The cardiovascular effects of metoclopramide in multiple system atrophy and pure autonomic failure

Metoclopramide (MCP), a central and peripheral dopaminergic blocker with cholinergic activity, has been proposed to treat orthostatic hypotension (OH) on the basis that it could antagonize the vasodilator and natriuretic effects of dopamine. The authors evaluated cardiovascular responses to MCP in 11 subjects with OH: 6 with multiple system atrophy (MSA) and 5 with pure autonomic failure (PAF), along with 6 healthy control subjects. Supine blood pressure (BP), heart rate (HR), and breathing were continuously monitored before, during, and after MCP infusion. The pre-MCP head-up tilt test was tolerated at 65 degrees for 10 minutes in all subjects except in one with PAF, who tolerated 30 degrees for only 5 minutes. Tilting confirmed the OH in patients with MSA (change in mean arterial pressure [deltaMAP] = -31 +/- 13 mm Hg) and PAF (AMAP = -34 +/- 8 mm Hg). Infusion of MCP was given in four 5-mg doses every 5 minutes, with the subject in a supine position. Infusion of MCP induced the following effects: (1) A transient hypotensive effect occurred after each infusion in both patients and control subjects, the fall in MAP being counteracted by an increase in HR in control subjects but not in patients; this acute MAP fall was mo resevere in patients. (2) A progressive reduction of MAP occurred during the test,which never returned to preinfusion levels in patients; this effect was so pronounced in two PAF patients as to prevent them from receiving the last dose. Post-MCP tilting was tolerated in control subjects but in only in 5 MSA patients and 4 PAF patients. In those patients who tolerated the test, the MAP fall was similar to, or worse than, that before MCP (MSA: deltaMAP = -28 +/- 16 mm Hg; PAF: deltaMAP = -38 +/- 16 mm Hg). The cardiovascular effect of MCP in normal subjects was a transient hypotension counterbalanced by reflex tachycardia. The lack of an HR increase and the progressive fall in supine BP in MSA and PAF patients, together with worsening orthostatic tolerance after MCP infusion, are effects that should strongly discourage the use of this drug in the treatment of OH.