Effects of methyldopa

In 1967, Henning and Van Zwieten provided conclusive evidence that the most important effect of methyldopa is on the vasomotor centers in the central nervous system(22). This central effect results in a decrease in sympathetic tone to the periphery. 

Pseudoephedrine (Sudafed, Novafed, Afrinol, Others) [OTC] [Decongestant/Sympothomimetic] Uses Deconge tant Action Stimulates a-adren gic rec tors w/ vasoconstriction Dose Adults. 30-60 mg PO q6—8h Peds. 4 mg/kg/24 h PO qid -1- in renal insuff Caution [C, +] Contra Poorly controlled HTN or CAD, w/MAOIs Disp Tabs, caps, Liq SE HTN, insomnia, tach, arrhythmias, nervousness, tremor Interactions T Risk of HTN crisis W/ MAOIs T effects W/BBs, sympathomimetics X effects W/TCAs -1- effect OF methyldopa, reserpine EMS Found in many OTC cough/cold pr >arations use sympathomimetics w/ caution, may T adverse effects OD May cause N/V, HTN, arrhythmias, and Szs symptomatic and supportive... 

The most common undesirable effect of methyldopa is sedation, particularly at the onset of treatment. With long-term therapy, patients may complain of persistent mental lassitude and impaired mental concentration. Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but are relatively infrequent. Lactation, associated with increased prolactin secretion, can occur both in men and in women treated with methyldopa. This toxicity is probably mediated by inhibition of dopaminergic mechanisms in the hypothalamus. 

Other important adverse effects of methyldopa are development of a positive Coombs test (occurring in 10-20% of patients undergoing therapy for longer than 12 months), which sometimes makes cross-matching blood for transfusion difficult and rarely is associated with hemolytic anemia, as well as hepatitis and drug fever. Discontinuation of the drug usually results in prompt reversal of these abnormalities. 

Receptor antagonists, especially -selective antagonists, administered centrally, block the antihypertensive effect of methyldopa, whether the latter is given centrally or intravenously. (3) Potent inhibitors of dopa decarboxylase, administered centrally, block methyldopa s antihypertensive effect, thus showing that metabolism of the parent drug in the central nervous system is necessary for its action. 

Mianserin has alpha-adrenoceptor activity and so might interact with methyldopa (17). In 11 patients with essential hypertension, the addition of mianserin 60 mg/day (in divided doses) for 2 weeks did not reduce the hypotensive effect of methyldopa. In patients treated with methyldopa, there were additive hypotensive effects after the first dose of mianserin, but these were not significant after 1 or 2 weeks of combined treatment. The results of this study appear to have justified the authors conclusion that adding mianserin to treatment with methyldopa will not result in loss of blood pressure control. 

CENTRALLY ACTING ANTIHYPERTENSIVES IRON COMPOUNDS 1 antihypertensive effect of methyldopa Ferrous sulphate and possibly ferrous gluconate may chelate methyldopa in the intestine and 1 its absorption Monitor BP at least weekly until stable... 

CENTRALLY ACTING ANTI HYPERTENSIVES SYMPATHOMIMETICS-INDIRECT 1. Indirect sympathomimetics may i the hypotensive effect of methyldopa 2. Methyldopa may 1 the mydriatic effect of ephedrine eye drops 1. Uncertain 2. Uncertain 1. Monitor BP at least weekly until stable 2. Watch for a poor response to ephedrine eye drops... 

Specific information on the effects of methyldopa toxicity in domesticated animals is lacking. 

Garratty G, Arndt P, Prince HE, Schtilman lA. The effect of methyldopa and procainamide on suppressor cell autoantibody production. Br J Haematol 1993 84 310. 

In spite of its rapid absorption and short half-life, the peak effect of methyldopa is delayed for 6 to 8 hours even after intravenons administration, and the duration of action of a single dose is nsnally about 24 hours this permits once-or twice-daily dosing. The discrepancy between the effects of methyldopa and the measured concentrations of the drug in plasma is most likely related to the time required for transport into the CNS, conversion to the active metabolite storage of a-methyl norepinephrine, and its subsequent release in the vicinity of relevant 0.2 receptors in the CNS. This is a good example of the potential for a complex relationship between a drug s pharmacokinetics and its pharmacodynamics. Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa, bnt it is not known if this is due to alteration in excretion of the drng or to an increase in transport into the CNS. 

In spite of its rapid absorption and short ty, the peak effect of methyldopa is delayed for... 

Garratty G, Amdt P, Prince HE, Shulman lA (1993) The effect of methyldopa and procainamide on suppressor cell activity in relation to red cell autoantibody production. Br J Haematol 84 310-315 Gottschall JL, Elliot W, Lianos E, McFarland JG, Wolfmeyer K, Aster RH (1991) Quinine-induced immune thrombocytopenia associated with hemolytic uremic syndrome a new clinical entity. Blood 77 306-310... 

Well documented. Concurrent use need not be avoided but the outcome should be well monitored. In patients on levodopa alone, the use of methyldopa may allow a reduction in the dosage of the levodopa (the reports cited " quote figures of between 30 and 70%) and may enhance the control ofParkinson s disease, but it should also be borne in mind that in some patients dyskinesias may be worsened. However, in the presence of carbidopa or benserazide the dopa decarboxylase effects of methyldopa would be expected to be less significant and so it seems unlikely that a dose reduction of levodopa would be required. The increased hypotensive effects seem to be small, but they too should be checked. 

The hypotensive effects of methyldopa and haloperidol might be expected to be additive. The CNS effects are not understood, although methyldopa can cause sedation, depression and dementia, and haloperidol can cause... 

The hypotensive adverse effects of chlorpromazine and other phenothiazines may be additive with the antihypertensive effects of methyldopa. Patients may feel faint and dizzy if they stand up quickly. An isolated report describes paradoxical hypertension in a patient given methyldopa and trifluoperazine. 

The real picture is considerably more complicated. A number of findings indicate, for example, that norepinephrine depletion only causes a reduction in blood pressure of therapeutic value if it occurs in central neurones. The replacement of norepinephrine by a-methylnorepinephrine in peripheral organs does not bring about any fall in blood pressure [135]. The hypotensive effect of methyldopa and its analogues does not run parallel to the catecholamine depletion caused by these substances in the heart [42]. 

Among the many experiments which have indicated that methyldopa exerts a central effect, one reported by Henning [108] may be mentioned here>. it was to be expected that dopa decarboxylase inhibitors, which prevent the conversion of methyldopa to its active metabolite a-methylnorepinephrine, would suppress the hypotensive effect of methyldopa. Of two such inhibitors tested, only Ro 4-4602 displayed this property. 

On the erroneous assumption that the hypotensive effect of methyldopa is due to inhibition of the enzyme dopa decarboxylase, numerous substances were tested as possible dopa decarboxylase inhibitors [102, 171, 178, 179, 194, 229]. The hypotensive effect of these substances, in so far as it existed at all, is most probably due to a mechanism similar to that suggested in the case of methyldopa-i.e. the substance, or one of its metabolites, is taken up in place of endogenous norepinephrine. 

Studies of the effect of methyldopa in patients with impaired renal function confirmed that renal blood flow and glomerular filtration rate were maintained regardless of posture, and suggested a mechanism of action other than some form of sympathetic blockade ... 

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