pair, since it already forms a pi bond. I'm confused about the other two nitrogen atoms. When we draw one of the resonance structures, we can see...
  • I'm asking as I fear that the 2-chloropropane might react with the pyridine ring to form k-isopropylpridine-4-carbohydrazidine where k=2,3,5. Or that no reaction will take place. Figure 1: Isoniazid Figure 2: Iproniazid Figure 3: 2-chloropropane
13. Realated Product Infomation