Levodopa
| 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 ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Sample |
| 8.1.1 Collection |
| 8.1.2 Storage |
| 8.1.3 Transport |
| 8.2 Toxicological Analytical Methods |
| 8.2.1 Tests for active ingredient |
| 8.2.2 Tests for biological sample |
| 8.3 Other laboratory analyses |
| 8.3.1 Biochemical investigations |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological or Haemostasiological investigations |
| 8.3.4 Other relevant biomedical analyses |
| 8.4 Interpretation |
| 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 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) |
1. NAME
1.1 Substance
Levodopa
(INN, 1992)
1.2 Group
Anti-parkinson drugs (N04)/Dopaminergic agents N04B)/Dopa and
dopa derivatives (N04BA)
(ATC classification index [WHO] 1992]
1.3 Synonyms
L-Dopa, Laevo-Dopa, Levodopum, Dopa, Dihydroxyphenylalanine
(Martindale, 1993)
1.4 Identification numbers
1.4.1 CAS number
59-92-7
1.4.2 Other numbers
RTECS
AY5600000
1.5 Brand names, Trade names
Madopar 250, Sinemet 250
(To be completed by each Centre using local data).
1.6 Manufacturers, Importers
Roche, Merck Sharp & Dohme
(To be completed by each Centre using local data).
1.7 Presentation, Formulation
Tablets with 200 mg L-dopa and 50 mg Benserazide.
(To be completed by each Centre using local data).
2. SUMMARY
2.1 Main risks and target organs
The principal target organ is C.V.S. The main risks are
cardiovascular. Additional risks are associated with the
gastrointestinal tract, and the peripheral as well as the
central nervous system.
2.2 Summary of clinical effects
Nausea and anorexia commonly occur and may be accompanied by
vomiting. Another effect includes abdominal pain,
constipation, diarrhoea and dysphagia; dyspepsia and
gastrointestinal bleeding.
The commonest cardiovascular effect is postural hypotension,
with faintness and dizziness. There may be palpitations
often accompanied by excess sweating. Cardiac arrhythmias,
particularly atrial and ventricular ectopic beats, have been
reported and hypertension has occasionally occurred.
Psychiatric symptoms include agitation, anxiety, elation and
insomnia or some times drowsiness and depression. More
severe effects include aggression, paranoid delusions,
hallucinations, suicidal behaviour and unmasking of dementia.
Involuntary movements are very common and usually start in
the mouth, jaws or tongue. Abnormal limb movements often
develop after several months and severe choreoathetoid
movements may also occur after prolonged high doses.
Oculogyric movements may rarely be exacerbated and muscle
twitching and blepharospasm occur occasionally.
Headache, weakness, ataxia, and rarely paraesthesia and
convulsions have occurred.
Polyuria, incontinence, and difficulty in micturition may
occur.
Blurred vision, mydriasis, diplopia and glaucoma are rare.
Uncommon effects include transient rises in tests for liver
function and blood urea nitrogen, abnormal respiratory
movements, loss of hair, skin rashes, activation of Horner's
syndrome, weight changes, and rarely agranulocytosis or
haemolytic anaemia.
2.3 Diagnosis
Clinical diagnosis is difficult due to the multiorgan
toxicity.
There is no specific diagnostic test. The usual screening
laboratory examination in urine and blood may be undertaken.
2.4 First aid measures and management principles
In case of ingestion, consider inducing vomiting or
undertaking gastric lavage (if seen early after ingestion).
Activated charcoal should also be considered.
For acute overdosage general supportive measures should also
be employed. Intravenous liquids should be administered as
necessary and an adequate airway maintained.
Electrocardiographic monitoring should be instituted and the
patient carefully observed for the possible development of
arrhythmias; if required, antiarrhythmic therapy should be
considered but is usually best avoided in cases of "torsades
de pointes" arrhythmias.
The value of dialysis in overdose is not known.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic origin.
3.2 Chemical structure
Structural formula
Molecular formula
C9H11NO4
Molecular weight
197.2
Chemical names
3-Hydroxy-L-tyrosine
(-)3-(3-4-Dihydroxyphenyl)-L-alanine
beta-(3,4-dihydroxyphenyl)propanoic acid
2-amino-3-(3,4-dihydroxyphenyl)propanoic acid
(Martindale, 1993; Merck Index, 1989)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
White or almost white, which darkens on
exposure to air and light.
3.3.1.2 State/Form
Crystalline powder
3.3.1.3 Description
Odourless, almost tasteless
Slightly soluble in water. Soluble in aqueous
solutions of mineral acids and alkali
carbonates; practically insoluble in alcohol,
chloroform, and ether.
Aqueous solutions are neutral to slightly acid,
and readily oxidized in air and light.
(Martindale, 1993; Merck Index, 1989)
3.3.2 Properties of the locally available formulation(s)
To be completed by each Centre using local data.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
At least 5 years.
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
Store in a dry place and prevent exposure to excessive
heat and light. Store in airtight containers at a
temperature not exceeding 40 °C.
(Martindale, 1993)
3.4.4 Bioavailability
To be completed by each Centre using local data.
3.4.5 Specific properties and composition
Extemporaneously prepared oral liquid dosage forms may
be unstable and manufacturers' formulations should be
used where possible.
(Martindale, 1993)
4. USES
4.1 Indications
4.1.1 Indications
L-Dopa is used in the treatment of idiopathic
Parkinson's disease, post-encephalitic parkinsonism,
symptomatic parkinsonism which may follow injury to the
nervous system by carbon monoxide intoxication or
manganese intoxication. It is indicated in elderly
patients believed to have developed parkinsonism in
conjunction with cerebral arteriosclerosis (PDR, 1986).
4.1.2 Description
Not relevant.
4.2 Therapeutic dosage
4.2.1 Adults
Oral
Administration without benserazide
The dose producing maximal improvement with tolerated
side effect must be determined and carefully titrated
for each individual patient. The usual initial dose is
125 mg twice daily increased appropriately every few
days, according to response, to a maximum between 1 g
and 8 g daily, divided in two or more doses and taken
with food. (Martindale, 1993)
Administration with benserazide
Initial dose is a quarter of a tablet (levodopa 200
mg/benserazide 50 mg) up to 4 times a day (200 mg
levodopa/day).
Initial dose may be half a tablet 3 times a day (300 mg
levodopa)if disease is advanced.
Recommended maximum maintenance dose is 4 tablets
(800 mg levodopa) daily in divided doses.
(Martindale, 1993)
4.2.2 Children
Levodopa is not usually used in children.
4.3 Contraindications
Levodopa is contraindicated for melanoma and glaucoma in
patients with known hypersensitivity to the drug.
Levodopa should be administered cautiously to patients with
severe cardiovascular or pulmonary disease, asthma, renal,
hepatic or endocrine disease.
Care should be exercised in administering levodopa to
patients with history of myocardial infarction who have
residual atrial nodal or ventricular arrhythmias. If
levodopa is necessary in this type of patient, it should be
used in a facility with a coronary care unit or an intensive
care unit.
One must be on the alert for the possibility of upper
gastrointestinal haemorrhage in those patients with a past
history of peptic ulcer disease.
Levodopa is contraindicated in patients with severe psychotic
disorders, it should be used with caution in patients with
psychiatric disturbance.
This drug should not be used in pregnancy and should not be
used in nursing mothers.
The safety under the age of 12 has not been established.
5. ROUTES OF ENTRY
5.1 Oral
The route of entry of levodopa is oral.
5.2 Inhalation
Not relevant.
5.3 Dermal
Not relevant.
5.4 Eye
Not relevant.
5.5 Parenteral
Not relevant.
5.6 Other
Not relevant.
6. KINETICS
6.1 Absorption by route of exposure
Levodopa is rapidly absorbed from the small intestine by an
active transport system for aromatic amino acids.
Concentrations of drug in plasma usually peak between 0.5 and
2 hours after an oral dose. The rate of absorption of
levodopa is greatly dependent upon the rate of gastric
emptying, the pH of gastric juice and the length of time the
drug is exposed to the degradative enzymes of the gastric
mucosa and intestinal flora. Hyperacidity of gastric juice,
and competition for absorption sites in the small intestine
by amino acids each may interfere with the bioavailability of
levodopa (Goodman & Gilman, 1990).
6.2 Distribution by route of exposure
It is widely distributed to most body tissues, but less to
the central nervous system (CNS). Little unchanged drug
reaches the cerebral circulation and probably less than 1%
penetrates into the CNS.
6.3 Biological half-life by route of exposure
Levodopa has relatively short plasma half-life of 1 to 3
hours (Goodman & Gilman, 1990).
6.4 Metabolism
More than 95% of levodopa is decarboxylated by the widely
distributed extracerebral aromatic l-amino acid
decarboxylase. The drug is extensively decarboxylated in its
first passage through the liver, which is rich in
decarboxylase.
A small amount is methylated to 3-0-methyldopa, which
accumulates in the CNS due to its long half-life. Most is
converted to dopamine, small amounts of which in turn are
metabolized to norepinephrine and epinephrine (adrenaline).
Biotransformation of dopamine proceeds rapidly to yield the
principal excretion products, 3-4-dihydroxy-phenylacetic acid
(DOPAC) and 3-methoxy-4-hydroxy-phenylacetic acid
(homovanillic acid, HVA). At least 30 metabolites of
levodopa have been identified.
The evidence indicates that the metabolism of levodopa may be
accelerated during prolonged therapy possibly due to enzyme
induction.
(Goodman & Gilman, 1990).
6.5 Elimination by route of exposure
Oral
Excretion
Metabolites of dopamine are rapidly excreted in the urine;
80% of a radioactively labelled dose is recovered within 24
hours. The principal metabolites DOPAC and HVA account for
up to 50% of the administered dose. Negligible amounts are
found in the faeces. After prolonged therapy with levodopa,
the ratio of DOPAC and HVA excreted may increase probably
reflecting a depletion of methyl donors necessary for
metabolism by catechol-O-methyl transferase; it is estimated
that about three fourths of dietary methionine is utilized
for metabolism of large doses of 1-dopa (Goodman & Gilman,
1990).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Peripheral decarboxylation of levodopa markedly
increases the concentration of dopamine in blood.
Dopamine is a pharmacologically active catecholamine
with prominent effects of alpha and beta adrenergic
receptors, and this point give the potentially toxic
effects.
7.1.2 Pharmacodynamics
Levodopa is the metabolic precursor of dopamine, does
cross the blood-brain barrier, and presumably is
converted to dopamine in the basal ganglia. This is
thought to be the mechanism whereby levodopa relieves
symptoms of Parkinson's disease, because it replaces
depleted brain dopamine in these patients.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Ingestion of up to 11 g was associated with
fatality in a 43 year old woman (Sturner, 1972)
Ingestion of 80 to 100 g by a 61 year old man
resulted in toxicity with complete recovery
(Hoehn, 1975)
Adult ingestion of 20 g has been reported with
recovery (Tech. Info, Poisindex 1975).
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
LD50 oral mice 1460 mg/kg (Blark et al., 1974)
LD50 oral rats 1780 mg/kg (Blark et al., 1974)
LD50 oral rabbits 609 mg/kg (Blark et al., 1974)
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
There is no data available, but may possibly activate
melanoma (Martindale, 1982).
7.4 Teratogenicity
Studies in rabbits have shown that levodopa causes visceral
and skeletal malformations in offspring.
7.5 Mutagenicity
No data available.
7.6 Interactions
Doses of pyridoxine that are only modestly in excess of the
recommended dietary allowance enhance the extracerebral
metabolism of levodopa at this step. Antipsychotic drugs,
such as phenothiazines, butyrophenones and reserpine can
produce a parkinsonism-like syndrome, and since these drugs
interfere with the therapeutic effects of levodopa, they are
contraindicated. Therefore the phenothiazines should not be
used to combat the emetic effect of levodopa.
Nonspecific monoamine oxidase inhibitors interfere with
inactivation of dopamine, norepinephrine and other
catecholamines. Hence, they unpredictably exaggerate the
central effects of levodopa and its catecholamine
metabolites. Hypertensive crisis and hyperpyrexia are very
real and dangerous sequelae of concurrent administration of
two such drugs.
Anticholinergic drugs such as phenidyl, benztropine,
procyclidine and others act synergistically with levodopa to
improve certain symptoms of parkinsonism, especially tremor.
However, large doses of anticholinergic drugs can slow
gastric emptying sufficiently to cause a delay in
reabsorption of levodopa by the small intestine.
The effect of levodopa is enhanced by amantadine,
benserazide, carbidopa, atropine and amphetamine.
Concurrent administration of levodopa with guanethidine,
methyldopa and other antihypertensive agents may cause
increased hypotension.
Cardiac arrhythmias due to levodopa may be augmented by
anaesthetic agents, such as cyclopropane or halothane.
Sympathomimetic agents such as epinephrine (adrenaline) or
isoprenaline may also enhance the cardiac side-effects of
levodopa.
Beta-adrenergic blocking agents such as propranolol may
enhance the action of levodopa on tremor and diminish the
cardiac side-effects.
In some patient the administration of antacids with levodopa
may enhance the gastrointestinal absorption of levodopa
(Goodman & Gilman, 1990).
7.7 Main adverse effects
The most serious adverse and frequently occurring reactions
associated with the administration of levodopa are
adventitious movements such as choreiform and/or dystonic
movements.
Other serious adverse reactions are cardiac irregularities
and/or palpitations, orthostatic hypotensive episodes,
bradykinetic episodes(the "on-off" phenomena), mental changes
including paranoid delusion and psychotic episodes,
depression with or without the development of suicidal
tendencies, dementia, and urinary retention.
Gastrointestinal bleeding, development of duodenal ulcer,
hypertension, phlebitis, haemolytic anaemia, agranulocytosis
and convulsions have rarely been observed.
Adverse reactions of less serious nature having a relatively
frequent occurrence are anorexia, nausea and vomiting,
abdominal pain, distress, dry mouth, dysphagia, sialorrhea,
ataxia, increased hand tremor, headache, dizziness, numbness,
weakness and faintness, bruxism, confusion, insomnia,
nightmares, hallucinations and delusions, agitation, anxiety,
malaise, fatigue and euphoria.
Occurring with lesser order or frequency are muscle twitching
and blepharospasm, trismus, burning sensation of the tongue,
bitter taste, diarrhoea, constipation, flatulence, flushing,
skin rash, increased sweating, bizarre breathing patterns,
urinary incontinence, diplopia, blurred vision, dilated
pupils, hot flushes, weight gain or loss, dark sweat and/or
urine.
Rarely, oculogyric crises, sense of stimulation, hiccups,
edema, loss of hair hoarseness, priapism and activation of
latent Horner's syndrome have been observed.
Elevation of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin,
alkaline phosphatase or protein-bound iodine have been
reported, occasional reduction in WBC, haemoglobin and
haematocrit have been noted. Leucopenia has occurred and
requires cessation at least temporarily, of levodopa
administration (Physician Desk Reference, 1986).
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Sample
8.1.1 Collection
8.1.2 Storage
8.1.3 Transport
8.2 Toxicological Analytical Methods
8.2.1 Tests for active ingredient
8.2.2 Tests for biological sample
8.3 Other laboratory analyses
It is advisable to carry out periodic evaluations of hepatic,
haematological, renal functions.
8.3.1 Biochemical investigations
8.3.2 Arterial blood gas analyses
8.3.3 Haematological or Haemostasiological investigations
8.3.4 Other relevant biomedical analyses
8.4 Interpretation
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Spasm or closing of eyelids are possible early sign of
overdose. Nausea, vomiting, cardiac arrhythmias,
involuntary movements of the body, including the face,
tongue, arms, hand, head, and upper body; choreiform
and other involuntary movements occur in 50% to 80% of
patients. This effect is dose related. Psychiatric
disturbances are usually present. Hypotension,
haemolytic anaemia, urinary retention, duodenal ulcer,
sialorrhea, ataxia, abdominal pain, dry mouth,
nightmares, tachypnoea, bruxism, confusion, insomnia
also occur.
9.1.2 Inhalation
Not relevant.
9.1.3 Skin exposure
Not relevant.
9.1.4 Eye contact
Not relevant.
9.1.5 Parenteral exposure
Not relevant.
9.1.6 Other
Not relevant.
9.2 Chronic poisoning
9.2.1 Ingestion
No data available.
9.2.2 Inhalation
Not relevant.
9.2.3 Skin exposure
Not relevant.
9.2.4 Eye contact
Not relevant.
9.2.5 Parenteral exposure
Not relevant.
9.2.6 Other
Not relevant.
9.3 Course, prognosis, cause of death
Usually, the symptoms are reversible when doses are decreased
or drug withdrawn. Fatal doses have been reported (American
Medical Association, 1986).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Hypotension
About 30% of patients develop slight orthostatic
hypotension early in therapy. It is usually
asymptomatic, but some patients experience dizziness
and rarely, syncope.
Cardiac irregularities
The beta-adrenergic action of dopamine on the heart, as
well as direct beta-adrenergic receptor stimulation by
other catecholamine metabolites of the drug, presents a
potentially serious effect of levodopa sinus
tachycardia, atrial and ventricular extrasystoles,
atrial flutter and fibrillation, and ventricular
tachycardia have been reported. Myocardial
contractility may be increased for several hours after
a large dose of levodopa.
9.4.2 Respiratory
Abnormal involuntary movements appear in approximately
50% of patients within 2 to 4 months after the
initiation of treatment. Rarely, exaggerated
respiratory movements can produce an irregular gasping
breath or hyperventilation (Goodman & Gilman, 1990).
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Levodopa has effects on the behaviour and these
result in euphoria, anxiety and insomnia, which
may progress to a toxic psychosis or acute
brain syndrome with delusions and
hallucinations and paranoia. Depression and
somnolence may also appear. (Goodman & Gilman,
1990)
9.4.3.2 Peripheral nervous system
Some patients developed severe oculogyric
crises.
9.4.3.3 Autonomic nervous system
Abnormal involuntary movements
These movements appear in approximately 50% of
patients within 2 to 4 months after the
initiation of treatment. They appear with
increasing frequency as drug administration
continues and are directly related to the
doses, the abnormal involuntary movements are
variable in type include faciolingual tics,
grimacing, head bobbing, and various
oscillatory and rocking movements of the arms,
legs or trunk.
(Goodman & Gilman, 1990)
9.4.3.4 Skeletal and smooth muscle
Not relevant
9.4.4 Gastrointestinal
The patients experience anorexia, nausea, vomiting
epigastric distress caused partially by stimulation of
the medullary emetic entre and is most likely to occur
if dosage is increased too rapidly. Bleeding and
perforation of peptic ulcers have been reported in a
few patients.
Other gastrointestinal disturbances are occasionally
reported but it is questionable whether they are
related to levodopa. They include abdominal pain,
diarrhoea, constipation and activation of peptic ulcer.
9.4.5 Hepatic
Increased blood LDH, bilirubin and alkaline phosphatase
levels are rare.
9.4.6 Urinary
9.4.6.1 Renal
Polyuria, incontinence and difficulty in
micturition may occur (Martindale, 1989)
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
Some patients presented adrenal suppression. Levodopa
increases plasma growth hormone levels and may produce
mild carbohydrate intolerance. Dopamine inhibits the
secretion of prolactin in man; it acts directly on the
relevant cells of the adenohypophysis and also
stimulate the release of a prolactin inhibitory factor.
Thus, levodopa decrease the secretion of prolactin
while dopaminergic antagonists have an opposite effect
(Goodman & Gilman, 1986).
9.4.8 Dermatological
Some patients developed diffuse alopecia (Martindale,
1989).
9.4.9 Eye, ear, nose throat: local effects
Oculogyric crisis (Martindale, 1989).
9.4.10 Haematological
Haemolytic anaemia and agranulocytosis have been
observed (Martindale, 1989).
9.4.11 Immunological
A vasculitis characterised by neuromyopathy,
periarteriolitis with eosinophilia and a lupus-like
auto-immune syndrome has been reported (Martindale,
1993).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Not relevant.
9.4.12.2 Fluid and electrolyte disturbances
Not relevant.
9.4.12.3 Others
Not relevant.
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy, breast-feeding
L-Dopa represent a risk for pregnancy and the nursing
mother. Use of medication should be carefully
considered in conjunction with bronchial asthma,
emphysema and other severe pulmonary cardiovascular
disease; history of convulsive disorders, diabetes,
endocrine diseases, glaucoma, hepatic function
impairment, history of suspected melanoma, history of
myocardial infarction with residual history of peptic
ulcer, psychotic states, renal function impairment,
urinary retention.
9.5 Other
No data available.
9.6 Summary
Not relevant.
10. MANAGEMENT
10.1 General principles
Reduction of dosage of levodopa causes the reversal of many
side effects particularly dyskinesias and mental effects.
Nausea may be diminished by taking an anti-emetic such
cyclizine hydrochloride. Orthostatic hypotension may
respond to the use of elastic stocking.
If overdosage occurs gastric lavage should be considered if
patient seen soon after poisoning. Activated charcoal with
sorbitol could be administered orally or through the
gastric tube. Hypotension treated by administration of
intravenous fluids. If arrhythmias develop anti-arrhythmic
therapy may be necessary but is usually best avoided,
especially in cases of "torsades de pointes" arrhythmias.
Pyridoxine has been given to reverse some toxic effects of
levodopa in doses of 10 mg intravenously, but the effect
has not been demonstrated. (Martindale, 1989).
10.2 Relevant laboratory analyses
Urine and blood routine test.
10.2.1 Sample collection
10.2.2 Biomedical analysis
10.2.3 Toxicological analysis
10.2.4 Other investigations
Cardiac control
Psychological test
Neurological surveillance.
10.3 Life supportive procedures and symptomatic/specific
treatment
General supportive management should be supplied.
10.4 Decontamination
Gastric decontamination should be considered within the
first 1 to 2 hours after ingestion.
10.5 Elimination
No elimination procedures recorded.
10.6 Antidote treatment
10.6.1 Adults
No antidote available.
10.6.2 Children
No antidote available.
10.7 Management discussion
Not relevant - see Section 2
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
American Medical Association (1986) Drug Evaluation, 6 Ed. USA
Saunders, p 1209.
Goodman & Gilman (1990) Las Bases Farmacologicas de la
Terapeutica, 7 ed. Mexico, Ed. Panamericana, pp 466-472.
Gevers F et al. (1978) Medical Pharmacology Los Altos-Lange pp
318-320.
Physicians Desk Reference (1986) USA, Barhart, p 1489.
United States Pharmacopeia Convention (1985) The United States
Pharmacopoeia, pp 585-6.
US Pharmacopeial Convention (1986) Drug information for the
health care provider. Rockville, pp 939-942.
Martindale, The Extra Pharmacopeia (1989) Ed. James Reynolds 28
Poison index.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Dr Patricia DORFMAN, Dr Julia HIGA de LANDONI
Servicio de Toxicologia
Hospital de Clinicas "Jose de San Martin"
Cordoba 2351 (1140) Cao. Fed. Bs. As.