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METHYLDOPA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Methyldopa is a centrally acting antihypertensive agent. The exact mechanism of antihypertensive action has not been conclusively demonstrated. However, the major antihypertensive effect appears to result from conversion to alpha-methylnorepinephrine, a potent alpha-2 adrenergic agonist.

Specific Substances

    1) Alpha-methyldopa
    2) Alpha methyldopa, L isomer
    3) Alfametildopa (Mexican)
    4) Methyldopum
    5) Methyldopum hydratum
    6) Metildopa
    7) MK 351
    8) CAS 555-30-6 (anhydrous)
    9) CAS 41372-08-1 (sesquihydrate)
    10) CAS 2544-09-4 (methyldopate)
    11) CAS 2508-79-4 (hydrochloride)

Available Forms Sources

    A) FORMS
    1) Methyldopa is available as 250 and 500 mg tablets (Prod Info methyldopa oral film coated tablets, 2008).
    2) Methyldopa 250 mg is available in combination with hydrochlorothiazide 15 mg or 25 mg tablets (Prod Info methyldopa, hydrochlorothiazide oral tablets, 2005).
    B) USES
    1) Methyldopa is used alone or in combination with hydrochlorothiazide to treat hypertension (Prod Info methyldopa oral film coated tablets, 2008; Prod Info methyldopa, hydrochlorothiazide oral tablets, 2005).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Methyldopa is used alone or in combination with hydrochlorothiazide to treat hypertension.
    B) PHARMACOLOGY: The exact mechanism of antihypertensive action has not been conclusively demonstrated. However, the major antihypertensive effect appears to result from conversion to alpha-methylnorepinephrine, a potent alpha-2 adrenergic agonist. Alpha-methylnorepinephrine acts centrally to stimulate alpha receptors. This results in a decrease in sympathetic outflow and decreased blood pressure.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Methyldopa is usually well tolerated and significant adverse effects are rare. Initially, sedation, headache, asthenia, and weakness may occur. Other effects include orthostatic hypotension, nausea, vomiting, diarrhea, constipation, and distention. Skin rash, toxic epidermal necrolysis, elevated liver enzymes, hepatitis, Coombs positive test, hemolytic anemia, granulocytopenia and thrombocytopenia have rarely been reported.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE: Nausea, vomiting, diarrhea, constipation, distention, dizziness, weakness, and lethargy may develop after overdose.
    2) SEVERE: Bradycardia, hypotension, lethargy, coma, hypothermia.
    0.2.20) REPRODUCTIVE
    A) Methyldopa is classified as FDA pregnancy category B. There are no adequate and well-controlled studies with methyldopa use during the first trimester of pregnancy. However, several published reports indicate methyldopa use during all trimesters of pregnancy has been relatively safe, and the possibility of fetal harm appears remote. Although methyldopa appears in human breast milk, the concentration will be too low to be pharmacologically significant and no adverse effects have been reported from exposure in breast milk.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Monitor CBC with differential with platelet count and liver enzymes and obtain an ECG in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. If bradycardia is severe enough to cause hypotension, treat with atropine.
    C) DECONTAMINATION
    1) PREHOSPITAL: No prehospital gastrointestinal decontamination is recommended.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is alert, not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or hemodynamic instability.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Methyldopa can be removed by hemodialysis; however, the use of hemodialysis to treat overdose has not been reported and most patients respond to supportive care.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with a small, inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Any patient with symptoms should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with significant CNS depression or hemodynamic instability should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Absorption: variable (8% to 61%); mean bioavailability: about 50%. Effects on blood pressure and heart rate are maximal in 4 to 6 hours following oral use; blood pressure usually returns to normal within 24 to 48 hours. Protein binding: less than 15%. Vd: 0.37 +/- 0.10 L/kg. Metabolism: extensively metabolized. Renal excretion: about 70% of the absorbed drug is excreted in the urine as methyldopa and its mono-O-sulfate conjugate; excretion is essentially complete in 36 hours. Renal clearance: about 130 mL/min. Elimination half-life: 105 minutes.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension or bradycardia, such as beta blockers and calcium channel blockers.

Range Of Toxicity

    A) TOXICITY: Ingestions ranging from 2.5 g to 45 g have caused hypotension, bradycardia, coma, and hypothermia in adults who eventually recovered. An adult died after ingesting 25 g of methyldopa. Prolonged profound hypotension, sinus bradycardia, and drowsiness developed in a woman after ingesting 300 methyldopa tablets (greater than 75 g). She recovered following supportive care.
    B) THERAPEUTIC DOSES: ADULTS: 250 mg orally 2 to 3 times daily to 2 g daily in 2 to 4 divided doses; MAX dose, 3 g daily. CHILDREN: Initially, 10 mg/kg orally daily in 2 to 4 divided doses; MAX dose, 65 mg/kg or 3 g daily, whichever is less.

Clinical Effects

Summary Of Exposure

    A) USES: Methyldopa is used alone or in combination with hydrochlorothiazide to treat hypertension.
    B) PHARMACOLOGY: The exact mechanism of antihypertensive action has not been conclusively demonstrated. However, the major antihypertensive effect appears to result from conversion to alpha-methylnorepinephrine, a potent alpha-2 adrenergic agonist. Alpha-methylnorepinephrine acts centrally to stimulate alpha receptors. This results in a decrease in sympathetic outflow and decreased blood pressure.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Methyldopa is usually well tolerated and significant adverse effects are rare. Initially, sedation, headache, asthenia, and weakness may occur. Other effects include orthostatic hypotension, nausea, vomiting, diarrhea, constipation, and distention. Skin rash, toxic epidermal necrolysis, elevated liver enzymes, hepatitis, Coombs positive test, hemolytic anemia, granulocytopenia and thrombocytopenia have rarely been reported.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE: Nausea, vomiting, diarrhea, constipation, distention, dizziness, weakness, and lethargy may develop after overdose.
    2) SEVERE: Bradycardia, hypotension, lethargy, coma, hypothermia.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Hypothermia has been reported after an acute overdose (Shnaps et al, 1982).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) KERATITIS: Reversible keratitis sicca has been reported in patients with methyldopa fever (Grant & Schuman, 1993).
    2) EXOTROPIA: A woman on methyldopa and complaining of headaches and intermittent diplopia developed convergence insufficiency with alternating exotropia. Her vision improved when her dose of methyldopa was decreased (Grant & Schuman, 1993).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Aggravation of angina pectoris and congestive heart failure have been rarely reported as adverse effects (Prod Info methyldopa oral film coated tablets, 2008).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Orthostatic hypotension may occur (Prod Info methyldopa oral film coated tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) Severe hypotension with dizziness, lightheadedness, weakness, and bradycardia have been reported following overdoses (Prod Info methyldopa oral film coated tablets, 2008; Shnaps et al, 1982; Taylor et al, 1978).
    b) CASE REPORT: Prolonged profound hypotension, sinus bradycardia, and drowsiness developed in a 50-year-old woman after ingesting 300 methyldopa tablets (greater than 75 g). Initially, she had a blood pressure of 59/27 mmHg, a heart rate of 49 beats/min, and Glasgow Coma Scale Score of 14. Following aggressive supportive care, including treatment with a large amount of fluids, ephedrine sulfate, IV infusion of norepinephrine for 41 hours, dopamine for 21 hours, and observation for 3 more days, she recovered and was discharged (Chan & Joynt, 2014).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Paradoxical hypertension has been reported in a 43-year-old patient taking a therapeutic dose of methyldopa (Zehnle, 1981).
    b) Paradoxical, acute hypertension, and seizures have been reported following IV administration of methyldopa (Feldman, 1967).
    D) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Bradycardia has been reported following overdoses (Prod Info methyldopa oral film coated tablets, 2008; Shnaps et al, 1982).
    b) CASE REPORT: A pulse of 40 to 45 beats/min was reported following ingestion of 12.5 g of methyldopa with hydrochlorothiazide by a 68-year-old woman (Jacobi et al, 1985).
    c) CASE REPORT: Prolonged profound hypotension, sinus bradycardia, and drowsiness developed in a 50-year-old woman after ingesting 300 methyldopa tablets (greater than 75 g). Initially, she had a blood pressure of 59/27 mmHg, a heart rate of 49 beats/min, and Glasgow Coma Scale Score of 14. Following aggressive supportive care, including treatment with a large amount of fluids, ephedrine sulfate, IV infusion of norepinephrine for 41 hours, dopamine for 21 hours, and observation for 3 more days, she recovered and was discharged (Chan & Joynt, 2014).
    E) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Conduction disturbances, including prolonged PR interval, have been reported with therapeutic doses (Sadjadi et al, 1984).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression, ranging from lethargy to coma may occur (Chan & Joynt, 2014; Prod Info methyldopa oral film coated tablets, 2008; Shnaps et al, 1982; Johnston & Smith, 1990; Baselt, 2000).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Acute hypertension and seizures have been reported following IV administration of methyldopa (Feldman, 1967).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) Paresthesias, headache, weakness, involuntary movements, and psychic disturbances have been reported (Baselt, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported with therapeutic use of methyldopa (Prod Info methyldopa oral film coated tablets, 2008; Anon, 1984; Baselt, 2000).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may be seen in the overdose situation (Prod Info methyldopa oral film coated tablets, 2008; Anon, 1984; Baselt, 2000).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea may occur following therapeutic use of methyldopa (Prod Info methyldopa oral film coated tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea may occur following overdoses (Prod Info methyldopa oral film coated tablets, 2008; Anon, 1984; Baselt, 2000).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation and distension may occur (Prod Info methyldopa oral film coated tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) Constipation and distension may occur following overdoses (Prod Info methyldopa oral film coated tablets, 2008).
    D) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has resulted from therapeutic use of methyldopa (Prod Info methyldopa oral film coated tablets, 2008).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) Liver injury may be noted following long term therapeutic use of methyldopa (Baselt, 2000; Thery, 1976; Toghill, 1974; Tysell & Knauer, 1971).
    b) Hepatotoxicity has been reported in pregnant women when methyldopa was used to treat hypertension of pregnancy (Ali et al, 2009; Smith & Piercy, 1995). Fatal toxic hepatitis has also been reported in pregnant women receiving methyldopa (Picaud et al, 1990).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic anemia and a positive Coombs test have been noted following long term therapeutic use of methyldopa (Jaffe, 1982; Boone & Carey, 1971) Surveyor et al, 1968; (Prod Info methyldopa oral film coated tablets, 2008).
    b) Immune hemolytic anemia, as well as chronic active hepatitis, developed in a 76-year-old man on prolonged methyldopa therapy (Shalev et al, 1983).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Granulocytopenia has been noted following long term therapeutic use of methyldopa (Prod Info methyldopa oral film coated tablets, 2008; Jaffe, 1982; Boone & Carey, 1971; Surveyor, 1971).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been noted following long term therapeutic use of methyldopa (Prod Info methyldopa oral film coated tablets, 2008; Jaffe, 1982; Boone & Carey, 1971; Surveyor, 1971).
    D) MALIGNANT LYMPHOMA
    1) WITH THERAPEUTIC USE
    a) Methyldopa has been reported to cause lymphoma with therapeutic use (Ahmad, 1995).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) LICHENOID DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Drug-induced lichen planus has been reported to occur following long-term methyldopa therapy, but is an uncommon event. The lichenoid dermatitis resolves on drug withdrawal (Thompson & Skaehill, 1994).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rash and toxic epidermal necrolysis are rare adverse effects following therapeutic dosing of methyldopa (Prod Info methyldopa oral film coated tablets, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Methyldopa is classified as FDA pregnancy category B. There are no adequate and well-controlled studies with methyldopa use during the first trimester of pregnancy. However, several published reports indicate methyldopa use during all trimesters of pregnancy has been relatively safe, and the possibility of fetal harm appears remote. Although methyldopa appears in human breast milk, the concentration will be too low to be pharmacologically significant and no adverse effects have been reported from exposure in breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies with methyldopa use during the first trimester of pregnancy (Prod Info methyldopa oral film coated tablets, 2008).
    B) NASAL OBSTRUCTION
    1) CASE REPORT: Neonatal nasal obstruction after maternal use of methyldopa during pregnancy has been reported (LeGras et al, 1990).
    C) LACK OF EFFECT
    1) Several published reports indicate methyldopa use during all trimesters of pregnancy has been relatively safe, and the possibility of fetal harm appears remote. Fetal outcome was improved among 332 pregnant hypertensive women who were treated with methyldopa in 5 studies (3 were controlled), and the majority of patients began methyldopa during the third trimester of pregnancy (Prod Info methyldopa oral film coated tablets, 2008).
    2) Long-term followup of 195 (97.5%) children whose mothers began methyldopa treatment between weeks 16 and 20 of pregnancy failed to uncover significant adverse effects even though they had a slightly lower average head circumference at birth compared with controls (mean 34.2 +/- 1.7 cm versus 34.6 +/- 1.3 cm, respectively). Children who were exposed to methyldopa scored consistently higher than children in the untreated group on 5 major indices of intellectual and motor development at 4 years of age, and by 7.5 years of age there were no significant differences in children of treated or untreated hypertensive women (Prod Info methyldopa oral film coated tablets, 2008).
    3) The wide use of methyldopa in pregnancy reflects the fact that it has a well-documented maternal and fetal safety record, including encouraging long-term (approximately 6 years) pediatric followup information (Khedun et al, 2000).
    D) ANIMAL STUDIES
    1) MICE/RABBITS/RATS: Reproduction studies indicated no evidence of fetal harm when oral methyldopa was given to mice (up to 1000 mg/kg), rabbits (up to 200 mg/kg), and rats (up to 100 mg/kg), which represented 16.6, 3.3, and 1.7 times the maximum daily human dose (MDHD) based on body weight assuming a patient weight of 50 kg, or 1.4, 1.1, and 0.2 times the MDHD based on body surface area, respectively (Prod Info methyldopa oral film coated tablets, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified methyldopa as FDA pregnancy category B (Prod Info methyldopa oral film coated tablets, 2008).
    2) Methyldopa is considered the drug of first choice in treating mild to moderate hypertension in pregnancy due to its lack of fetal adverse effects in utero (Anon, 1990; Khedun et al, 2000; Neerhof, 1997).
    B) PLACENTAL VASCULAR RESISTANCE
    1) Methyldopa reduces placental vascular resistance (Rey, 1992).
    C) LACK OF EFFECT
    1) Fetal outcome was improved among 332 pregnant hypertensive women who were treated with methyldopa in 5 studies (3 were controlled), and the majority of patients began methyldopa during the third trimester of pregnancy (Prod Info methyldopa oral film coated tablets, 2008).
    2) Methyldopa normalized maternal blood pressure and pulse in 28 women with mild third trimester gestational hypertension (33.54 +/- 1.17 weeks) without adversely affecting placental and fetal circulation in a prospective, observational, cohort study. Blood velocity waveform indices in the uterine, umbilical, and fetal middle cerebral arteries were within normal limits during methyldopa therapy and not significantly different from the control group (n=28; healthy pregnant women). For the methyldopa group, doses ranged from 750 mg to 2000 mg/day, gestational age at delivery was 39.07 +/- 1.15 weeks, newborn birth weights were 3283 +/- 372 grams, and newborn Apgar scores were 8.71 +/- 1.15. The same parameters were not significantly different for the control group: gestational age at delivery, 39.39 +/- 0.63 weeks; newborn birth weights, 3489 +/- 245 grams; and newborn Apgar scores, 8.89 +/- 0.63 (Folic et al, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) The American Academy of Pediatrics considers methyldopa to be usually compatible with breastfeeding (Anon, 2001).
    2) Although methyldopa appears in breast milk in small quantities, the concentration will most likely be too low to be pharmacologically significant. The relatively low oral bioavailability further reduces the amount to which an infant could be exposed. No short-term adverse effects have been reported from exposure to methyldopa via breast milk (Anon, 2001a).
    3) Three women with hypertension continued methyldopa therapy while breastfeeding. The levels of free alpha-methyldopa excreted in breast milk ranged from 0.02 to 1.14 mcg/mL. Six hours after maternal ingestion, two infant plasma levels were less than 0.05 mcg/mL; the third infant plasma level was 0.09 mcg/mL at 10 hours after maternal ingestion. An estimated 855 mcg per day (1 gram) for the mother would result in 195 mcg, or 0.02% of the maternal dose, for the breastfed infant (White et al, 1985).
    4) Seven women who were breastfeeding received methyldopa 750 mg to 2000 mg per day. Milk concentrations of free methyldopa were 0 to 0.02 mcg/mL, and concentrations of conjugated methyldopa were 0.1 to 0.9 mcg/mL. These levels were considered very low and unlikely to affect the infant. The estimated infant dose would be 0.9 mg per day if the infant consumed 1 L of milk (Berglund et al, 1984).
    B) LACK OF EFFECT
    1) CASE REPORT: One case study reports a woman who continued taking methyldopa while breastfeeding her infant. Urine analysis from the infant did show methyldopa, confirming that methyldopa passes into breast milk. The infant did not show any adverse reactions (Hauser et al, 1985).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Methyldopa did not affect fertility in male and female rats given doses of 100 mg/kg/day (1.7 times the maximum daily human dose (MDHD) based on body weight or 0.2 times the MDHD based on body surface area). However, a decrease in sperm count, sperm motility, number of late spermatids, and the male fertility index occurred when male rats received doses of 200 and 400 mg/kg/day (3.3 and 6.7 times the MDHD based on body weight or 0.5 and 1 times the MDHD based on body surface area, respectively) (Prod Info methyldopa oral film coated tablets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Monitor CBC with differential with platelet count and liver enzymes and obtain an ECG in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor blood pressure. Central venous pressure monitoring may be necessary to guide therapy in patients with severe hypotension.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Methyldopa and its conjugate (after acid hydrolysis) have been analyzed in serum and urine using fluorometry and high-performance liquid chromatography (Hoskins & Holliday, 1982; Kim & Koda, 1977). Assays in biological fluids have been reported using ultraviolet spectrophotometry of the intact drug (Baselt, 2000).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant CNS depression or hemodynamic instability should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with a small inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with symptoms should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Monitor CBC with differential with platelet count and liver enzymes and obtain an ECG in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital gastrointestinal decontamination is recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Institute continuous cardiac monitoring and obtain an ECG.
    4) Monitor CBC with differential with platelet count, and liver enzymes in symptomatic patients.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) BRADYCARDIA
    1) Atropine has been used to treat bradycardia (Taylor et al, 1978).
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Although there are no published data regarding use of hemodialysis or hemoperfusion following methyldopa overdoses, data following therapeutic use suggest that these procedures may be of value following severe intoxication refractory to conventional therapy (Yeh et al, 1970; Prod Info methyldopa oral tablets, 2006); however, good supportive care is more important than elimination enhancement.
    2) Approximately 60% of an absorbed dose was removed during 6 hours of hemodialysis, and 22% to 39% of an administered dose during 20 to 30 hours of peritoneal dialysis (Yeh et al, 1970).

Abstracts

Case Reports

    A) ADULT
    1) A 42-year-old man schizophrenic ingested 25 grams of methyldopa. He was drowsy and dysarthric for a few hours, had a heart rate of 60 bpm and blood pressure of 80/40 mmHg. Atropine 1.5 mg intravenously was his only drug therapy (Taylor et al, 1978).
    2) A 60-year-old man ingested 45 grams of methyldopa, along with unknown amounts of phenytoin and propoxyphene. He was stuporous with Cheyne-Stokes respirations, hypotensive, and had vomiting and profuse diarrhea. He responded to fluids, dopamine, and norepinephrine (Anon, 1984).
    3) A 19-year-old man presented with coma, hypotension, bradycardia, and hypothermia 10 hours after ingestion of 2.5 grams of methyldopa. Complete recovery occurred by the third day, with no specific therapy reported (Shnaps et al, 1982).
    4) A 68-year-old woman ingested 12.5 grams of methyldopa with hydrochlorothiazide. Nine hours postingestion she developed bradycardia (40 to 45 beats/minute), hypotension (80/50 mmHg), and disorientation. She alternated between episodes of extreme hypertension after administration of metaraminol or norepinephrine, and extreme hypotension after administration of nitroprusside. Administration of two therapeutic doses of doxepin 5 days postingestion was associated with bradycardia, hypotension, and apnea, which responded to dopamine and atropine (Jacobi et al, 1985).
    B) PEDIATRIC
    1) A 59 kilogram 13-year-old ingested 25 to 30 grams of methyldopa. He was lethargic, hypotensive, and received peritoneal dialysis (Anon, 1984).

Range Of Toxicity

Summary

    A) TOXICITY: Ingestions ranging from 2.5 g to 45 g have caused hypotension, bradycardia, coma, and hypothermia in adults who eventually recovered. An adult died after ingesting 25 g of methyldopa. Prolonged profound hypotension, sinus bradycardia, and drowsiness developed in a woman after ingesting 300 methyldopa tablets (greater than 75 g). She recovered following supportive care.
    B) THERAPEUTIC DOSES: ADULTS: 250 mg orally 2 to 3 times daily to 2 g daily in 2 to 4 divided doses; MAX dose, 3 g daily. CHILDREN: Initially, 10 mg/kg orally daily in 2 to 4 divided doses; MAX dose, 65 mg/kg or 3 g daily, whichever is less.

Therapeutic Dose

    7.2.1) ADULT
    A) Initial, 250 mg orally 2 to 3 times daily; maintenance: 500 to 2000 mg orally daily in 2 to 4 divided doses; MAX dose, 3 g daily (Prod Info methyldopa oral film coated tablets, 2008).
    7.2.2) PEDIATRIC
    A) Initial, 10 mg/kg orally daily in 2 to 4 divided doses; MAX dose, 65 mg/kg or 3 g daily, whichever is less (Prod Info methyldopa oral film coated tablets, 2008).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) A 44-year-old woman died after taking approximately 25 g of methyldopa (Alha et al, 1971).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) Survival has been reported in a 42-year-old man who ingested 25 g (Taylor et al, 1978), in a 13-year-old boy who ingested 25 to 30 g (Anon, 1984), and in a 60-year-old man who ingested 45 g (Anon, 1984).
    2) Prolonged profound hypotension, sinus bradycardia, and drowsiness developed in a 50-year-old woman after ingesting 300 methyldopa tablets (greater than 75 g). Initially, she had a blood pressure of 59/27 mmHg, a heart rate of 49 beats/min, and Glasgow Coma Scale Score of 14. Following aggressive supportive care, including treatment with a large amount of fluids, ephedrine sulfate, IV infusion of norepinephrine for 41 hours, dopamine for 21 hours, and observation for 3 more days, she recovered and was discharged (Chan & Joynt, 2014).
    3) A 19-year-old man presented with coma, hypotension, bradycardia, and hypothermia 10 hours after ingesting 2.5 g of methyldopa, which resulted in a 10-hour serum methyldopa concentration of 19.2 mcg/mL. Complete recovery occurred by the third day, with no specific therapy reported (Shnaps et al, 1982).
    4) A 68-year-old woman ingested 12.5 g of methyldopa with hydrochlorothiazide. Nine hours postingestion she developed bradycardia (40 to 45 beats/minute), hypotension (80/50 mmHg), and disorientation. She alternated between episodes of extreme hypertension after administration of metaraminol or norepinephrine, and extreme hypotension after administration of nitroprusside. Administration of two therapeutic doses of doxepin 5 days postingestion was associated with bradycardia, hypotension, and apnea, which responded to dopamine and atropine (Jacobi et al, 1985).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) It has been reported that patients receiving therapeutic doses of methyldopa (250 to 750 mg/day) demonstrate serum methyldopa concentrations of 2 mcg/mL (Shnaps et al, 1982).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Postmortem levels in a reported fatality were 9 mcg/mL in blood and 1400 mcg/mL in the urine (Baselt, 2000).
    2) Levels in the serum of 7.2 and 9.4 mcg/mL, respectively, and in the urine of 126 and 129 mcg/mL, respectively, have been reported in two non-fatal cases (Baselt, 2000).
    3) The serum concentration was 19 mcg/mL approximately 10 hours after ingestion of 2.5 grams of methyldopa in an adult. Coma, hypotension, bradycardia and hypothermia developed; complete recovery occurred (Shnaps et al, 1982).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 5300 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)RAT:
    a) 5 g/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of antihypertensive action has not been conclusively demonstrated (Prod Info Aldomet, 94). However, the major antihypertensive effect appears to result from conversion to alpha-methylnorepinephrine, a potent alpha-2 adrenergic agonist (Prod Info Aldomet, 94; Day et al, 1973; Weinshilboum, 1980; Henning & Rubenson, 1971). Alpha-methylnorepinephrine acts centrally to stimulate alpha receptors (Heise & Kroneberg, 1972; Finch & Haeusler, 1973; Henning & Rubenson, 1971). This results in a decrease in sympathetic outflow and decreased blood pressure (Weinshilboum, 1980).

Physicochemical

Physical Characteristics

    A) METHYLDOPA: White to yellowish-white, odorless fine powder or colorless crystals which may contain friable lumps (S Sweetman , 2001; Budavari, 1996).
    B) METHYLDOPATE HYDROCHLORIDE: White crystalline powder (Budavari, 1996).

Ph

    A) METHYLDOPATE HYDROCHLORIDE: 3-5 (1% aqueous solution)

Molecular Weight

    A) METHYLDOPA: 238.2
    B) METHYLDOPATE HYDROCHLORIDE: 275.7

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