Orthostatic hypotension (OH) is a sudden, decrease in blood pressure
when a person assumes a standing position and is characterized by lightheadedness,
dizziness, blurred vision and syncope.
Causes for orthostatic hypotension can be cardiovascular, endocrine
or neurological in nature. Neurogenic OH (NOH) results from a deficient
release of norepinephrine, the neurotransmitter used by autonomic nerves
to send signals to the blood vessels and the heart.
Current Treatment
Midodrine is currently the only FDA approved therapeutic for the treatment
of orthostatic hypotension and does not specifically address neurogenic
orthostatic hypotension. Midodrine, originally developed by Shire
under the brand name ProAmatine, is
Midodrine (ProAmatine®) increases blood pressure, vasoconstriction, pupil dilation
Side effects include hypertension, piloerection,
US Annual Sales approximately $60 million
Shire, Mylan Pharmaceuticals, Eon Labs, Impax Laboratories
Fludrocortisone (Florinef®)
Retains Na+ in blood stream
Simply adds volume
Not FDA approved for this indication
Side effects include hypertension, water & sodium retention,
K+ loss
We estimate that nearly 300,000 patients suffer from chronic, symptomatic
neurogenic orthostatic hypotension in the US and EU. This condition
is commonly associated with Parkinson's Disease, Pure Autonomic Failure
(PAF) and Multiple System Atrophy (MSA), a name that encompasses disorders
previously known as striatonigral degeneration, olivoponto-cerebellar
atrophy and the Shy-Drager syndrome. (top)
Intra dialytic hypotension, or IDH, is the most common adverse event
during routine hemodialysis. IDH is often defined as a decrease in
systolic blood pressure by
³
20 mm Hg or a decrease in mean
arterial pressure by 10 mm Hg. IDH has been reported in approximately
25% of all hemodialysis patients, with elderly patients reporting higher
incidences. Many adverse hemodialysis events, including headaches,
lightheadedness, nausea, cramps, and seizures, are associated with
IDH. These complications can routinely interrupt dialysis sessions,
resulting in insufficient uremia toxin removal and necessitating repetition
of the procedure. Interruptions due to IDH increase the costs of both
the dialysis treatment sessions and the long-term care of less healthy
hemodialysis patients. Pivotal clinical studies conducted by DSP have
demonstrated the efficacy of droxidopa in the prevention of vertigo,
dizziness and weakness associated with hypotension in hemodialysis
patients. Subsequently, in 2000, after showing benefit in clinical
trials, DSP received expanded marketing approval in Japan for this
indication. We plan to initiate a clinical trial with droxidopa in
IDH prior to the end of 2007. (top)
Hypotension Associated with Fibromyalgia and Chronic Fatigue Syndrome
Independent clinical studies and ongoing research suggest that defects
in the autonomic nervous system - such as altered norepinephrine levels
and activity - may play a role in either the underlying cause or exacerbation
of the symptoms associated with multiple diseases commonly grouped
as dysautonomias. These indications include: chronic pain, urinary
stress incontinence, postural orthostatic tachycardia syndrome, neurocardiogenic
syncope, fibromyalgia and chronic fatigue syndrome.
Scientists and physicians have suggested a strong
association and/or significant correlation of symptoms between low
blood pressure (caused by either NOH or neurally mediated hypotension
(NMH)) and two specific dysautonomias, fibromyalgia
(FM), and chronic fatigue syndrome (CFS). Unlike OH, which is a problem
with blood pressure regulation immediately after standing, NMH is characterized
by a drop in blood pressure only after standing for long periods of
time. NMH occurs due to a miscommunication between the heart and brain
resulting in a failure to maintain appropriate increases in heart rate
after standing for prolonged periods. This is believed to be a problem
related specifically to deficient nerve function in the left ventricle
that prevents the heart rate from increasing when needed. Instead of
increasing, the heart rate actually drops, preventing the necessary
amount of blood from being circulated. This leads to NMH symptoms like
dizziness and fainting, which are often seen in patients with FM, CFS
and other dysautonomias. As norepinephrine naturally regulates both
heart rate and vasoconstriction, droxidopa could be an appropriate
alternative therapy to treat these specific symptoms by enhancing
the body’s
ability to naturally regulate these functions. Further studies will
be needed to determine the contribution of either NMH or NOH to other
major components of autonomic diseases such as pain, fatigue, weakness,
and incontinence. Furthermore, randomized trials will be needed to
indicate whether droxidopa improves the hypotension and whether this
in turn shows benefit in additional symptomology within these disease
syndromes.
