Hypotensive effect of methyldopa

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 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... 

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 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. 

The primary hemodynamic alteration responsible for the hypotensive effects of a-methyldopa remains in dispute. A en the patient is supine, the reduction in blood pressure produced by a-methyldopa correlates best with a decrease in peripheral vascular resistance, cardiac output being only slightly reduced. When the patient is upright, the fall in blood pressure corresponds more closely with a reduced cardiac output. 

Reversal of hypotensive effects of clonidine, reserpine, a-methyldopa, and guanethidine... 

TCAs CENTRALLY ACTING ANTI HYPERTENSIVES 1. Possibly hypotensive effect of donidine and moxonidine antagonized by TCAs (some case reports of hypertensive crisis). 2. Conversely, donidine and moxonidine may exacerbate the sedative effects of TCAs, particularly during initiation of therapy 3. Methyldopa may 1 effect of antidepressants 1 and 2. Uncertain 3. Methyldopa can cause depression 1. Monitor BP at least weekly until stable 2. Warn patients of the risk of sedation and advise them to avoid driving or operating machinery if they suffer from sedation. 3. Methyldopa should be avoided in patients with depression... 

Tricyclic antidepressants reverse the hypotensive effects of postganglionic blocking agents, guanethidine, reser-pine, clonidine, and alpha-methyldopa, and the addition of a tricyclic can result in loss of blood pressure control (159,179). Sudden withdrawal of a tricyclic compound from a patient stabilized with these compounds can also result in serious hypotension. An additional reason for avoiding drugs such as reserpine, methyldopa, and... 

TCAs may reverse the hypotensive effects of certain sympatholytic antihypertensives (e.g., guanethidine, methyldopa, and clonidine) because of inhibition of presynaptic uptake of the... 

Nortriptyline may decrease hypotensive effects of centrally acting antihypertensive drugs, such as guanethidine, guanabenz, guanadrel, clonidine, methyldopa, and reser-pine. Concomitant use with disulfiram or ethchlorvynol may cause delirium and tachycardia. 

Methyldopa can increase the effects of levodopa and permit a reduction in the dosage in some patients taking levodopa alone, but it can aiso worsen dyskinesias in others. This interaction would not be expected to be significant in a patient taking levodopa with benserazide or carbidopa but this does not appear to have been studied. A small increase in the hypotensive actions of methyldopa may also occur. 

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 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. 

Simple addition of the hypotensive effects of both drugs seems to be the explanation for the increased hypotension and orthostasis. The suggested explanation for the hypertensive interaction with methyldopa and trifluoperazine is that the phenothiazine blocked the reuptake of the false transmitter (alpha-methyl noradrenaline) that is produced during when methyldopa is given. ... 

Aleksandrow, D., Januszewicz, Wl. and Wocial, B., Hypotensive effect of aldomet (a-methyldopa) in the treatment of hypertension its effect on the catecholamines turnover, Polskiego Tygodnika Lekarskiego 17, 47 (1962). 

The mechanism of the central hypotensive effects of L-dopa, a-methyldopa and m-tyrosine has been studied with the aid of peripheral decarboxylase inhibitors.56,57 jhe effects of L-dopa on the cardiovascular system have been reviewed.58 A comparative study of the dose-dependent antihypertensive actions, and the norepinephrine-depleting activities, of a-methyltyramine and a-methyloctopamine in renal rats has been published.59... 

Diuretics and alcohol increase the hypotensive action of methyldopa (37 ). Ox-prenolol too is said to augment the hypotensive action, rendering it possible to reduce methyldopa dosage and thereby lowering the incidence of side effects (54< ). Interaction between methyldopa and haloperidol, both of which affect dopamine in the CNS, was found to result in an acute dementia in 2 patients who received the drugs simultaneously. The condition was reversible, and the mental condition was again normal 3 days after withdrawal of the haloperidol (148 ). 

A number of theories have been put forward to account for the hypotensive action of a-methyldopa. Current evidence suggests that for a-methyldopa to be an antihypertensive agent, it must be converted to a-methyl-norepinephrine however, its site of action appears to be in the brain rather than in the periphery. Systemically administered a-methyldopa rapidly enters the brain, where it accumulates in noradrenergic nerves, is converted to a-methylnorepinephrine, and is released. Released a-methylnorepinephrine activates CNS a-adrenoceptors whose function is to decrease sympathetic outflow. Why a-methylnorepinephrine decreases sympathetic outflow more effectively than does the naturally occurring transmitter is not entirely clear. 

Reduction in arterial blood pressure by clonidine is accompanied by decreased renal vascular resistance and maintenance of renal blood flow. As with methyldopa, clonidine reduces blood pressure in the supine position and only rarely causes postural hypotension. Pressor effects of clonidine are not observed after ingestion of therapeutic doses of clonidine, but severe hypertension can complicate a massive overdose. 

Methyldopa [Aldomet) [Antihypertensive/Centrally Acting Antiadrenergic] Uses HTN Action Centrally acting antihypertensive Dose Adults. 250-500 mg PO bid-dd (max 2-3 g/d) or 250 mg-1 g IV q6-8h Peds. 10 mg/kg/24 h PO in 2-3 + doses (max 40 mg/kg/24 h - q6-l2h) or 5-10 mg/kg/dose IV q6-8h to total dose of 20—40 mg/kg/24 h i in renal insuff/elderly Caution [B (PO), C (IV), +] Contra Liver Dz MAOIs Disp Tabs, inj SE Discolors urine inidal transient sedadon/drowsiness frequent, edema, hemolydc anemia, hepadc disorders Interactions T Effects W/ anesthetics, diuredcs, levodopa, Li, methotrimeprazine, thioxanthenes, vasodilators, verapamil T effects OF haloperidol, Li, tolbutamide 1 effects W7amphetamines, Fe, phenothiazine, TCAs 1 effects OF ephedrine EMS Use diuredcs, verapamil, and sympathomimedcs w/ caudon may T risk hypotension, arrhythmias and pressors effects OD May cause profound hypotension, drowsiness, and impaired myocardial conduction activated charcoal may be effective... 

Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. The effects of low but clinically effective doses resemble those of centrally acting agents (eg, methyldopa) in that sympathetic reflexes remain largely intact, blood pressure is reduced in supine as well as in standing patients, and postural hypotension is mild. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms. 

ADRENERGIC NEURONE BLOCKERS-GUANETHIDINE CENTRALLY ACTING ANTIHYPERTENSIVES-METHYLDOPA MAOIs Risk of adrenergic syndrome (see above). Reports of an enhanced hypotensive effect and hallucinations with methyldopa, which may cause depression Due to inhibition of MAOI, which breaks down sympathomimetics Avoid concurrent use. Onset may be 6-24 hours after ingestion... 

In the brain, methyldopa is enzymatically decarboxy-lated to a-methyldopamine, which undergoes subsequent enzymatic conversion, via hydroxylation, to a-methylnorepinephrine, an a-adrenergic agonist. Stimulation of central inhibitory a-adrenergic receptors causes a decrease in sympathetic outflow manifested as a decrease in blood pressure. A decrease in plasma renin activity may also play a role in methyldopa s hypotensive effects. 

Plasma concentrations of norepinephrine fall in association with the rednction in arterial pressnre, and this reflects the decrease in sympathetic tone. Renin secretion also is reduced by methyldopa, but this is not a major effect of the drng and is not necessary for its hypotensive effects. Salt and water often are gradnally retained with prolonged use of methyldopa, and this tends to blnnt the antihypertensive effect. This has been termed psendo-tolerance, and can be overcome with concnrrent nse of a diuretic. 

Two cases of marked CNS adverse effects have been attributed to the use of methyldopa and haloperidol. Another patient became irritable and a ressive. In a small pilot study, the combination of methyldopa and haloperidol lowered blood pressure, and symptomatic hypotension occurred in one patient. The combination also caused marked sedation. 

The manufacturers of methyldopa note that a reduced antihypertensive effect may occur with phenothiazines, as well as mentioning the risk of additive hypotensive effects ... 

Tizanidine alone can cause hypotension, an efTeet whieh is usually minimised by titration of the dose. Patients should be warned about this effeet. Because of this, the manufacturers caution that tizanidine might inerease the effects of antihypertensive drugs, including diuretics, and recommend caution on concurrent use. This is a prudent precaution. The US manufacturer specifically states that tizanidine (an (X2-adrenergic agonist that is structurally related to clonidine) should not be used with other otj-adren-ergic agonists [e.g. clonidine, methyldopa]. ... 

Muscholl [153] and Stone and Porter [237] have discussed the pharmacology and mechanism of action of methyldopa in review articles. In contrast to previous views, inhibition of dopa decarboxylase is not considered essential for the drug s hypotensive effect. It is now assumed that a-methylnorepinephrine, which is formed from a-methyldopa by decarboxylation and / -hydroxylation, is... 

The proposal that a central effect might be the cause of the decrease of peripheral resistance brought about by a-methyldopa is supported by evidence that a centrally mediated hypotensive effect may be demonstrated in the cat. ... 

The antihypertensive effects of a-methylated catecholamine analogs have been studied.In renal hypertensive rats, prolonged treatment with a-methyldopa, a-methyl- m-tyrosine, a-meth-yltyrosine or metaraminol produces dose-dependent decreases in blood pressure and dose-dependent depletion of myocardial catecholamines. The same order of relative activities was found in regard to noradrenaline depletion and antihypertensive effect, but there was no relationship between the degree of catecholamine depletion and the intensity of the hypotensive effect. 

Reserpine and imipramine may inhibit the hypotensive action concurrent use of MAO inhibitors augments it (S" ). There is some evidence that the administration of tricyclic antidepressants in combination with a-methyldopa wUl lead to a loss of the hypotensive effect, but certainly not as marked as... 

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