Phenylephrine Therapy to Treat Refractory Orthostatic Hypotension in a Patient with Parkinson’s Disease
Orthostatic hypotension (OH) is characterized by abnormal decrease in systolic blood pressure (BP) greater than 20 mm Hg or diastolic BP greater than 10 mm Hg when standing from a supine or sitting position. The symptoms of OH can include syncope, lightheadedness, clamminess, palpitations, diaphoresis, anxiety, visual changes, and nausea; these symptoms are resolved by sitting or lying down. Multiple factors can contribute to OH, and some of the common causes include medications such as antihypertensive and psychotropic drugs, hypovolemia, aging, deconditioning often caused by immobility leading to venous pooling, decreased vasoconstriction, and autonomic nervous system (ANS) dysfunction.1,2
ANS dysregulation due to Parkinson’s disease (PD) is one of the four different forms of primary autonomic failure, which include multiple system atrophy, pure autonomic failure, and dopamine beta-hydroxylase deficiency.3 In patients with PD, the prevalence of OH is estimated to be 20%.4 The high prevalence of OH in this particular population is mainly due to dopaminergic drugs worsening or inducing OH, and PD as a cause of OH involving autonomic system and decreased delivery of the neurotransmitter norepinephrine (NE) to vascular adrenoreceptors.5
It is believed that levodopa therapy also can cause OH. Levodopa converted to peripheral dopamine can have a hypotensive effect via vasodilation mediated by the systemic dopamine receptors and can displace the NE from the nerve terminals.6,7 The therapy of OH is directed against relieving the symptoms by treating the causes or, if nonresponsive to treatment, providing mechanisms to prevent injuries from falls. Given that these patients are taking chronic antiparkinsonian medications, which can cause OH, the management of OH in patients with PD can be complicated. There is no definite pharmacological therapy that has consistently alleviated symptoms in this patient population, and many patients find themselves unable to function—or even to stand up—because of their symptomatic burden.
We present a case of OH in a patient with PD undergoing carbidopa and levodopa therapy who responded to phenylephrine therapy, and discuss the likely pathophysiology of how the phenylephrine therapy was effective in treating this particular patient.
A 74-year-old man with PD presented to an outpatient Cardiology Clinic with a history of syncope/presyncope associated with lightheadedness, fatigue, and dizziness. He reported low systolic BP to the range of 50 to 60 mm Hg after physical activity, and this was documented on the abnormal tilt table test when his systolic BP dropped to 52 mm Hg without compensatory increase in heart rate. A previous echocardiogram and stress test have been normal.
The patient denied any chest pain, shortness of breath, or palpitations. Given the history of the PD, he has been on long-term carbidopa, levodopa, and amantadine therapy. His OH has been a long-term issue. Previously, he has worn surgical support stockings.
Prior to this visit, the patient tried midodrine and fludrocortisone, but reported no significant relief of symptoms; he stopped taking these medications due to a concern for increased resting BP. The rest of his home medications include simvastatin, clonazepam, levothyroxine, and aspirin/dipyridamole.
Vital signs on physical examinations showed sitting BP of 124/76 mm Hg and heart rate of 76 bpm, and standing BP of 80/60 mm Hg and heart rate of 84 bpm. Cardiac exam showed a regular rate, normal S1 and S2 with no jugular venous distention. The rest of the exam was unremarkable. The patient was prescribed a pair of moderate-compression support stockings and daily sodium chloride tablet, as well as being told to increase dietary salt intake.
During the return visit 2 months later, the patient was still noting presyncopal symptoms, and the post-exercise BP was reported to be 53/40 mm Hg. Fludrocortisone 0.1 mg once a day was added at that time, and approximately 1 month later, midodrine 10 mg was added for episodes of lightheadedness and documented OH in the office. Despite taking salt tablets, midodrine, and fludrocortisone, the patient’s sitting BP was 118/58 mm Hg and standing BP was 88/48 mm Hg, where he became lightheaded. Given the limited therapeutic options, his physicians added over-the-counter phenylephrine 10 mg every 4 hours, as it had recently become available.
During a follow-up visit 1 week after starting oral phenylephrine therapy, the patient reported marked improvement of his symptoms. Although he once had an episode of lightheadedness and fatigue in the morning with the lowest BP of 79/61 mm Hg, his usual range of systolic BP was from 90 to 140 mm Hg and diastolic BP from 60 to 90 mm Hg.
On physical examinations, his sitting BP was 116/72 mm Hg with a heart rate of 66 bpm, and the standing BP significantly was well maintained at 102/60 mm Hg with a heart rate of 62 bpm. While the home and office BP readings improved, the patient still had complaints of lightheadedness, although vastly improved. Subsequently, his aspirin/dipyridamole was discontinued, noting that it could also cause some drop in BP, and the patient’s symptoms improved further. During the subsequent 3 weeks, he self-discontinued the oral phenylephrine and had two episodes of syncope, which occurred when standing up from a prolonged period of sitting. When the patient restarted the oral phenylephrine, he did not have any more syncopal episodes and was able to resume a satisfactory lifestyle.
The management of OH in patients with PD is difficult because the effects of antihypotensive drugs such as alpha 1-adrenergic agonists (midodrine, phenylephrine), mineralocorticoids (fludrocortisone), vasopressins (desmopressin), and somatostatins (octreotide) have not been systematically studied in patients taking antiparkinsonian medications.8 Even though midodrine and fludrocortisone are often the first-line therapy and most commonly used, the response to these medications has been varied. This leaves most patients with absolutely intolerable OH.
With the literature on the positron-emission tomography (PET) study of 18F fluorodopamine uptake on patients with PD who have OH, which showed decreased concentrations of 6-18F fluorodopamine in the septal and lateral ventricular myocardium indicative of generalized sympathetic peripheral denervation and significantly lower plasma NE concentrations,9 we can hypothesize that the treatment of the OH with phenylephrine can work by itself or in combination with midodrine because it directly stimulates the alpha 1-adrenergic agonists in the postsynaptic denervated region caused by PD.
In addition, another study has shown a reduction of neurons in the thoracic spinal cord and the presence of Lewy bodies in sympathetic ganglia of patients with PD, suggesting that the neuronal loss in the sympathetic nervous system plays a role in the OH.10 Through vasoconstriction to raise the peripheral resistance as a response to the adrenergic activation, phenylephrine can target low NE state in patients with PD to treat hypotension, given that midodrine with its active metabolite desglymidodrine is limited by its short half-life.11 In addition, the vasoconstriction from phenylephrine can offset the effect of the peripheral dopamine, which results from the decarboxylation of levodopa to cause vasodilation and NE displacement at the synaptic sites.
Syncope/presyncope due to OH is a common complaint among patients with PD. A targeted therapy is needed for alleviation of symptoms with minimal side effects. In addition to the autonomic dysfunction of PD, the side effect of antiparkinsonian therapy often exacerbates or causes OH. This case describes a patient with PD who presented with a refractory OH who gained a significant benefit from the oral phenylephrine obtained over the counter. It should be emphasized that this is an unapproved use of this medication and that underlying causes of the OH should be thoroughly evaluated and other treatment options fully considered before taking this purely palliative approach. This case illustrates a role of an alpha-adrenergic agonist such as phenylephrine as an additional therapy for the symptomatic treatment of this growing population of patients, for whom there are limited other options to maintain a reasonable quality of life. Naturally, close attention must be directed to the potentially negative side effects of oral phenylephrine, such as hypertension and other cardiovascular issues. However, there are likely a growing number of patients, such as this case patient, who are truly unable to function with their orthostasis and for whom the benefits of this therapy, including a marked improvement in quality of life, might outweigh the risks.
The authors report no relevant financial relationships.
From the Department of Internal Medicine, Cardiology Division, University of Rochester Medical Center, Rochester, NY.