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Ethionamide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of the locally available formulation(s)
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation(s)
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple qualitative test(s)
         8.2.1.2 Advanced qualitative confirmation test(s)
         8.2.1.3 Simple quantitative method(s)
         8.2.1.4 Advance quantitative method(s)
      8.2.2 Test for biological specimens
         8.2.2.1 Simple qualitative test(s)
         8.2.2.2 Advanced qualitative confirmation test(s)
         8.2.2.3 Simple quantitative method(s)
         8.2.2.4 Advance quantitative method(s)
         8.2.2.5 Other dedicated method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Interpretation of toxicological analyses
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin Exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, and throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and Electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    1. NAME

       1.1 Substance 

           Ethionamide   (INN)

           (WHO, 1992)

       1.2 Group

           ATC classification index

           Antimycobacterials (J04)/Drugs for the treatment of
           tuberculosis (J04A)/Thiocarbamide derivatives(J04AD).

           (WHO, 1992)

       1.3 Synonyms

           Etionamide
           1314-TH
           Amidazine
           Ethioniamide 

           (Budavari, 1989)

           (To be completed by each Centre using local data)

       1.4 Identification numbers

           1.4.1 CAS number

                 536-33-4

           1.4.2 Other numbers

                 RTECS

                 NS0350000

       1.5 Brand names, Trade names

           Ethatyl (SCS, S. Afr.)
           Etiocidan (Cidan, Spain)
           Panathide (Propan, S. Afr.)
           Regenicide (Gedeon, Richter)
           Thioniden (Kaken, Jpn)
           Trecator (Belg., Theraplix, Fr)
           Trecator-SC (Wyeth, USA)
           Trescatyl (May & Baker, S. Afr; May & Baker, UK)
           Tubenamide (Meiji. Jpn)
           Resitran (Mla. Phil.)

           (To be completed by each Centre using local data)

       1.6 Manufacturers, Importers

           To be completed by each Centre using local data

       1.7 Presentation, Formulation

           Tablets 250 mg, in packs of 100  (PDR, 1992)

           (To be completed by each Centre using local data)

    2. SUMMARY

       2.1 Main risks and target organs

           Most common adverse reactions are gastrointestinal 
           disturbances including anorexia, nausea, vomiting, excessive 
           salivation, a metallic taste, stomatitis and diarrhoea and 
           hepatitis. Central nervous system effects include dizziness, 
           drowsiness, headaches, convulsions, peripheral neuropathy, 
           tremors and paraesthesias. 

           There is no experience in acute overdose of ethionamide. One 
           of the metabolites resembles isoniazid and one should watch 
           for similar symptoms. 

       2.2 Summary of clinical effects

           TOXIC REACTIONS FROM ETHIONAMIDE

           SITE               REACTIONS
         
           Gastrointestinal   Anorexia, vomiting, stomatitis, diarrhoea, 
           System             excessive salivation, metallic taste, 
                              hepatotoxicity. 
                              
           Central Nervous    Mental depression, anxiety or psychosis, 
           System             encephalopathy with pellagra-like 
                              symptoms, dizziness, drowsiness, headache, 
                              convulsion, peripheral neuropathy, 
                              tremors, paraesthesias. 
                              
           Eye                Optic neuritis, optic atrophy, diplopia. 
                              
           Nose               Olefactory disturbances
                              
           Ear                Deafness
                              
           Endocrine          Hypothyroidism, gynaecomastia, impotence, 
                              menorrhagia, hypoglycaemia 
                              
           Integumentary      Alopecia, acne, severe allergic rashes, 
                              photodermatitis. 
                              
           Haematology        Thrombocytopenia
                              
           Skeletal system    Rheumatic pains
                              
           Cardiovascular     Postural hypotension

           (Reynolds, 1989; Gilman et al., 1990)
               
       2.3 Diagnosis

           Clinical diagnosis is difficult to determine because of the 
           lack of history of toxic ingestions. 

           Quantitative Analysis

           Confirmatory tests can be used to document poisoning using 
           High Pressure Liquid Chromatography on plasma, serum or urine 
           or a colour reaction on urine; detection limit 10 ng/mL. 

           Qualitative Analysis

           Presence of sulphoxide derivative of ethionamide gives a 
           yellow colour in the acid extract. 

       2.4 First aid measures and management principles

           Whether the presentation of the patient is an overdose or an 
           adverse drug event, the first principle is to evaluate the 
           vital functions and provide life-support measures to 
           stabilize the victim.  Screening and confirmatory tests to 
           document poisoning in biological fluids should be done. (For 
           details, see 10.1) 

           Maintain patient airway, adequate breathing and circulation.  
           Decontaminate with activated charcoal and follow with 
           cathartic. 
                      
           Although the drug is extensively metabolised by the liver in 
           toxic doses, excretion may be enhanced with diuretics. 

           There are no known antidotes for ethionamide overdose. 
                      
    3. PHYSICO-CHEMICAL PROPERTIES

       3.1 Origin of the substance

           Synthesized from the interaction of 2-ethylisonicotinonitrile 
           and H2S in the presence of triethanolamine (Budavari, 1989).

       3.2 Chemical structure

           Structural formula

            

           Molecular formula
            
           C8H10N2S

           Molecular weight

           166.2

           Structural Chemical names

           2-Ethylpyridine-4-carbothioamide
           2-ethyl-4-pyridinecarbothioamide
           2-ethylththioisonicotinamide
           3-ethylisothionicotinamide
           2-ethylisothionicotinamide
           2-ethyl-4-thiocarbamoylpyridine
           alpha-ethylisonicotinoylthioamide

           (Reynolds, 1993; Budavari, 1989)

       3.3 Physical properties

           3.3.1 Properties of the substance

                 3.3.1.1 Colour

                         Yellow (darkens on exposure to light)

                 3.3.1.2 State/Form

                         Crystal or crystalline powder

                 3.3.1.3 Description

                         Slight sulphide-like odour.

                         Melting range   158C to 164C.
                
                         pH   6.0 to 7.0 in a 1 in 100 slurry in
                         water.

                         Soluble in 1 in 30 of alcohol. 
                         Very sparingly soluble in water.
                         Slightly soluble in chloroform (1 in 500) 
                         Slightly soluble in ether (1 in 320). 
                         Soluble in methyl alcohol. 
                         Sparingly soluble in propylene glycol.

                         (Reynolds 1993, Budavari 1989, European
                         Pharmacopoeia, 1986)

           3.3.2 Properties of the locally available formulation(s) 

                 It is stable at all ordinary temperatures and levels of 
                 humidity. 

                 (To be completed by each Centre using local data). 

       3.4 Other characteristics

           3.4.1 Shelf-life of the substance

                 No data available.

           3.4.2 Shelf-life of the locally available formulation(s) 

                 To be completed by each Centre using local data. 
                 
           3.4.3 Storage conditions

                 Preserve in air-tight containers at less than 40C, 
                 preferably between 15 to 30C. 

           3.4.4 Bioavailability

                 To be completed by each Centre using local data. 

           3.4.5 Specific properties and composition

                 To be completed by each Centre using local data

    4. USES

       4.1 Indications

           4.1.1 Indications
                      
                 For the treatment of pulmonary and extrapulmonary 
                 tuberculosis in conjunction with other antituberculous 
                 agents (when resistance to primary agents has 
                 developed). 

                 For the treatment of leprosy, as part of multi-drug 
                 regimens. 

                 In the treatment of pulmonary disease in Mycobacterium 
                 kansasii and other atypical mycobacteria. 
                      
           4.1.2 Description

                 Not applicable

       4.2 Therapeutic dosage

           4.2.1 Adults

                 Oral
                              
                  Tuberculosis 

                 0.5 to 1 g daily in divided doses (PDR, 1992) 

                 15 to 20 mg/kg (given as a single daily dose, up to 
                 maximum of 1 g (Reynolds, 1993). 
                              
                  Leprosy 

                 250 to 375 mg daily (Reynolds, 1989; Gilman et al., 
                 1990) 

                 5 mg/kg (as a single daily dose)(Reynolds, 1993) 

           4.2.2 Children

                 Oral

                  Tuberculosis

                 12 to 15 mg/kg body weight daily to a maximum of 750 mg 
                 daily in divided doses. 

                 Some children have received 20 mg/kg daily.
                 (Reynolds, 1989)
                      
                 15 to 20 mg/kg (given as a single daily dose) 
                 (Reynolds, 1993) 

                 Note: Optimum dose for children has not been 
                 established. A report showed the maximum daily dose as 
                 750 mg (Shirkey, 1977). 

       4.3 Contraindications

           Ethionamide should not be given to pregnant women unless the 
           benefits outweigh its possible risk. 

           To be used with caution in women of child-bearing age. 

           Severe liver disease.  

           Severe hypersensitivity.

           Note: Caution is necessary in administering ethionamide to 
           patients with depression or other psychiatric diseases, 
           chronic alcoholism, epilepsy, hypothyroidism or diabetes 
           mellitus.  

    5. ROUTES OF ENTRY

       5.1 Oral

           This is the usual route of administration for therapeutic 
           use. 

       5.2 Inhalation

           Unknown.

       5.3 Dermal

           Unknown.

       5.4 Eye

           Unknown.

       5.5 Parenteral

           Ethionamide hydrochloride has been given intravenously, but 
           there is no commercial preparation. 

       5.6 Other

           Ethionamide has been administered as rectal suppositories. 

    6. KINETICS

       6.1 Absorption by route of exposure

           Oral

           Approximately 80% of a gastrointestinal oral dose of 
           ethionamide is rapidly absorbed from the gastrointestinal 
           tract.  Following a single 1 g oral dose in adults, peak 
           plasma concentration of ethionamide averaging 20 ug/mL are 
           attained within 3 hours and less than 1 ug/mL at 24 hours. 
           Following a single 250 mg oral dose in adults, peak plasma 
           concentrations of ethionamide average 1-4 ug/ml (McEvoy, 
           1990). 

           After oral administration, the bioavailability is circa 100%. 
           (USPDI, 1993) 

           Rectal

           Relative bioavailability after rectal administration was 
           57.3% of that following oral administration. 

           Parenteral

           No data available.

       6.2 Distribution by route of exposure

           Oral

           It is widely distributed throughout body tissues and fluids. 

           It crosses the placenta and penetrates the meninges, 
           appearing in the CSF in concentrations equivalent to those in 
           the serum. 

           (Reynolds, 1989;  Gilman et al., 1990)

           Protein binding is low (10%) (USPDI, 1993).

       6.3 Biological half-life by route of exposure

           Oral

           Half-life is 2 to 3 hours (Reynolds, 1989).

       6.4 Metabolism

           Ethionamide is extensively metabolized, probably in the 
           liver, to ethionamide sulphoxide, 2-ethylisonicotinic acid 
           and 2-ethylisonicotinamide. The sulfoxide is the main active 
           metabolite (Moffat, 1986; McEvoy, 1993). 

       6.5 Elimination by route of exposure

           Less than 1% of a dose appears in the urine as unchanged 
           drug, the remainder is excreted in the urine as inactive 
           metabolites. 

    7. PHARMACOLOGY AND TOXICOLOGY

       7.1 Mode of action

           7.1.1 Toxicodynamics

                 In view of the structural similarity of the metabolite 
                 2-methylisonicotinic acid to isoniazid, it has been 
                 suggested that toxicity is due to pyridoxine deficiency 
                 (Manapat, 1992). 

           7.1.2 Pharmacodynamics

                 Ethionamide inhibits the synthesis of mycolic acids and 
                 stimulates oxidation-reduction reactions. Treated cells 
                 lose acid-fastness, thus the mechanism of action 
                 appears to be similar to that of INH. Specific sites of 
                 action may be different, since strains of 
                 M.tuberculosis that are resistant to high 
                 concentrations of INH are susceptible to ethionamide. 

                 Both the drug and the sulphoxide metabolite are active 
                 against M.tuberculosis. 2-ethylisonicotinic acid and 2-
                 ethylisonicotinamide are not active metabolites. 

                 It is bacteriostatic against M. tuberculosis at 
                 therapeutic concentrations, but may be bactericidal at 
                 higher concentrations. The average MIC (Minimum 
                 Inhibitory Concentration) for Mycobacterium 
                 tuberculosis is 0.6 - 2.5 mg/mL (Lorian, 1980). Most 
                 susceptible organisms are inhibited by 10 ug/mL or 
                 less.  

                 It is bactericidal against M. leprae and a minimum 
                 inhibiting concentration (MIC) of 0.05 ug/mL has been 
                 reported in mice. 

                 Resistance develops rapidly if used alone and there is 
                 complete cross-resistance with prothionamide, 
                 thiacetazone and thiambutosine. (Reynolds, 1989) 

       7.2 Toxicity

           7.2.1 Human data

                 7.2.1.1 Adults

                         There is no experience with acute overdoses. 
                         Some of the adverse effects are dose-dependent 
                         and would be expected in an overdose situation. 
                         The most serious effects are neuropsychiatric 
                         symptoms and liver necrosis. 

                         In clinical use, neuropsychiatric symptoms, 
                         such as headache, sleeping, insomnia, 
                         depression and paraesthesia may occur. 
                         Elevation of liver transaminase enzymes has 
                         been known to develop. (British Tuberculosis 
                         Association, 1968). 

                         No special precautions are required due to age, 
                         as doses are adjusted according to patient 
                         response. However, dose should be modified 
                         depending on liver and renal status. (Dollery, 
                         1991) 

                 7.2.1.2 Children

                         No data available.

           7.2.2 Relevant animal data

                 A rat study showed the sublethal neurotoxicity level of 
                 ethionamide to be 1300 mg/kg. The principal signs were 
                 paralysis, loss of screen grip and decreased motor 
                 activity (Manapat et al., 1992). 

           7.2.3 Relevant in vitro data

                 No data available.

       7.3 Carcinogenicity

           No data available.
           
       7.4 Teratogenicity

           Teratogenic effects have been reported in rabbits, mice and 

           rats, in which high doses have led to abortions and some 
           malformations. 
           Conflicting reports exist in the literature concerning 
           congenital malformations in children when exposed to the drug 
           in utero. One observation attributes 7 malformations among 23 
           children exposed to ethionamide whereas in another study with 
           70 infants no such relationship to drug treatment during 
           pregnancy was found. (Dollery, 1991) 

       7.5 Mutagenicity

           Ethionamide was not found to be mutagenic as shown by Ames 
           Salmonella and Micronuclei Assay Test (Peters, 1983). 

       7.6 Interactions

           Ethionamide taken with pyrazinamide may lead to abnormalities 
           of liver function and the use of these two agents together 
           should be avoided (Reynolds, 1989). 

           The use of rifampicin with the thiomides (ethionamide or 
           prothionamide) as part of the regimens recommended by WHO for 
           the treatment of multibacillary leprosy has been associated 
           with an unexpectedly high incidence of hepatotoxicity (Pattyn 
           et al., 1984; Reynolds, 1989). 

           Adverse nervous system effects of ethionamide,
           cylcoserine and isoniazid may be additive (McEvoy, 1990).

           The side effects of other tuberculostatic agents may be 
           enhanced when ethionamide is administered concomitantly 
           (Griffin, 1988). 

           Alcohol may contribute to psychotropic reactions in an 
           ethionamide treated patient. More study is needed to clarify 
           the clinical significance of this interaction. (Griffin, 
           1988) 

       7.7 Main adverse effects

           The most common adverse effects are dose-related, viz: 
           gastrointestinal disturbances, including anorexia, excessive 
           salivation, a metallic taste, nausea, vomiting, stomatitis, 
           diarrhoea and hepatitis.  

           Dizziness, drowsiness, headache, postural hypotension and 
           asthenia may also occur occasionally. 

           Other side effects reported include acne, allergic reactions 
           alopecia, convulsions, deafness, dermatitis (including 
           photodermatitis), visual disturbances, tremors, 
           gynaecomastia, impotence, menstrual disturbances, olfactory 
           disorders, peripheral and optic neuropathy, thrombocytopenia 
           and rheumatic pains.  Mental disturbances, including 
           depression, anxiety and psychosis have been provoked.  A 

           pellagra-like syndrome with encephalopathy has been reported 
           rarely.  A tendency towards hypoglycaemia may occur and could 
           be of significance in patients with diabetes mellitus. 
           Hypothyroidism has also occurred.  Racial differences in 
           tolerance may occur, e.g. Chinese and Africans are often more 
           tolerant of ethionamide than are Europeans (Reynolds, 1989). 

           Note: Many patients cannot tolerate therapeutic doses of 
           ethionamide and have to discontinue treatment. 

    8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

       8.1 Material sampling plan

           8.1.1 Sampling and specimen collection

                 8.1.1.1 Toxicological analyses

                 8.1.1.2 Biomedical analyses

                 8.1.1.3 Arterial blood gas analysis

                 8.1.1.4 Haematological analyses

                 8.1.1.5 Other (unspecified) analyses

                         Plasma, serum, or urine may be used; however, 
                         blood is preferably collected on the third hour 
                         post-ingestion. 

           8.1.2 Storage of laboratory samples and specimens 

                 8.1.2.1 Toxicological analyses

                 8.1.2.2 Biomedical analyses

                 8.1.2.3 Arterial blood gas analysis

                 8.1.2.4 Haematological analyses

                 8.1.2.5 Other (unspecified) analyses

                         The blood obtained should be frozen at -20 to
                         -40. 

           8.1.3 Transport of laboratory samples and specimens

                 8.1.3.1 Toxicological analyses

                 8.1.3.2 Biomedical analyses

                 8.1.3.3 Arterial blood gas analysis

                 8.1.3.4 Haematological analyses

                 8.1.3.5 Other (unspecified) analyses

                         The blood sample should be transported, 
                         refrigerated and separated within 2 hours of 
                         collection. 

       8.2 Toxicological Analyses and Their Interpretation

           8.2.1 Tests on toxic ingredient(s) of material

                 8.2.1.1 Simple qualitative test(s)

                         Description 

                         Yellow crystal or a yellow crystalline powder, 
                         darkening on exposure to light, with a slight 
                         sulphide-like odour. 

                         Identity Tests

                         The assay exhibits an absorbence maximum at 290 
                         +2 nm. 

                         Dissolve 1 g of ethionamide tablets in 50 ml of 
                         methanol and filter through a medium porosity 
                         sintered-glass funnel.  Evaporate the filtrate 
                         on a steam bath and the obtained residue melts 
                         between 155 and 164 (USP, 1985). 

                 8.2.1.2 Advanced qualitative confirmation test(s)

                 8.2.1.3 Simple quantitative method(s)

                 8.2.1.4 Advance quantitative method(s)

           8.2.2 Test for biological specimens

                 8.2.2.1 Simple qualitative test(s)

                         Qualitative analysis of urine based on a colour 
                         reaction. 

                 8.2.2.2 Advanced qualitative confirmation test(s)

                 8.2.2.3 Simple quantitative method(s)

                 8.2.2.4 Advance quantitative method(s)

                         Quantification analysis using High Pressure 
                         Liquid Chromatography on plasma, serum, or 
                         urine. 

                 8.2.2.5 Other dedicated method(s)

           8.2.3 Interpretation of toxicological analyses

                 Blood levels would peak by the third hour; levels at 6 
                 to 20 ug/ml are considered therapeutic. 

                  A yellow urine colour reaction detects the presence of 
                 a sulfoxide derivative. 

       8.3 Interpretation of toxicological analyses

           8.3.1 Biochemical analysis

                 8.3.1.1 Blood, plasma or serum

                         Liver function tests such as ALT, AST, Alkaline 
                         Phosphatase, Direct and Indirect Bilirubin; 
                         Prothrombin time; Blood Sugar; BUN, Creatinine 

                 8.3.1.2 Urine

                         Urinalysis to detect glucose, protein, and 
                         leucocytes; hourly urine output determination. 

                 8.3.1.3 Other fluids

           8.3.2 Arterial blood gas analyses

                 Not relevant.

           8.3.3 Haematological analyses

                 In severe cases of jaundice or suspected 
                 hepatotoxicity, a full blood count and prothrombin time 
                 must be monitored for coagulopathy. 

           8.3.4 Interpretation of biomedical investigations

                 Transient increase in serum bilirubin, AST (SGOT) and 
                 ALT (SGPT) concentrations have been reported in 
                 patients receiving ethionamide.  Hepatitis (with or 
                 without jaundice) has also been reported.  
                 Hepatotoxicity generally is reversible on 
                 discontinuation of the drug. 

       8.4 Other biomedical (diagnostic) investigations and their 
           interpretation 

           T3, T4; urinary coproporphyrin, ophthalmoscopy.

       8.5 Overall Interpretation of all toxicological analyses and 
           toxicological investigations 

       8.6 References

           United States Pharmacopeia, The National formulary (1985) 

           21st rev., 16th ed., Rockville MD, United States 
           Pharmacopeial Convention,,  pp 413. 
    
    9. CLINICAL EFFECTS

       9.1 Acute poisoning

           9.1.1 Ingestion

                 None reported.

           9.1.2 Inhalation

                 None reported.
                 
           9.1.3 Skin exposure

                 Not relevant.

           9.1.4 Eye contact

                 None reported.

           9.1.5 Parenteral exposure

                 None reported.

           9.1.6 Other

                 None reported.

       9.2 Chronic poisoning

           9.2.1 Ingestion

                 None reported.

           9.2.2 Inhalation

                 None reported.

           9.2.3 Skin Exposure

                 Not relevant.

           9.2.4 Eye contact

                 None reported.

           9.2.5 Parenteral exposure

                 None reported.

           9.2.6 Other

       9.3 Course, prognosis, cause of death

           None reported.
           
       9.4 Systematic description of clinical effects

           9.4.1 Cardiovascular

                 None reported.

           9.4.2 Respiratory

                 None reported.

           9.4.3 Neurological

                 9.4.3.1 Central nervous system (CNS)

                         May cause encephalopathy with pellagra-like 
                         symptoms; headaches; sleepiness, insomnia, 
                         depression, tremors, convulsions (British 
                         Tuberculosis Assn., 1968) 

                 9.4.3.2 Peripheral nervous system

                         Peripheral nerve symptoms consisting of 
                         paraesthesias, motor weakness or sensory 
                         impairment have been observed, following 
                         therapeutic doses (Snavely, 1984). 

                 9.4.3.3 Autonomic nervous system 
            
                         None reported.

                 9.4.3.4 Skeletal and smooth muscle 

                         None reported.

           9.4.4 Gastrointestinal

                  Dose-related 

                 Anorexia, excessive salivation, metallic taste, nausea, 
                 vomiting, stomatitis, and diarrhoea. 

           9.4.5 Hepatic

                 Although jaundice is rare, hepatitis may occur in about 
                 5% of patients. 

                 One study showed a 13% incidence of hepatitis when drug 
                 is combined with rifampicin and dapsone. The 
                 hepatocellular injury is non dose-related, especially 
                 among diabetics. 

           9.4.6 Urinary

                 9.4.6.1 Renal

                         None reported.

                 9.4.6.2 Other

           9.4.7 Endocrine and reproductive systems

                  Thyroid

                 May cause a disturbance in the synthesis of thyroid 
                 hormone resulting in hypothyroidism. 

                 Ethionamide inhibits the trapping of technetium and 
                 organification of iodine at concentration seen 
                 clinically (Drucker 1984). 

                  Other

                 Gynaecomastia
                 Menorrhagia
                 Impotence
                 Hypoglycaemia

           9.4.8 Dermatological

                 Dermatitis (photodermatitis)
                 Acne
                 Alopecia

           9.4.9 Eye, ear, nose, and throat: local effects 

                  Local effects

                 None reported.

                  Systemic effects

                 Optic neuritis, optic atrophy, degeneration of the 
                 chiasma, deafness, olefactory disturbances (Holdiness, 
                 1987). 
                 
           9.4.10 Haematological

                  May cause acute porphyria because it has been shown to 
                  be porphyrinogenic in animals. 

                  Thrombocytopenia

           9.4.11 Immunological

                  None reported.

           9.4.12 Metabolic

                  9.4.12.1 Acid-base disturbances

                           None reported.

                  9.4.12.2 Fluid and Electrolyte disturbances

                           None reported.

                  9.4.12.3 Others

                           Hypoglycaemia when given to diabetic 
                           patients. 

           9.4.13 Allergic reactions

                  Hypersensitivity reactions may occur.

           9.4.14 Other clinical effects

                  Rheumatic pains.

           9.4.15 Special risks

                  Pregnancy

                  CNS malformations have been reported (Schardein, 
                  1976). 

                  Conflicting reports exist for congenital malformations 
                  of children born to mothers receiving the drug during 
                  pregnancy. Therefore, it is suggested that the drug be 
                  avoided during pregnancy or in women of childbearing 
                  potential unless the benefits outweigh its possible 
                  hazard. (Dollery, 1991) 
                  
                  Breast-feeding
                  
                  As far as can be determined there are no data 
                  published indicating the secretion of ethionamide in 
                  breast milk in measurable quantities (Dollery, 1991). 

                  Enzyme deficiencies

                  None reported.

       9.5 Others

           No data available

       9.6 Summary

           Not applicable

    10. MANAGEMENT

        10.1 General  principles

             Whenever the presentation of the patient is an overdose or 
             adverse drug event, the first principle is to evaluate the 
             vital functions and provide life-support measures to 
             stabilize the victim. 

             Decontamination should be considered to reduce further 
             absorption, if patient seen early after poisoning.  

             There are no specific antidotes for ethionamide overdose; 
             however, high dose pyridoxine has been found to inhibit its 
             neurotoxic effects (Gennaro et al., 1985). 

             Pellagra-like symptoms can be reversed by niacin.

        10.2 Relevant laboratory analyses

             Bio-medical tests: (i.e., baseline liver function; platelet 
             count, blood sugar, prothrombin time). 

             10.2.1 Sample collection

                    Plasma, serum or urine may be used, however, blood 
                    is preferably collected on the third hour post-
                    ingestion.  Samples obtained should be frozen at  
                    -20 to -40 C and separated within 2 hours of 
                    collection. 

             10.2.2 Biomedical analysis

                    Blood

                    Liver function tests such as ALT, AST, alkaline 
                    phosphatase, Direct and Indirect Bilirubin; 
                    Prothrombin time; Blood sugar; BUN, Creatinine. 

                    Urine

                    Urinalysis to detect glucose, protein, and 
                    leucocytes; hourly urine output determination. 

             10.2.3 Toxicological analysis

                    Blood levels taken on the third hour post-ingestion 
                    whose values are beyond 20 ug/ml are considered 
                    toxic. 

             10.2.4 Other investigations

                    Not relevant

        10.3 Life supportive procedures and symptomatic/specific 
             treatment 

             Treatment is mainly supportive.  If patient is in a 
             critical condition (i.e. cardiorespiratory distress) 
             maintain a clear airway, aspirate secretions if these are 
             present in the airway, administer oxygen, perform 
             endotracheal intubation if indicated, provide artificial 
             ventilation, if warranted. Maintain a patent intravenous 
             line to support circulation. Monitor vital signs 
             (sensorium, blood pressure, heart and respiratory rate) 
             regularly and correct hypotension with isotonic fluids or 
             inotropic agents.  Monitor fluids and electrolyte balance 
             (i.e., input and urine output). 

             If there are cardiac dysrhythmias, antiarrhythmic agents 
             are best avoided, especially if the "torsades de pointes" 
             type of arrhythmia is present. 

             If bleeding ensues, correct by doing appropriate component 
             transfusion only if indicated.  

             Reevaluate other drugs which patient may be taking and 
             which may interact with ethionamide. 

        10.4 Decontamination

             Methods to reduce gastrointestinal absorption consist of 
             inducing emesis or performing gastric lavage. 

             Perform gastric lavage if dose was high and ingestion was 
             recent. Protect airway if patient is unconscious. 

             Administer activated charcoal (1 mg/kg). (Note: The use of 
             cathartics is generally no longer recommended). 

        10.5 Elimination

             No documented information available.

        10.6 Antidote treatment

             10.6.1 Adults

                    There are no specific antidotes for ethionamide 
                    overdose. However, high dose pyridoxine may inhibit 
                    its neurotoxic effects (Gennaro et al., 1985) 
                    because of its similarity to isoniazid. This 
                    possible antidotal effect has not been documented. 

             10.6.2 Children

                    There is no specific antidote.  However, high dose 
                    pyridoxine may prevent neurotoxicities. 

        10.7 Management discussion

             Despite ethionamide's synthesis in 1956, there is still 
             paucity of both clinical and experimental data, 
             specifically in the management of acute poisoning overdose. 

             Drug induced hepatotoxicity was shown to be decreased by 
             pre-administration of methimazole (MMI)(Ruse, 1991). 

             High dose pyridoxine may prevent neurotoxicities.

             Pellagra-like symptoms can be reversed by niacin.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Abnormalities of liver function (but no jaundice) occurred 
             in 12 of 80 patients treated with ethionamide as part of 
             their antituberculous chemotherapy.  However, 10 of these 
             patients were also taking pyrazinamide.  The use of these 2 
             agents together may increase the risk of hepatotoxicity and 
             should be avoided (Reynolds, 1989). 

             A girl developed acute hepatic necrosis and died after 
             treatment with ethionamide, isoniazid and aminosalicylic 
             acid.  It was considered that ethionamide was the most 
             likely cause (Reynolds, 1989). 

             A report of encephalopathy with pellagra-like symptoms 
             occurring in association with ethionamide in 2 patients, 
             and with ethionamide and cycloserine in one patient. 
             Treatment was with nicotinamide and compound vitamin 
             preparations (Reynolds, 1989). 

        11.2 Internally extracted data on cases

             No data available.

        11.3 Internal cases

             To be completed by each Centre using local data.

    12. ADDITIONAL INFORMATION

        12.1 Availability of antidotes

             To be completed by each Centre using local data.

        12.2 Specific preventive measures

             Caution is necessary in administration ethionamide to 
             patients with depression or other psychiatric illnesses, 
             chronic alcoholism, or epilepsy. 

             As there have been reports of goitre and hypothyroidism 
             associated with the use of ethionamide it should  be 
             administered with care to patients requiring treatment for 
             hypothyroidism. 

             Difficulty may be experienced in controlling diabetes. 
             The side effects of other tuberculostatic agents may 
             be increased when ethionamide is used concurrently.
                      
             Ethionamide is contraindicated in pregnant and lactating 
             women, in patients with severe liver disease, and those 
             with severe hypersensitivity to the drug. 
         
        12.3 Other

             No data available.

    13. REFERENCES
            
        British Tuberculosis Association (1968) Comparison of toxicity 
        of prothionamide and ethionamide: a report from the research 
        committee of the british tuberculosis association. Tubercule, 
        49(2): 125-135 

        Budavari S ed. (1989) The Merck Index, an encyclopedia of 
        chemicals, drugs, and biologicals, 11th ed. Rahway,   New 
        Jersey, Merck and Co., Inc.  p 590. 

        Dollery C ed. (1991) Therapeutic Drugs, Volume 1. Edinburgh, 
        Churchill & Livingstone. 

        Drucker D et al. (1984) Ethionamide-induced goitrous 
        hypothyroidism. Ann Intern Med, 100(6): 837-9 

        European Pharmacopoeia (1980-1986) 2nd. ed., Maison Neuve, 
        Council of Europe, p 142. 

        Gennaro AR ed. (1985) Remington's pharmaceutical sciences, 17th 
        ed. Easton, Pennsylvania,  Mack Publishing Company,  p 1216. 

        Gilman AG, Rall TW, Nies AS & Taylor P eds. (1990) Goodman and 
        Gilman's the pharmacological basis of therapeutics, 8th ed. New 
        York, Pergamon Press, pp 1154-1155 

        Griffin JP, O,Grady J, Well FO,& D'Arcy (1988) A manual of 
        adverse drug interactions, Butterworth and Co Ltd. 

        Holdiness MR (1984) Clinical pharmacokinetics of antituberculous 
        drugs. A review. Clin Pharmacokinetics, 9(6): 571-574 

        Lorian V ed. (1980) Antibiotics in laboratory medicine, 
        Baltimore Press, Williams and Wilkins Company, pp 160-165. 

        McEvoy GK ed. (1990) American hospital formulary service, drug 
        information, Bethesda, American Society of Hospital Pharmacists, 
        pp 343-344. 

        McEvoy GK ed. (1993) American hospital formulary service, drug 
        information, Bethesda, American Society of Hospital Pharmacists, 
        pp 343-344. 

        Manapat BD et al. (1992) The effectiveness of pyridoxine in 
        modifying the neurotoxidome of ethionamide overdose in sprague-
        dawley rats. Manilla, Pharmacokinetic research paper, UP College 
        of Medicine-Department of Pharmacology. 

        Moffat AC ed. (1986) Clarke's isolation and identification of 
        drugs in pharmaceuticals, body fluids, and post-mortem material. 
        2nd ed.  London, The Pharmaceutical Press, pp 597-598. 
         
        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 
        29th ed. London, The Pharmaceutical Press, pp 562-563. 
        
        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 
        30th ed. London, The Pharmaceutical Press, p 166. 
            
        Osol A et al. (1973)  The united states dispensatory, 27th ed. , 
        JB Lippincott Company,  p 509. 

        Pattyn SR et al. (1984) Hepatotoxicity of the combination of 
        rifampicin-ethionamide. Int J Lepr and Other Mycobacterial 
        Diseases, 1: 1-6 

        Peters JH (1983) Mutagenic activity of antileprosy drugs and 
        their derivatives. Int J Lepr and Other Mycobacterial Diseases, 
        51(1): 45-53 

        Physician's Desk Reference (1992) 46th ed. Ordell NJ, Medical
        Economics, p 2527.

        Ruse MJ (1991) The effect of methimazole on thioamide 
        bioactivation and toxicity. Toxicol Lett, 58(1): 37-41 

        Schardein JL (1976)  Drugs as teratogens.  CRC Press, Inc,  
        p 202. 

        Shirkey HC (1984) Pediatric drug handbook , W B  Saunders 
        Company. 

        Snavely SR et al. (1984) The neurotoxicity of antibacterial 
        agents. Ann Intern Med, 100(1): 92-104 

        USPDI (1983) Drug Information for the Health Care Professional. 
        Vol. 1, Rockville MD, United States Pharmacopeial Convention,  
        pp 396-397. 

        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 
        index. Oslo, WHO Collaborating Centre for Drug Statistics 
        Methodology, p 61. 

        WHO (1992) International nonproprietary names (INN) for 
        pharmaceutical substances. Geneva, World Health Organisation,  
        p 208. 
            
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)
         
        Author       Dr Perlita Young, M.D.
                     National Poison Control and Information Service
                     University of the Philippines
                     College of Medicine
                     Philippine General Hospital
                     Ermita, Manila 1000
                     Philippines

                     Tel: 63-2-5218251
                     Fax: 63-2-501078

        Date         January 1992

        Reviewer     Dr M.C. Alonzo
                     CIAT 7- piso
                     Hospital de Clinicas
                     Av. Italia s/n
                     Montevideo
                     Uruguay

                     Tel: 598-2-804000
                     Fax: 598-2-470300

        Peer Review  Drs Maramba, Critchley, Caitens, Panganiban, 
                     Ombega, Ten Ham & Ms Kaye. Newcastle-upon-Tyne, 
                     United Kingdom, February 1992. 




    See Also:
       Toxicological Abbreviations
       Ethionamide  (IARC Summary & Evaluation, Volume 13, 1977)