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Methyldopa

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
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
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   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 ANALYSES 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 Advanced Quantitative Method(s)
      8.2.2 Tests 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 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      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 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, 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 Other
   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)
    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Methyldopa
     1.2 Group
       Antihypertensive agent
     1.3 Synonyms
       3-hydroxy- -methyl-l-tyrosine
       Alpha-methyldopa
       L-2-amino-2-methyl-3-(3,4-dihydroxyphenyl) propionic acid  -
       methyldopa
       Levo-2-amino-2-(3,4-dihydroxibenzyl) propionic acid 
       sesquihydrate
       Levo-3-(3,4-dihydroxiphenyl)-2-methyl-l-alanine-sesquihydrate
       Methyldopum
       Methyldopum hydratum
       Metildopa
       MK 351
       NCI-C55721
       NR.C.2294
     1.4 Identification numbers
       1.4.1 CAS number
             Anhydrous:   555-30-6
       1.4.2 Other numbers
             NIOSH: AY 5950000
     1.5 Brand names, Trade names
       Aldomet (Argentina, Australia, Brazil, Canada, Denmark, France,
       Italy, Netherlands, Norway, South Africa, Spain, Sweden, 
       Switzerland, UK); Aldometil (Germany);  Alphamex (South Africa);
       Baypresol (Spain); Co-Caps Methyldopa (UK); Dopamet (Canada, 
       Denmark, Norway, Sweden, Switzerland, UK); Dopegyt (Hungary); 
       Elanpress (Italy); Equibar (France); Grospisk (Japan); 
       Hyperpax (Denmark, Netherlands, Norway, Switzerland); Hyperpaxa 
       (Sweden); Hypodopa (Pakistan); Hypolar (UL); Hy-po-tone 
       (South Africa); Medimet 250 (Canada); Medomet (UK); Medopa (Japan); 
       Medopal (Norway); Medopren (Italy); Methopa (Australia); Mrthoplain 
       (Japan); Mulfasin (Netherlands); Normopress (South Africa); 
       Novomedopa (Canada); Presinol (Belgium, Germany, Italy); 
       Sembrina (Germany, Italy, Netherlands, Switzerland); Sinepress 
       (South Africa).
     1.6 Manufacturers, Importers
       Merck Sharp & Dohme; DDSA Pharmaceuticals; Protea; ICN; Dumex; 
       Berk Pharmaceuticals; Recordati; Biogalenique; Ercopharm; 
       Wilson; Lagap; Lennon; Apothekernes Laboratorium; Malesci; USV; 
       Schwults; Novopharm; Bayer; Bayropharm; Boehringer Mannheim; 
       Boehringer Ingelheim; Rolab.
    2. SUMMARY
     2.1 Main risks and target organs
       Acute overdose: the target organs are the central nervous     
       systemand the cardiovascular system.  The main risks are 
       hypotension, bradycardia, cardiac arrhythmia and hypothermia. 
       
       Chronic poisoning and adverse effects: the target organs are 
       the central nervous system, cardiovascular system, liver, 
       pancreas and immunological system.
     2.2 Summary of clinical effects

       Acute: drowsiness, coma, hypotension, bradycardia, dry mouth, 
       impairment of atrioventricular conduction, and hypothermia.
       
       Chronic: CNS manifestations - sedation, parkinsonism, 
       choreoathetoid movements, headache, vertigo.
       
       Cardiovascular effects - bradycardia, prolonged carotid sinus
       hypersensitivity, myocarditis, pericarditis, aggravation of 
       angina pectoris, postural hypotension, first-degree heart block.
       
       Gastrointestinal effects - diarrhea, colitis, dryness of the 
       mouth, black tongue, reversible malabsorption, pancreatitis.
       
       Liver disorders - hepatitis.
       
       Hypersensitivity reactions - rash, urticaria, eczema, 
       lichenoid eruptions.
       
       Hematological manifestations - positive Coomb's test, 
       leukopenia, hemolysis.
     2.3 Diagnosis
       The diagnosis depends on the patient's history and clinical
       presentation.
       
       Appropriate diagnostic tests in patients with chronic 
       poisoning or adverse reactions include: 
       
                 Blood:    liver enzyme levels
                           complete blood count
                           BUN
                           Coomb's test
                           glucose
                           amylase
       
                 Urine:    urinalysis
       
                 Other:    Electrocardiogram in acute poisoning
     2.4 First aid measures and management principles
       Stabilization
       
                    Make a proper assessment of airway, breathing,    
                    circulation, and neurological status of the        
                    patient.
       
                    Open and maintain at least one intravenous route.
       
                    Control cardiac arrhythmias with an appropriate   
                    drug regimen.
       
                    Correct hypotension as required.
       
        Decontamination
       
                    Ipecac syrup or gastric lavage may be useful if
                    treatment is performed within the first few hours
                    after ingestion.

       
                    There is no specific antidote.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Methyldopa is the L-isomer of alpha-methyldopa.
       
       It was originally synthesized as an analog of 
       3,4-dihydroxyphenylalanine (Gerber, 1990).
       
       Methyldopa may be prepared from dimethoxyphenyl-acetonitrile 
       by successive interaction with sodium ethoxide, ammonium 
       carbonate, and potassium cyanide, followed by resolution of 
       the racemic product (Osol, 1980).
     3.2 Chemical structure
       Molecular weight:  238.2
     3.3 Physical properties
       3.3.1 Properties of the substance
             Methyldopa is a colourless or almost colourless 
             crystal or a white to yellowish-white odourless fine powder
             which may contain friable lumps.
             
             Methyldopa melts at 290C.
             
             Methyldopa 1.13 g is approximately equivalent to 1 g of 
             anhydrous methyldopa.
             
             Slightly soluble in water and alcohol; practically 
             insoluble in chloroform and ether; dissolves in 
             dilute mineral acids.
             
             Practically insoluble in the common organic solvents 
             (Reynolds, 1989).
             
             When heated to decomposition it emits toxic fumes of 
             nitrogen oxides (Sax, 1989).
             
             Methyldopa may also contain: blue opaspray, 
             candelilla wax, colloidal silicon dioxide, 
             edetate disodium, hydroxypropyl cellulose, 
             hydroxypropyl methylcellulose, methylparaben, 
             microcrystalline cellulose, polyethylene glycol, 
             pregelatinized starch, propylparabens, stearic 
             acid (Barnhart, 1987).
       3.3.2 Properties of the locally available formulation
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             The shelf-life of the commercially available 
             preparations is four years.
       3.4.2 Shelf-life of the locally available formulation
       3.4.3 Storage conditions
             Store in well-closed containers, at temperatures below 
             30C (86F).
             
             Protect from light, keep dry.
       3.4.4 Bioavailability
             No data available.

       3.4.5 Specific properties and composition
             No data available.
    4. USES
     4.1 Indications
       Hypertension
       
       Treatment of moderate to severe hypertension usually in 
       combination with diuretic or a beta-blocking agent.
       
       Dyskinesias
       
       Methyldopa has been used in the treatment of severe 
       dyskinesias (Reynolds, 1989).
       
       Menopausal symptoms
       
       Methyldopa may reduce the incidence of hot flushes in 
       menopausal women but its role is limited by a high 
       incidence of side effects (Reynolds, 1989).
     4.2 Therapeutic dosage
       4.2.1 Adults
             Hypertension
             
             The usual starting oral dose is 250 mg of anhydrous 
             methyldopa two or three times daily for the first 48 
             hours. The daily dosage then may be increased or 
             decreased, at intervals of not less than two days, until 
             the desired response is obtained.  To minimize sedation, 
             increase the dose in the evening.
             
             No advantage is obtained at doses larger than 3 g daily.
             
             The usual maintenance dosage is 500 mg to 2 g of 
             anhydrous methyldopa daily in two to four doses. In the 
             elderly, the usual dose is 125 mg twice daily, with a 
             maximum of 2 g/day.
             
             A gradual hypotensive response occurs in most patients 
             in 12 to 24 hours.
             
             Since methyldopa has short duration of action, 
             withdrawal is followed by a return of hypertension, 
             usually within 48 hours (Barnhart, 1987; Reynolds, 
             1989).
             
             Hypertensive crisis
             
             Methyldopate hydrochloride is usually given by 
             intermittent intravenous infusion of 250 to 500 mg every 
             6 to 8 hours if necessary.  After the blood pressure has 
             been controlled, oral medication should be substituted 
             (American Medical Association, 1988).
       4.2.2 Children
             A suggested initial dose is 10 mg/kg body weight daily 
             in two divided doses.  The daily dosage then is 
             increased or decreased until an adequate response is 

             obtained (Barnhart, 1987; Reynolds, 1989), and increased 
             as necessary to a maximum of 65 mg/kg or 3 g daily.
             
             For postoperative hypertension the suggested dose is 20-
             40 mg/kg daily divided into four doses.  After blood 
             pressure has been controlled, oral medication should be 
             substituted.
     4.3 Contraindications
       Active hepatic disease, such as acute hepatitis and active    
       cirrhosis.
       
       If previous therapy with methyldopa has been associated with
       liver disorders.
       
       Methyldopa is not recommended for patients with 
       pheochromocytoma (Barnhart, 1987; Reynolds, 1989).
       
       Precautions:
       
       Methyldopa is removed by dialysis, which may impair control of
       blood pressure.
       
       Rarely, involuntary choreoathetoid movements have been 
       observed during therapy with methyldopa in patients with 
       severe bilateralcerebrovascular disease.  Therapy should then 
       be stopped.
       
       Older patients with advanced arteriosclerotic disease should 
       be given lower dose of methyldopa to avoid syncope (Osol, 
       1980).
       
       Methyldopa should be used with caution in patients with 
       impaired kidney function or mental depression.
       
       Methyldopa has been reported to aggravate porphyria.
       
       It crosses the placenta and appears in breast milk.
    5. ROUTES OF ENTRY
     5.1 Oral
       This is most the common route of administration.  Accidental 
       or intentional ingestion of large doses may occur.
     5.2 Inhalation
       No data available.
     5.3 Dermal
       No data available.
     5.4 Eye
       No data available.
     5.5 Parenteral
       No data available.
     5.6 Other
       No data available.
    6. KINETICS
     6.1 Absorption by route of exposure
       When administered orally, methyldopa is absorbed by an active
       amino acid transport. Methyldopa is incompletely and variably
       absorbed from the gastrointestinal tract. Oral bioavailability 

       is variable (50%).
       
       Peak concentrations in plasma occur after 2 to 3 hours.
       
       When administered orally, the maximum effect of a single dose
       occurs after 4 to 6 hours, although after repeated doses the
       maximum hypotensive effect may not occur until the second day. 
       
     6.2 Distribution by route of exposure
       The volume of distribution is 0.4 l/kg.
       
       Plasma protein binding is reported to be minimal.
       
       Plasma level of methyldopa does not correlate with its 
       clinical effect (Ellenhorn and Barceloux, 1988).
       
       It crosses the placenta.
       
       Methyldopa crosses the blood brain barrier.  The transport of
       methyldopa into CNS is apparently an active process.
     6.3 Biological half-life by route of exposure
       The half-life of methyldopa is about 2 hours (Noji & Kelen,
       1989).
     6.4 Metabolism
       Methyldopa is partly conjugated, mainly to the methyldopa-O-
       sulphate.  The major metabolite probably contributes little to
       the therapeutic effect except in patients with renal failure.
       
       Other metabolites include methyldopamine, methylnorepinephrine,
        and O-methylated compounds (Gerber,1990)
     6.5 Elimination by route of exposure
       Methyldopa is excreted by the kidneys.  Elimination is phasic.
       95% of the drug is eliminated in the initial phase with a half-
       life of 0.21 hour.  In the second phase, the elimination half-
       life averages 1.28 hours (Ellenhorn and Barceloux, 1988).
       
       Twenty-five percent of unchanged methyldopa is excreted in the
       urine within 24 hours (Winchester, 1990).
       
       Methyldopa is excreted in the urine primarily as the sulphate
       conjugate (50 to 70%) and as the parent drug (25%).  The
       remaining fraction is excreted as other metabolites (Gerber,
       1990).  Small amounts are eliminated in breast milk.
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Some effects, such as coma and mental depression, are 
             due to the effects of methyldopa on the CNS. 
             
             Methyldopa produces a number of side effects due to 
             alpha-2-adrenergic agonist effects.
             
             Salt and water retention occurs during prolonged use of 
             methyldopa and this tends to blunt the effect (Gerber, 
             1990).
             

             Inhibition of suppressor-lymphocyte function is a 
             possible mechanism of methyldopa-induced autoimmune 
             haemolytic anemia (Reynolds, 1989).
             
             Reversible agranulocytosis associated with methyldopa 
             was shown to be caused by the presence of methyldopa-
             dependent granulocyte antibodies (Reynolds, 1989).
             
             Many adverse effects produced by methyldopa are due to
             hypersensitivity reactions.
       7.1.2 Pharmacodynamics
             Methyldopa is a centrally acting antihypertensive agent. 
             It is metabolized to alpha-methylnorepinephrine in the 
             brain, and this compound is thought to activate central 
             alpha-2 adrenergic receptors (Gerber, 1990).
             
             Methyldopa has no direct effect on cardiac function and 
             usually does not reduce glomerular filtration rate, 
             renalblood flow, or filtration fraction.
             
             Methyldopa reduces vascular resistance.  The fall in
             arterial pressure is maximal 6 to 8 hours after an oral 
             dose.
             
             Plasma concentrations of norepinephrine fall in 
             association with the reduction in arterial pressure.  
             This reflects the decrease in sympathetic tone.
             
             Renin secretion is decreased but this is not the prime
             mechanism of action of methyldopa.
             
             Use of methyldopa may reverse left ventricular 
             hypertrophy within 12 weeks (Gerber, 1990).
             
             Methyldopa reduces both supine and standing blood 
             pressure with infrequent symptomatic postural 
             hypotension.  Exercise hypotension and diurnal pressure 
             variations rarely occur (Barnhart, 1987).
             
             After a single therapeutic dose, the hypotensive effect 
             occurs in 2 or more hours, is maximal effect in 6 to 8 
             hours, and continues with diminishing intensity for 18 
             to 24 hours.
             
             On discontinuation, the blood pressure returns to
             pretreatment levels in 24 to 48 hours (Osol, 1980).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     Toxic dose:    7.5 g
                     
                     Death has been reported after ingestion of 25 g 
                     (Noji & Kelen, 1989)
                     
                     No adverse reactions were reported in patients 
                     taking 6 g/day (Ellenhorn and Barceloux, 1988) 

                     but ingestion of 2.5 g produced coma, 
                     hypothermia, hypotension, bradycardia, and dry mouth 
                     in one 19 year-old man.
             7.2.1.2 Children
                     No data available.
       7.2.2 Relevant animal data
             TDLo (rat, oral)         7.5 mg/kg 
             TDLo rat, s/c)           300 mg/kg
             LD50 (rat, oral)         5000 mg/kg
             LD50 (rat, i/p)          300 mg/kg
             LD50 (mouse, i/p)        150 mg/kg
             LD50 (mouse, oral)       5.3 to 15 mg/kg
             LD50 (mouse, IV)         1900 mg/kg
             LD50 (rabbit, oral)      713 mg/kg
             LD50 (rabbit, IV)        713 mg/kg
             
             (Sax, 1989; Winchester, 1990)
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       Foetal blood pressure is reduced in infants of mothers given
       methyldopa (Reynolds, 1989).
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Hypotension can be increased by concurrent administration of
       diuretics, other antihypertensive agents, and general
       anaesthetics (Gerber, 1990;  Reynolds, 1989).
       
       Concomitant use of methyldopa and digoxin may produce 
       symptomatic sinus bradycardia.
       
       Methyldopa and levodopa may enhance each other's therapeutic 
       or adverse effects. but it has also been claimed that 
       methyldopa may inhibit the therapeutic response to levodopa 
       (Reynolds, 1989).
       
       Concomitant use of methyldopa and lithium carbonate appeared 
       to induce signs of lithium toxicity (Reynolds, 1989).
       
       The action of methyldopa may be decreased by simultaneous use 
       of non-steroidal anti-inflammatory agents.
       
       CNS depressants including alcohol and narcotic analgesics, may
       potentiate the hypotensive action of methyldopa to a dangerous
       degree. When methyldopa is administered with sedatives,
       hypnotics, tranquilizers, or other central nervous system
       depressants, further central nervous system depression may 
       occur.
       
       The hypotensive action of methyldopa may be inhibited by
       amphetamines and other sympathomimetic drugs, monoaminoxidase
       inhibitors, and tricyclic antidepressants (Osol, 1980).
       

       Methyldopa may increase the hypoglycaemic effects of 
       tolbutamide (Ellenhorn and Barceloux, 1988).
       
       Methyldopa may increase prothrombin time if added to treatment
       with anticoagulants.
       
       Methyldopa may decrease the effect of ephedrine, since it 
       reduces the quantity of norepinephrine in sympathetic nerve 
       endings.
       
       Methyldopa used with haloperidol and chlorpromazine may 
       produce psychomotor retardation, memory impairment, and 
       inability to concentrate.
       
       Methyldopa used with monoaminoxidase inhibitor drugs may 
       produce headache and hypertension (Barnhart 1987; Reynolds 
       1989).
       
       Interference with diagnostic tests:
       
       Methyldopa may interfere with the measurement of:
       
       urinary uric acid by the phosphotungstate method
       urinary catecholamines by the fluorescent technique, tests
       for the diagnosis of pheochromocytoma serum creatinine by the 
       alkaline picrate method SGOT by the colorimetric method
       (Reynolds, 1989)
     7.7 Main adverse effects
       The main adverse effects are:
       
       Sedation, headache, asthenia, drowsiness, depression, impaired
       mental acuity, impaired ability to concentrate, lapses of 
       memory, nightmares, nausea, dryness of the mouth, nasal 
       stuffiness, dizziness, vertigo, edema, disorders of sexual 
       function, weight gain, orthostatic hypotension with 
       lightheadedness.
       
       Less frequent:
       
       Breast enlargement, lactation, hyperprolactinemia, black or 
       sore tongue, salivary gland inflammation, pancreatitis, 
       paresthesias, Bell's palsy, parkinsonism, diarrhoea, 
       constipation, fever, arthralgia, myalgia, uraemia, myocarditis,
       aggravation of angina pectoris, bradycardia, atrioventricular 
       conduction disturbances.  A paradoxical pressor response is seen 
       after intravenous methyldopate hydrochloride.
       
       Rebound hypertension has been reported after abrupt withdrawal 
       of oral administration.
       
       Thrombocytopenia, leucopenia, granulocytopenia, haemolytic
       anaemia.
       
       Fever, jaundice, liver damage.
       
       Systemic lupus erythematosus-like syndrome, rash, urticaria,

       eczema, hyperkeratosis.
       
       Infrequent CNS effects include reversible mild psychosis,
       depression, and blurred vision.
    8. TOXICOLOGICAL ANALYSES 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 Advanced Quantitative Method(s)
       8.2.2 Tests 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 Advanced Quantitative Method(s)
                     A fluorometric and high-performance liquid
                     chromatography method for methyldopa 
                     determination is available.
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
             A toxic blood range has not been defined.  Blood levels 
             correlate only roughly with the overdosage (Ellenhorn 
             and Barceloux, 1988).
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
                     Liver enzyme levels, BUN, blood glucose.
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
             Complete blood count, Coomb's test.
       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
             Acute overdosage may produce coma, hypothermia,
             hypotension, bradycardia, dry mouth, and atrioventricular 
             conduction disturbances.
       9.1.2 Inhalation
             No data available.
       9.1.3 Skin exposure
             No data available.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             A paradoxical pressure response was seen after 
             intravenous methyldopate hydrochloride.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Neurological: sedation, postural hypotension, dizziness, 
             dry mouth, headache, decreased mental acuity, sleep 
             disturbances, parkinsonism, blurred vision, coma.
             
             Methyldopa may cause confusion in elderly patients.
             
             Cardiovascular: bradycardia, hypotension, myocarditis,
             atrioventricular conduction disturbances.
             
             Haematological: haemolytic anaemia, leucopenia,
             thrombocytopenia, haemolysis.
             
             Lupus-like syndrome.
             
             Sodium retention, edema, weight gain.
             
             Renal: nocturia.
             
             Pancreatitis.
             
             Noji & Kelen, 1989; Ellenhorn and Barceloux, 1988;
             Winchester, 1990).
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Overdose may produce coma, hypothermia, hypotension, 
       bradycardia, dry mouth, and atrioventricular conduction 

       disturbances.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute: bradycardia, hypotension, first-degree heart 
             block may occur.
             
             Chronic:
             
             Bradycardia, prolonged carotid sinus hypersensitivity,
             myocarditis, aggravation of angina pectoris.  
             Symptomatic postural hypotension may occur, mainly in 
             patients who are depleted of salt and water as a result 
             of intense use of diuretics.
             
             First-degree heart block, edema, and pericarditis
             (Barnhart, 1987; Gerber, 1990; Noji & Kelen, 1989).
             
             A paradoxical pressor response is seen after intravenous 
             methyldopate hydrochloride.  Rebound hypertension has 
             been reported after abrupt withdrawal of oral methyldopa 
             (Scott, 1976).
             
             Sodium retention may lead to edema.
       9.4.2 Respiratory
             Acute: no data available.
             
             Chronic:  nasal stuffiness.  Granulomatous pneumonitis 
             was diagnosed in four patients (Reynolds, 1989).
       9.4.3 Neurological
             9.4.3.1 CNS
                     Acute:  coma.
                     
                     Chronic: sedation, headache, drowsiness, 
                     dizziness, lightheadedness, paresthesias, 
                     parkinsonism, Bell's palsy, decreased mental 
                     acuity, choreoathetoid movements, blurred 
                     vision.  Psychic disturbances including 
                     nightmares and reversible mild psychoses or 
                     depression (Gerber, 1990; Reynolds, 1989; 
                     Winchester, 1990).
             9.4.3.2 Peripheral nervous system
                     No data available.
             9.4.3.3 Autonomic nervous system
                     No data available.
             9.4.3.4 Skeletal and smooth muscle
                     Acute: No data available.
                     
                     Chronic:  Mild arthralgia, myalgia (Barnhart, 
                     1987).
       9.4.4 Gastrointestinal
             Acute: Dry mouth
             
             Chronic:  nausea, vomiting, abdominal distention,
             constipation, flatus, diarrhoea, colitis, dry mouth, 
             sore or black tongue, pancreatitis and increased serum 
             amylase concentrations, sialoadenitis (Barnhart, 1987; 

             Gerber, 1990).
             
             Reversible malabsorption was related (Reynolds, 1989).
             
             Persistent oral ulceration has been reported (Reynolds, 
             1989).
       9.4.5 Hepatic
             Acute: No data available.
             
             Chronic: liver disorders such as granulomatous hepatitis,
             abnormal liver function.
             
             Re-exposure to methyldopa caused fatal hepatic necrosis 
             in one case (Reynolds, 1989).
       9.4.6 Urinary
             9.4.6.1 Renal
                     Acute: No data available.
                     
                     Chronic: Nocturia, uremia.
             9.4.6.2 Other
                     Acute and chronic: No data available.
       9.4.7 Endocrine and reproductive systems
             Acute: No data available.
             
             Chronic: breast enlargement, gynaecomastia, lactation,
             menorrhea, decreased libido, impotence and impaired
             ejaculation (American Medical Association, 1988; 
             Barnhart, 1987; Ellenhorn and Barceloux, 1988; Reynolds, 
             1989).
       9.4.8 Dermatological
             Acute: No data available.
             
             Chronic: Rash, urticaria, eczema, hyperkeratosis, 
             lichenoid eruptions, and ulceration of the soles of the 
             feet (Ellenhorn and Barceloux, 1988; Osol, 1980).
       9.4.9 Eye, ear, nose, throat: local effects
             Acute: No data available.
             
             Chronic: Blurred vision.  Nasal congestion.
       9.4.10 Haematological
              Acute: No data available.
              
              Chronic: Positive Coomb's test, reversible leucopenia,
              immune thrombocytopenia, eosinophilia.
              
              Haemolysis may occur in patients with 
              glucose-6-phosphate dehydrogenase deficiency.
              
              Positive test for antinuclear antibody, cells LE, and
              rheumatoid factor may be observed  (Barnhart, 1987).
       9.4.11 Immunological
              Acute: No data available.
              
              Chronic: Methyldopa may induce positive lupus and
              rheumatoid factor tests.  Drug-related fever, 
              myocarditis, pericarditis.  Rash, urticaria, eczema, 

              hyperkeratosis, lichenoid eruptions, and ulceration of 
              the soles of the feet (Ellenhorn and Barceloux, 1988; 
              Gerber, 1990; Osol, 1980; Reynolds, 1989).
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       Acute: No data available.
                       
                       Chronic: sodium and water retention.
              9.4.12.3 Others
                       Acute: hypothermia
                       
                       Chronic: hyperthermia, weight gain.  
                       Methyldopa may decrease HDL cholesterol levels 
                       (American Medical Association, 1988; Gerber, 
                       1990).
       9.4.13 Allergic reactions
              Acute: No data available.
              
              Chronic: Rash, urticaria, eczema, hyperkeratosis, 
              lichenoid eruptions, and ulcerations of the soles of 
              the feet (Reynolds, 1989; Osol, 1980).
       9.4.14 Other clinical effects
              No data available.
       9.4.15 Special risks
              Methyldopa crosses the placenta and is distributed into 
              breast milk.
              
              Tremor in 7 infants was associated with maternal 
              methyldopa therapy during pregnancy.
              
              No evidence of developmental retardation was found in
              children whose mothers had received methyldopa prior to 
              21-weeks gestation (Reynolds, 1989).
              
              Haemolysis occurred in patients with 
              glucose-6-phosphate dehydrogenase deficiency (Ellenhorn and 
              Barceloux, 1988).
              
              Reduced blood pressure in infants of mothers given
              methyldopa has been reported
     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Monitor vital signs, blood pressure and ECG.
         
         Assess airway, breathing, circulation and neurological 
         status of the patient.
         
         Open and maintain at least one intravenous route.
         
         Control hypotension as required.
         

         Control cardiac arrhythmia with proper drug regimen.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
         10.2.2 Biomedical analysis
                In chronic poisoning - biological analysis valuable 
                for the diagnosis are: liver enzyme levels, complete 
                blood count, including platelet count, Coomb's test, 
                BUN, blood glucose.
         10.2.3 Toxicological analysis
                A fluorometric and high-performance liquid 
                chromatography method for methyldopa determination is 
                available.
                
                In patients receiving therapeutic doses of methyldopa 
                the serum concentration is approximately of 2 
                microgram/ml (Reynolds, 1989).
                
                A toxic blood concentration has not been defined 
                (Ellenhorn and Barceloux, 1988).
                
                Blood levels correlate only roughly with the 
                overdosage.
         10.2.4 Other investigations
                Electrocardiogram may show arrhythmia (mainly 
                bradycardia).
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         For control of hypotension, dopamine is recommended.
      10.4 Decontamination
         Ipecac syrup or gastric lavage may be useful if treatment is
         instituted within the first few hours after ingestion, if 
         the patient is conscious.
         
         In conscious patients, gastric lavage may only be performed 
         after endotracheal intubation.
         
         Charcoal and cathartics have not been clinically evaluated 
         in methyldopa overdosage (Ellenhorn and Barceloux, 1988).
      10.5 Elimination
         Haemodialysis has been reported to remove 60% of methyldopa 
         after therapeutic administration in dialysis patients 
         (Winchester, 1990).
         
         However, the rapid elimination of methyldopa indicates that
         haemodialysis may not be useful in acute poisoning.
      10.6 Antidote treatment
         10.6.1 Adults
                There is no antidote.
         10.6.2 Children
                There is no antidote.
      10.7 Management discussion
         The emphasis of management is the control of hypotension.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Only one fatal case of confirmed methyldopa poisoning has 
         been reported. A 44 year-old woman took approximately 15 g 

         of methyldopa.  The blood level was 0.9 microgram/ml, with a 
         urinary concentration of 140 microgram/l.  In addition, 
         fatty degeneration of liver cells was observed, with changes 
         associated with hypertension in the heart and kidney 
         (Tamminen, 1970).
         
         A 19-year-old man ingested 2.5 g of methyldopa.  Ten hours 
         later he was admitted in coma. Blood pressure: 90/60; pulse: 
         44; body temperature: 35C. He developed dry mouth and sinus 
         bradycardia. Laboratory results, including blood, urine 
         toxicology screen, were all normal. After receiving 
         intravenous fluids he became fully conscious on the second 
         day.  Serum methyldopa on admission was 19.2 microgram/ml 
         (compared with a typical therapeutic  concentration of 1.0 
         +/- 0.8 microgram/ml). He recovered (Shnaps, 1982).
      11.2 Internally extracted data on cases
      11.3 Internal cases
         To be added by the PC using the monograph.
    12. Additional information
      12.1 Availability of antidotes
         There are no antidotes.
      12.2 Specific preventive measures
         The product should be kept out of the reach of children.
      12.3 Other
         No data available.
    13. REFERENCES
    American Medical Association (1988)  Drug Evaluations, 6th 
    edition-Philadelphia, W.B. Saunders Co.
    
    Barnhart ER (publ.) (1987)  Physicians' Desk Reference.  41 ed. 
    New Jersey, Medical Economics Co. Inc.
    
    Budavari S, ed (1989)  The Merck Index: and encyclopedia of 
    chemicals, drugs and biological, 11th Ed. Rahway, New Jersey, Merck and Co. 
    Inc.
    
    Ellenhorn MJ and Barceloux DG (1988)  Medical Toxicology.  
    Diagnosis and treatment of human poisoning.  New York, Elsevier.
    
    Gerber JG & Nies A (1990) In: Gilman AG, Rall TW, Nies AS & 
    Taylor P (eds.)  Goodman and Gilman's.  The Pharmacological Basis of
    Therapeutics.  8th ed. New York, Pergamon Press.
    
    Noji EK & Helen GD (1989)  Manual of toxicologic emergencies.  
    Chicago, Year Book Medical Publishers, Inc.
    
    Osol A & Pratt R (1990)  The United States Dispensatory 27th ed. 
    Philadelphia, JB  Lippincott Company.
    
    Reynolds JEF (ed) (1989)  Martindale The Extra Pharmacopoeia 29th 
    ed.  London, The Pharmaceutical Press.
    
    Sax NI & Lewis RJ (1989)  Dangerous properties of industrial 
    materials, 7th ed.  New York, Van Nostrand Reinhold.
    
    Scott JN & McDevitt DG (1976)  Rebound hypertension after acute

    methyldopa withdrawal.  Br  Med  J  2:367.
    
    Shnaps Y, Almog S, Halkin H (1982)  Methyldopa poisoning.  J 
    Toxicol Clin  Toxicol  119(5):501-503.
    
    Tamminem V & Alpha A (1970)  Fatal methyldopa poisoning.  Bull 
    Int Assoc for Toxicol  7(2):2.
    
    Winchester J (1990)  Nitroprusside and selected antihypertensives 
    In: Haddad LM & Winchester JF eds.  Clinical management of poisoning 
    and drug overdose.  Philadelphia, W. Saunders Co.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Author:        Rosane Maria Salvi
                   Applied Toxicology Centre PUCRS
                   Travessa Sul, 270  ap 303
                   90440  Porto Alegre
                   Brazil
    
                   Tel: 55-51-
                   Fax: 55-51-2246563
    
    Date:          January 1992
    
    Peer Review:   London, United Kingdom, September 1992
                   (Fitzpatrick, Jaeger, Rahde, Ruggerone, Szajewski)



    See Also:
       Toxicological Abbreviations