Effects of promethazine and midodrine on orthostatic tolerance

Astronauts experience both orthostatic hypotension and space motion sickness during re-entry. Midodrine, an alpha1-adrenergic agonist, is used to treat orthostatic hypotension. Promethazine, a histamine H1-receptor antagonist, is prescribed for space motion sickness. Many astronauts need both midodrine and promethazine. This study evaluated the interactive effects of midodrine and promethazine on hemodynamic responses to upright tilt.

Subjects (5 men; 3 women) were studied four times: control (no drug); midodrine only; promethazine only; or midodrine plus promethazine. Hemodynamic parameters, plasma norepinephrine, renin activity, and aldosterone were measured supine and upright.

Rates of presyncope were 38% with no drug; 0% with midodrine alone; 100% with promethazine alone; and 63% with both drugs. Supine to upright decreases in systolic pressure were greater with promethazine alone than control (P < 0.01); midodrine (P < 0.05) or both drugs (P < 0.05). Supine to upright increases in plasma norepinephrine, renin activity, and aldosterone all were significantly reduced with promethazine alone compared to control (P < 0.05, P < 0.05, P < 0.05) and midodrine alone (P < 0.05, P < 0.01, P < 0.01). Cardiac output fell more with promethazine alone than with no drug (P < 0.05) or with midodrine plus promethazine (P < 0.05).

Promethazine significantly increased the incidence of orthostatic hypotension in subjects, even when combined with midodrine. Inhibition of sympathetic responses, likely via enhancement of the inhibitive effects of GABA, by promethazine may underlie the increased orthostatic hypotension. Promethazine also appears to inhibit responses of the renin angiotensisn system during orthostatic challenge.