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 290°C.
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
30°C (86°F).
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: 35°C. 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)