Indications:
Agidopa tablets are used to treat hypertension. Methyldopa remains the drug of first choice for treatment of hypertension in pregnancy.
Administration, dosage:
Administration:
Oral administration.
Dosage:
Adults:
Initial treatment: The usual starting dosage of methyldopa is 250 mg, two to three times a day for the first 48 hours. Thereafter, the dosage should be adjusted according to the patient’s response and tolerance, preferably at intervals of not less than two days. To minimize the sedation, start dosage increases in the evening. When methyldopa is given concomitatntly with other antihypertensive, the initial dosage of methyldopa should be limited to 500 mg/daily in divided doses.
Maintenance therapy: The usual daily dosage of methyldopa is 0.5 to 2 g/day in 2 – 4 divided doses. The maximum recommended daily dosage is 3 g.
Elderly:
The initial dose is 125 mg, twice daily, increasing slowly as required. The maximum dose is 2 g/day.
Children:
Initial dosage is based on 10 mg/kg of bodyweight daily in 2 – 4 divided doses. The maximum dose is 65 mg/kg or 3 g daily.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine after use.
Contraindications:
Hypersensitivity to any of the ingredients of Agidopa.
Active hepatic disease, such as acute hepatitis and active cirrhosis.
Liver disorders associated with previous methyldopa therapy.
Phaeochromocytoma.
Therapy with monoamine oxidase (MAO) inhibitors.
Warnings and precautions for use:
Methyldopa should be used with caution:
In patients with a history of previous liver disease or dysfunction; severe renal failure; history of hemolytic anemia; Parkinson disease; depression or mental illness; porphyria; cerebral atherosclerosis.
Periodic white and red blood counts and hepatic function tests should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs.
Methyldopa may cause drowsiness, so patients should not drive and operate machines.
Pregnancy and lactation:
Pregnancy:
The risk of methyldopa during pregnancy has not been known. Methyldopa can be used in patients with pregnancy-induced hypertension. Methyldopa has been shown not to have teratogenic effects on the fetus, but in some infants born by mothers who have been treated with methyldopa during pregnancy, there is sometimes a period of hypotension.
Lactation:
Methyldopa is excreted into human milk. Therapeutic doses used for breast-feeding mothers can cause risks to infants. So, Agidopa should not be used in nursing women.
Effects on ability to drive and use machines:
Agidopa may cause drowsiness, so Agidopa should not be taken when driving and operating machines.
Interactions, incompatibilities of medicine:
Interaction of the drug with other drugs and other types of interactions:
Caution should be advised when methyldopa is used concomitantly with the following medicines:
Other antihypertensive medicines: Methyldopa may potentiate antihypertensive effect, increase adverse reactions or manifestations of drug idiosyncrasy.
Anesthetics: Doses of anesthetics must be reduced; if hypotension does occur during anesthesia, it usually can be controlled by vasopressors.
Lithium: Methyldopa may increase toxicity of lithium.
MAOIs with methyldopa: Severe hypotension.
Amphetamine, central nervous system stimulating medicines, tricyclic antidepressants: These medicines may counteract the activity of methyldopa in treating hypertension and cause loss of blood pressure control.
Haematinic drug containing iron: It reduces concentrations of methyldopa in plasma and reduces the antihypertensive effect of methyldopa.
Oral contraceptives: Because it may increase risk of vascular damage and cause difficulty in controlling blood pressure.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Side effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); cannot be estimated from the available data “Not known”.
With prolonged methyldopa therapy, 10 to 20% of patients develop a positive direct Coombs test and this on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications.
The most common is sedative effects, at least 30% of patients; dizziness and dry mouth in 18% and 10% of patients taking medicine, respectively. Headache occurs when starting the methyldopa therapy and disappears with continued treatment (10%).
Common
Body as a whole: Headache, dizziness, fever.
Circulatory: Postural hypotension, orthostatic hypotension, edema.
Central nervous system: Sedation.
Endocrine: Decreased libido.
Gastrointestinal: Dry mouth, nausea, vomiting, diarrhea.
Respiratory: Stuffy nose.
Uncommon
Body as a whole: Asthenia.
Nervous system: Decreased mental acuity, paraesthesia.
Psychiatric: Nightmares, depression.
Rare
Blood: Bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, haemolytic anaemia, megaloblastic anemia.
Circulatory: Bradycardia, aggravation of angina pectoris, heart failure, sick sinus syndrome.
Central nervous system: Facial paralysis, involuntary choreoathetotic movements, symptoms of cerebrovascular insufficiency, Parkinsonism.
Endocrine: Amenorrhea, gynecomastia, galactorrhea.
Gastrointestinal: Colitis, sialadenitis, black tongue, flatulence, pancreatitis.
Skin: Rash, toxic epidermal necrolysis.
Hepatobiliary: Jaundice, hepatitis, microscopic focal necrosis.
Musculoskeletal: Arthralgia with or without joint swelling, myalgia.
Others: Myocarditis, pericarditis, lupus-like syndrome.
Guidelines for management of ADR
If Coombs-positive hemolytic anemia occurs (which usually occurs 6 and 12 months after the start of therapy), the cause may be methyldopa, in this case methyldopa should be discontinued. Lowest incidence is at daily dosage of 1 g or less. Usually the anemia remits promptly. If not, corticosteroids may be given, in necessary case blood transfusion may be indicated, and other causes of anemia should be considered. If the hemolytic anemia is related to methyldopa, the medicine should not be reinstituted.
Hemolytic anemia occasionally occurs unrelated to positive or negative Coombs’ test. This case occurs in patients with deficiency of glucose – 6 – phosphate dehydrogenase, with higher incidence in malaria-exposed populations than in non-malaria-exposed populations.
Sedative effects may occur during the initial period of therapy or whenever the dose is increased, but disappear with the continuation of treatment.
When using methyldopa, drug-induced fever is primarily toxic effect. Occasionally, fever has been accompanied by eosinophilia and/or abnormalities in liver function tests, fever may occur periodically but usually within the first 3 weeks of methyldopa therapy.
Jaundice may occur with onset usually within the first 2 to 3 months of therapy.
Discontinue the medicine and contact your doctor if you experience side effects during the methyldopa therapy.
Overdose and management:
Overdose:
Acute overdosage may cause hypotension with other responses attributable to with brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, constipation, distention, flatus, diarrhea, nausea, vomiting).
Management:
In case of overdose, symptomatic and supportive measures should be employed. Lavage and induction of emesis may be given if ingestion is recent. If the drug is absorbed, infusions may be helpful to promote urinary excretion. Otherwise, management includes special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, and cerebral activity.
Sympathomimetic drugs e.g. levarterenol, epinephrine, metaraminol may be indicated.
Methyldopa can be removed from the circulation by hemodialysis.
Pharmacodynamic properties:
Pharmacological group: Antiadrenergic agents, centrally acting.
ATC code: C02A B01, C02A B02
Methyldopa is an structurally related antihypertensive drug that is with structure related to catecholamines and their precursors. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methylnorepinephrine in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Therefore, methyldopa is considered as a centrally acting antiadrenergic drug. Methyldopa also reduces plasma renin activity and this reduction contributes to the hypotensive effect of methyldopa. Methyldopa inhibits the decarboxylation of dihydroxyphenylalanine (dopa) (the precursor of norepinephrine) and of 5 – hydroxytryptophan (the precursor of serotonin). Although the antihypertensive effect of methyldopa is not primarily due to the inhibition of decarboxylase but some contribution of peripheral mechanisms to the antihypertensive activity of methyldopa cannot be excluded. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.
Methyldopa reduces both supine and standing blood pressure. Methyldopa has no direct effect on kidney and cardiac function. Cardiac output is usually maintained without cardiac acceleration. In some patients the heart rate is slowed. Renal blood flow, glomerular filtration rate, or filter fraction are not affected. Thus, blood pressure-lowering effect can be maintained even in patients with renal failure. Symptoms of posture hypotension, exercise hypotension and diurnal blood pressure variations rarely occur.
Methyldopa may be used in combination with other antihypertensive drugs, particularly thiazide diuretics including thiazide combined with amiloride. Methyldopa may also be combined with beta blockers.
Pharmacokinetic properties:
Absorption: The absorption of methyldopa is not completely. The average bioavailability is only 25% of the dose and changes greatly between patients. The maximum plasma concentration is achieved within 2 – 4 hours after oral administration, the maximum antihypertensive effect occurs after 4 to 6 hours.
Plasma half-life is 1 – 2 hours in patients with normal renal function and increases with impaired renal function.
Distribution: The volume distribution of the drug is 0.6 liter/kg.
Metabolism: Because antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methylnorepinephrine, so plasma concentrations of methyldopa have little predictive value for methyldopa effectiveness.
Elimination: Approximately 70% of the dose is excreted via the kidney, of which 60% is free methyldopa, the remainder is conjugated metabolite.
Storage conditions, shelf life, quality specification of the medicine:
Storage: Protect from humidity and light, below 300C.
Shelf life: 36 months from the manufacture date.
Quality specification: In house.
