Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function.
Atomoxetine, a selective norepinephrine transporter blocker, could increase blood pressure by elevating norepinephrine concentration in peripheral sympathetic neurons. This effect may be masked in healthy subjects by central sympatholytic mechanisms. To test this hypothesis we studied the pressor effect of 18 mg of atomoxetine (pediatric dose) in 21 patients with damage of the central (10 subjects) and peripheral (11 subjects) autonomic nervous system. Atomoxetine was administered in a randomized, crossover, placebo-controlled fashion, and blood pressure and heart rate were measured at baseline and for 60 minutes after drug intake. Atomoxetine acutely increased seated and standing systolic blood pressure in patients with central autonomic failure by 54+/-26 (mean+/-standard deviation; P=0.004) and 45+/-23 mm Hg (P=0.016), respectively, as compared with placebo. At the end of the observation period the mean seated systolic blood pressure in the atomoxetine group was in the hypertensive range (149+/-26, range 113 to 209 mm Hg). However, in patients with peripheral autonomic failure, atomoxetine did not elicit a pressor response; seated and standing systolic blood pressure increased by 4+/-18 mm Hg (P=0.695) and 0.6+/-8 mm Hg (P=0.546) with atomoxetine as compared with placebo. In conclusion, atomoxetine induces a dramatic increase in blood pressure in patients with central autonomic failure even at very low doses. These findings suggest that a functional central sympatholytic pathway is essential to avoid hypertension in patients treated with this drug. Caution should be exercised when this medication is used in patients with milder form of autonomic impairment.
Shibao
Cyndya
C
Department of Medicine, Division of Clinical Pharmacology, and the Autonomic Dysfunction Center, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Raj
Satish R
SR
Gamboa
Alfredo
A
Diedrich
André
A
Choi
Leena
L
Black
Bonnie K
BK
Robertson
David
D
Biaggioni
Italo
I
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000368:Aged; D000069445:Atomoxetine Hydrochloride; D001342:Autonomic Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000503:physiopathology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000097:blood; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D011187:Posture; D011437:Propylamines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D013599:Systole
D018759:Adrenergic Uptake Inhibitors; D018377:Neurotransmitter Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride