Treatment of orthostatic hypotension in Parkinson’s disease

Orthostatic hypotension (OH) is common in Parkinson’s disease (PD) and 30-50% of patients suffer with it.^1-2 OH can be symptomatic or asymptomatic and according to Palma et al 16% of these patients with OH are symptomatic.³

Those patients with symptoms will feel dizziness, unsteadiness and light-headedness on standing up leading to a fall and possibly loss of consciousness. They can also complain of fatigue and pain in the neck and shoulders called coat hanger pain when they are up and about. Characteristically these symptoms get better on sitting down. It is uncommon to have symptoms of OH while sitting down.

Symptoms of cerebral hypo-perfusion emerge when blood pressure (BP) standing falls below the lower limit of the cerebral auto-regulatory range and this usually occurs when mean BP standing is <75mmHg, which corresponds to ~90/60mmHg (systolic/diastolic) at the heart level.³

These symptoms can lead to recurrent falls, significant morbidity, at times and mortality and can effect activities of daily living.^4,5 On the other hand, a significant proportion of patients with OH will have supine hypertension (SH), defined as a systolic BP 150mmHg and diastolic BP 90mmHg and can lead to end organ damage and is a limiting factor in the treatment.⁶ Hence it is important to actively look for these autonomic changes in PD and manage them accordingly.

Mechanism of orthostatic hypotension and supine hypertension

In PD, OH is considered to be a neurotransmitter disorder as degeneration of postganglionic efferent sympathetic neurons lead to impaired release of norepinephrine and defective vasoconstriction on standing up, hence low blood pressure.³

The mechanism for SH is unclear. Increased vascular resistance due to residual sympathetic activity has been suggested in Multisystem Atrophy (MSA).⁷

Clinical approach to Parkinson’s disease patients with supine hypertension

Correct diagnosis of OH can only be possible with screening all PD patients with proper lying BP and then immediate standing and three minutes standing. Patient should have rested lying down for 10 minutes before lying BP is taken. By definition OH is a sustained reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of 10mmHg, or both, within three minutes of standing or head-up tilt to at least 60°C on a tilt table.⁸

If three minutes standing is not diagnostic then the screening should be prolonged to 10 minutes standing. If these measurements are not helpful in diagnosing and patient has got symptoms of OH then home BP monitoring or 24 hours BP monitoring can be informative and it will also be valuable in diagnosing post prandial hypotension and supine hypertension.

Prolonged tilt table test at times needs to be done to diagnose and in specialist centres autonomic reflex testing, plasma fractionated catecholamine levels and sudomotor function testing can be asked for the diagnosis.⁹ Orthostatic Hypotension Questionnaire has been validated since 2012 and will provide further evidence.¹⁰

Treatment of orthostatic hypotension

Medication review

The first important step in the treatment should be to review PD patients’ medications. Anti-hypertensive especially diuretics and vasodilators, alpha blockers for urinary symptoms and antidepressants are commonly responsible for OH. Also antiparkinsonian medications can lower BP so there doses should be adjusted accordingly.

Physical measures

Patients should be counselled to:

• Put extra salt in diet (6-10gm/day)
• Intake of at least 2 litres of fluid per day
• Taking boluses of 500mls of very cold water
• Stand up slowly from lying and sitting position and cross legs when sitting
• Sleep with head of the bed raised to 45°
• Avoid large sugary meals with alcohol as it can cause post prandial hypotension and divide the meals into 4-5 smaller meals.
• Abdominal binders have been shown to be effective by reducing splanchnic venous pooling¹¹ but knee high compression stocking are cumbersome for older patients hence not effective.¹²

Pharmacological measures

If medication review and physical measures are not effectively controlling OH then consideration should be given to the pharmacological measures. One of the therapeutic challenges will be SH as Palma et al study showed that 44% of PD patients has supine BP greater than 140/90 mmHg.³ Another study showed that 71.1% of PD patients with OH had no proper circadian rhythm as compare to that of the control population (48%). The prevalence of the non-dipper or riser patterns was higher in patients with orthostatic hypotension (77.8 vs. 66.7%).¹³

Choice of pharmacological agents should be tailored according to patient’s needs, comorbidities and potential side effects of those medications.

Fludrocortisone is a synthetic mineralocorticoid and increases renal sodium and water absorption hence expanding the intravascular volume and helping in OH. It takes 7-10 days to cause its clinical effect. It is advised that the dosage should never be more than 0.2mg/day because it doesn’t increase the efficacy of the drug and causes side effects with hypokalemia, ankle oedema and worsening of heart failure¹⁴ and long term use is associated with higher risk of hospitalizations in patients with OH.¹⁵

Midodrine is an adrenoceptor agonist and causes vasoconstriction leading to increase in BP. Treatment should begin with small dose of 2.5mg three times a day and can be increased later on until 10mg three times a day. It is well tolerated with usual side effects of pilo-erection, itching of scalp and urinary retention. It is best taken before getting out of bed, around midday and mid-afternoon, avoiding it before going to bed as there is risk of SH.

Droxidopa is a noradrenaline precursor that is converted into noradrenaline by the dopa-decarboxylase. Droxidopa has been shown to be to improve OH symptoms with one to two weeks treatment in PD patients in placebo controlled trials^16,17 and a recent paper of Francois et al showed that fewer OH patients reported falling after one, three, and six months of droxidopa treatment and further improvements reported in OH symptoms, physical function, and QOL measures were maintained for six months following treatment initiation.¹⁸

The starting dose is 100mg three times per day and can be titrated to 1800mg per day. It is now approved for OH in United States for PD, MSA and pure autonomic failure but not yet available in Europe.

DOPA decarboxylase inhibitors (DDCI, eg. carbidopa) can block the conversion of droxidopa to norepinephrine and decrease theoretically the efficacy of droxidopa but more studies are needed specifically to address this issue. In practice, patients receiving droxidopa still had an increase in their blood pressure and symptomatic improvement when taking DDCI at clinically indicated dosages.

Atomoxetine is a norepinephrine reuptake inhibitor and increases the availability of norepinephrine at the neurovascular junction. Small trials have shown it to be effective in PD but more so in pure autonomic failure¹⁹ and in fact superior in improving upright systolic BP and symptoms related to OH when compared with midodrine.²⁰

Pyridostigmine, a cholinesterase inhibitor has got modest effect and at times is combined with midodrine or atomoxetine but has got lot of gastrointestinal side effects.²¹

Yohimbine, dihydroergotamine and psuedoehpedrine are rarely used now a days because of their side effects profile. There are also anecdotal evidence for domperidone use in OH but QT prolongation should be considered beforehand.²²

Recombinant Erythropoietin for the patients with anaemia has a positive influence on OH with improvement in anaemia and increases blood pressure.²³

Treatment of supine hypertension

Treatment for SH can be challenging but patients should avoid napping in supine position in the daytime and presser agents like midodrine should be preferred as compare to fludrocortisone and the last dose administration should be no later than 4pm. At night tilting up of the bed 30-45°C lowers the BP.

A snack before going to bed with alcohol can lower the BP. Pharmacological intervention for high BP overnight can be considered and should be in form of short acting anti-hypertensive like losartan, GTN patch or clonidine.^24,25 One needs to be mindful about the effect of these anti-hypertensive in the daytime because they can cause OH.

Conclusion

Orthostatic hypotension is common in Parkinson’s disease. It can impair the quality of life and can lead to falls, morbidity and mortality. Its only when we are actively looking for it by doing proper lying and standing BP that we can diagnose it. Different treatment options are available and should be used to reduce the burden of illness as Parkinson’s.

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Dr Jazia Rasheed, Associate specialist, Frailty Assessment unit, Yeovil hospital Foundation trust, Yeovil, Somerset.

Dr Waseem Ahmad Bashir, consultant geriatrician, care of older people, Yeovil hospital Foundation trust, Yeovil, Somerset.

Dr Rani Sophia, consultant geriatrician, Frailty Assessment unit, Yeovil hospital Foundation trust, Yeovil, Somerset.

[email protected]

Conflict of interest: none

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