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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. 



    See Also:
       Toxicological Abbreviations