Alpha-Methyl dopa

Alpha Methyl dopa is an antihypertensive agent belonging to the alpha-2 adrenergic agonist

Alpha Methyl dopa is approved for the treatment of Hypertension.

Alpha Methyl Dopa gets variably and partially absorbed from the gastrointestinal tract with bioavailability of approx 42%. It crosses the blood-brain barrier and placenta; enters breast milk (approx 20-35%) with volume of distribution of about 0.23 L/kg. It extensively gets metabolized in the liver and gastrointestinal tract which is then converted to active α-methyl norepinephrine via decarboxylation in the CNS. Alpha Methyl dopa get excreted via urine (approx 70%, as unchanged drug and mono-O-sulfate conjugate) with an elimination half-life of about 1.5-2 hours.

Alpha Methyl Dopa is available in the dosage forms as tablets and Injections.

Alpha Methyl Dopa is available in France, Canada, Brazil, Denmark, Australia, India

Alpha Methyl Dopa, belonging to the alpha-2 adrenergic agonist, acts as an antihypertensive agent. High blood pressure adds to the work load of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if the blood pressure is controlled.

Alpha Methyl Dopa works by controlling impulses along certain nerve pathways. As a result, it relaxes blood vessels so that blood passes through them more easily. This helps to lower blood pressure.

The onset of action of Alpha methyl dopa occurs within 3-6 hours for single dose and 48-72 hours for multiple doses.

The Duration of Action for Alpha methyl dopa was 12-24 hours for single dose and 24-48 hours for multiple doses.

The Tmax was found within 4-6 hours following the administration of Alpha Methyl dopa and Cmax was about 975 ng/ml.

Alpha Methyl Dopa is available in the form of tablets and injection

Tablets:

Alpha Methyl dopa tablets to be swallowed whole with water. Alpha methyl dopa comes as a tablet to be taken by mouth. It is usually taken two times a day.

Injections :

1. Inject a needle into the person’s vein.
2. Push a small plastic catheter over the needle and into the vein.
3. Remove the needle, leaving the catheter in place.
4. Place an access cap over the catheter, which allows them to administer medications without having to re-inject a needle.

Alpha Methyl dopa is an antihypertensive agent belonging to the alpha-2 adrenergic agonist class.

Alpha Methyl Dopa is approved for the treatment of Hypertension.

Alpha-methyldopa is converted to methyl norepinephrine centrally to reduce the adrenergic outflow by the alpha-2 agonistic action from central nervous system, leading to reduced total peripheral resistance and decreased systemic blood pressure. Alpha-2 agonistic activity does not affect cardiac output or renal blood flow.; hence, this drug is useful in hypertensive patients with renal insufficiency

Alpha Methyl Dopa is approved for use in the following clinical indications.

Hypertension:

Alpha methyl dopa is available in the form of tablets and injections.

Hypertension

• Initial: 250 mg taken by mouth every 8 to 12 hour for two days, increase every 2 days whenever necessary.

• Maintenance: 250-1000 mg/day divided taken every 6 to 12 hours, usually no more than 3 g/day

• IV (methyldopa): 250-1000 mg infusion over 30-60 minutes taken every 6 to 8 hours whenever necessary; no more than 4 g/day

Hypertensive Crisis

20-40 mg/kg/day divided IV every 6 hour. No more than 65 mg/kg/day or 3 g/day (whichever is less)

Alpha Methyl dopa can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Alpha Methyl Dopa is available in various dosage strengths as Dosage forms 125 mg, 250 mg, 500 mg, 50 mg/ml.

Alpha Methyl Dopa is available in the form of tablets and injection.

Alpha Methyl dopa is approved for the treatment of Hypertension.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient's requirements

Alpha Methyl Dopa may be contraindicated in the following

• With active hepatic disease, such as acute hepatitis and active cirrhosis
• With liver disorders previously associated with alpha methyldopa therapy
• With hypersensitivity to any component of these products.
• On therapy with monoamine oxidase (MAO) inhibitors.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• With prolonged Methyldopa therapy, 10% to 20% of patient develop a positive direct Coombs test which usually occurs between 6 and 12 months of Methyldopa therapy. Lowest incidence is at the daily dosage of 1 g or less. This, on rare occasions may be associated with the hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.
• Prior existence or development of a positive direct Coombs test is not in itself a contraindication to the use of Methyldopa. If a positive Coombs test develops during Methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test, there is less often a positive indirect Coombs test which may interfere with cross matching of blood.
• Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.
• If Coombs-positive hemolytic anemia occurs, the cause may be Methyldopa, and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given, and other causes of anemia should be considered. If the hemolytic anemia is related to Methyldopa, the drug should not be reinstituted.
• When Methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after Methyldopa is stopped.
• The need for transfusion arise in a patient receiving Methyldopa, both a direct and an indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross-matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.
• Occasionally, fever has occurred within the first three weeks of Methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin, and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first 2 to 3 months of therapy. In some patients the findings are consistent with those of cholestasis. In others, the findings are consistent with hepatitis and hepatocellular injury
• Rarely, fatal hepatic necrosis has been reported after the use of Methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determinations of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with Methyldopa. If caused by Methyldopa, the temperature and abnormalities in liver function characteristically had reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.
• Rarely a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the drug. Rare cases of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.

Precautions

General

• Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction.
• Some patients are taking Methyldopa experience clinical edema or weight increase which may be controlled by the use of a diuretic. Methyldopa should not be continued if the edema progresses or signs of heart failure appear.
• Hypertension has recurred occasionally after dialysis in the patient given Methyldopa because the drug is removed by this procedure.
• Rarely, have involuntary choreoathetotic movements have been observed during therapy with Methyldopa in patients with severe bilateral cerebrovascular disease. If these movements occur, stop therapy.

Sodium Rich Foods: Intake of sodium-containing foods when you are on Alpha methyldopa will reduce the blood-pressure-lowering effect of methyl dopa. It is better to avoid salted foods while taking this medicine.

The adverse reactions related to molecule Alpha Methyl Dopa can be categorized as

• Common Adverse effects:

Nausea, Diarrhea, Headache, Dizziness, Sedation, dry mouth, rash.

• Less Common adverse effects:

Nervousness, Elevated liver enzymes, joint paint, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesias, bradycardia, cold extremities, hypotension, palpitations, syncope, Anxiety, lethargy, diarrhea, vomiting, Pruritus, drug-induced Parkinson’s disease

• Rare adverse effects:

Hemolytic anemia, Lupus-like syndrome, Myocarditis, Pancreatitis, Hepatoxicity, Immune thrombocytopenia, reversible leukopenia, involuntary choreoathetotic movements, weight gain, rebound hypertension. etc.

The clinically relevant drug interactions of Alpha Methyl Dopa are briefly summarized here

• May increase lithium toxicity.
• May potentiate the effect of other antihypertensive drugs (e.g. atenolol).
• Sympathomimetics (e.g., phenylephrine), phenothiazines (e.g. chlorpromazine), and TCAs (e.g. amitriptyline) may diminish antihypertensive effect of methyldopa.
• Iron preparations (e.g., ferrous sulfate) may reduce the serum concentration of methyldopa.
• Potentially Fatal: Enhanced adverse or toxic effect with MAOIs (e.g. phenelzine).

The common side of Alpha Methyl Dopa includes the following:

Nausea, Diarrhea, Headache, Dizziness, Sedation, dry mouth, rash.

The use of Alpha Methyl Dopa should be prudent in the following group of special populations:

Pregnancy

Pregnancy Category (FDA): B

Reproduction studies performed with methyldopa at oral doses up to 1000 mg/kg in the mice, 200 mg/kg in rabbits and 100 mg/kg in rats revealed no evidence of harm to the fetus. These doses are 16.6 times, 3.3 times and 1.7 times, respectively, the maximum daily human dose when compared on the basis of body weight; 1.4 times, 1.1 times and 0.2 times, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg. There are, however, no adequate and well-controlled studies in pregnant women in the first trimester of pregnancy. Because animal reproduction studies are not always predictive of human response, methyldopa should be used during pregnancy only if clearly needed.

Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of fetal harm appears remote. In five studies, three of which were controlled, involving 332 pregnant hypertensive women, treatment with methyldopa was associated with an improved fetal outcome. The majority of these women were in the third trimester when methyldopa therapy was begun.

In one study, women who had begun methyldopa treatment between weeks 16 and 20 of pregnancy gave birth to infants whose average head circumference was reduced by a small amount (34.2 ± 1.7 cm vs. 34.6 ± 1.3 cm [mean ± 1 S.D.]). Long-term follow-up of 195 (97.5%) of the children born to methyldopa-treated pregnant women (including those who began treatment between weeks 16 and 20) failed to uncover any significant adverse effect on the children. At four years of age, the developmental delay commonly seen in children born to hypertensive mothers was less evident in those whose mothers were treated with methyldopa during pregnancy than those whose mothers were untreated. The children of the treated group scored consistently higher than the children of the untreated group on five major indices of intellectual and motor development. At age 7 and one-half developmental scores and intelligence indices showed no significant differences in children of treated or untreated hypertensive women.

• Labor and Delivery

There is no FDA guidance on use of Methyldopa during labor and delivery.

• Nursing Mothers

Methyldopa appears in breast milk. Therefore, caution should be exercised when methyldopa is given to a nursing woman.

• Pediatric Use

There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of Hypertension in pediatric patients.

• Geriatic Use

Of the total number of subjects (1685) in clinical studies of methyldopa, 223 patients were 65 years of age and over while 33 patients were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

• Gender

There is no FDA guidance on the use of Methyldopa with respect to specific gender populations.

• Race

There is no FDA guidance on the use of Methyldopa with respect to specific racial populations.

• Females of Reproductive Potential and Males

There is no FDA guidance on the use of Methyldopa in women of reproductive potentials and males.

• Immunocompromised Patients

There is no FDA guidance one the use of Methyldopa in patients who are immunocompromised.

• Symptoms:

Acute hypotension, excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, abdominal distention, flatus, diarrhoea, nausea, vomiting.

• Management:

Symptomatic and supportive treatment. If ingestion is recent, may perform gastric lavage or induce emesis. Administration of sympathomimetic agents may be considered.

1. https://go.drugbank.com/drugs/DB00968
2. https://reference.medscape.com/drug/aldomet-methyldopa-342385
3. https://www.mims.com/india/drug/info/methyldopa?type=full&mtype=generic
4. https://www.ncbi.nlm.nih.gov/books/NBK551671/#article-25081.s5
5. https://www.drugs.com/dosage/methyldopa.html
6. Kwan KC, Foltz EL, et, al. Pharmacokinetics of methyldopa in man. Journal of Pharmacology and Experimental Therapeutics. 1976 Aug 1;198(2):264-77.