Multiple System Atrophy Medication

Updated: Oct 26, 2022
  • Author: André Diedrich, MD, PhD; Chief Editor: Selim R Benbadis, MD  more...
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Medication Summary

As previously mentioned, pharmacologic therapy for multiple system atrophy (MSA) is directed mainly toward alleviation of symptoms of the movement disorder and orthostatic hypotension (see Table 9, below). Medications can also be used to treat urinary incontinence, constipation, erectile dysfunction, and supine hypertension. In recent years, neuroprotective therapy has been successfully applied in the mouse model. [39] But studies in humans (e.g., rifampicin rasagiline) did not show beneficial effects on slowing down the disease. [40, 41] Transgenic MSA mouse models do not have the same human phenotype but may be the best choice to explore new therapies. [42]

Medical therapy of movement disorder

The movement-disorder component of MSA is usually treated with levodopa, dopaminergic agonists, anticholinergic agents, or amantadine, but results are rarely as favorable in MSA as in classic Parkinson disease.

Drugs that now are not commonly used in patients with MSA include nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, somatostatin analogues, and caffeine.

Medical therapy of orthostatic hypotension

Many agents have been advocated for the management of orthostatic hypotension. Table 9, below, shows some of the most widely used drugs. However, drug therapy of orthostatic hypotension is limited by supine hypertension, which affects about 60% of patients with MSA. [43]

In February 2014, droxidopa was approved by the FDA for the treatment of orthostatic hypotension. It is a synthetic amino precursor prodrug and is converted to norepinephrine. [44]

Water is a uniquely powerful pressor agent in the management of orthostatic hypotension in patients with MSA. It acts by increasing sympathetic activity. On average, 16 ounces of water will raise BP about 30 mm Hg. Patients may understandably be skeptical that something so commonplace could help raise their BP, so it does require patient education. No other beverage (not juice or coffee or even Gatorade) is as good as a pressor agent as water in patients with autonomic dysfunction. Its major limitations are a short (1-hour) half-life and increased urination (inconvenient when autonomic impairment makes urination difficult).

Patients should drink 16 ounces of water on awakening each morning, even before they get out of bed. Patients should learn to use water prophylactically; they will be able to do much more in the hour after ingesting water than at other times. A repeat dosing midmorning or at lunch and at midafternoon may give the patient additional capacity for activity during this part of the day. Conversely, since patients with autonomic failure commonly have supine hypertension, we discourage them from drinking large amounts of water within the 2 hours prior to bedtime, although we allow them to drink when they are thirsty.

Table 9. Drugs Used to Manage Orthostatic Hypotension in MSA (Open Table in a new window)



Description or Mechanism


Fludrocortisone (Florinef)

Mineralocorticoid; sodium retention, primarily in extravascular compartment, causes tissue edema to venous capacitance bed in lower extremity. With this edema, venous bed accommodates decreased volume of blood in an upright posture (high doses, late effect); increases sensitivity to norepinephrine (even with small doses)

Sympathomimetic amines


Alpha1-adrenoreceptor agonist acts directly on vasculature, causes venous and arteriolar vasoconstriction




Droxidopa is a synthetic precursor of norepinephrine. It acts by conversion to norepinephrine in the body.

Recombinant erythropoietin (EPO)

Epoetin alfa

Increases sensitivity to pressor effects of angiotensin II; increases plasma endothelin level; increases cytosolic free calcium in vascular smooth muscle; increases intravascular volume


Indomethacin, ibuprofen

Inhibition of vasodilator prostaglandins proposed but not proven


Diphenhydramine, cimetidine

Reduce vasodilatation caused by histamine release

Somatostatin analogs


Reduce splanchnic capacitance

Vasopressin agonists

Desmopressin (DDAVP)

Vasopressin analogs; no effect on V1 receptors, which are responsible for vasopressin-induced vasoconstriction; acts on V2 receptors on renal tubuli, which are responsible for antidiuretic effect; prevents nocturnal diuresis, raises BP in morning

Other sympathomimetics


Alpha2-adrenoreceptor antagonist


Adenosine receptor antagonist

Medical therapy of supine hypertension

The presence of supine hypertension can complicate the pharmacologic management of patients with MSA, but a rational approach to its treatment is often successful. Simply avoiding the supine position is often enough to control hypertension during the day. Treatment of supine hypertension is required at night. Elevating the head of the bed is useful but rarely sufficient. Short-acting vasodilators are effective in controlling hypertension.

The management of patients with orthostatic hypotension and supine hypertension can be challenging, but adequate BP control is often achieved by combining the nonpharmacologic approach, as previously described, with the following medications:

  • Nitrates, transdermal nitroglycerin (0.1–0.2 mg/h)

  • Hydralazine (50 mg)

  • Nifedipine; short-acting calcium blocker (10-30 mg)

  • Clonidine (0.1 mg), early in the evening [45]


Antiparkinson Agents, COMT Inhibitors

Class Summary

Patients with MSA may have an initial response to levodopa, but this response usually diminishes over time. Withdrawal of levodopa can cause a patient's condition to deteriorate, but this is much more prominent in Parkinson disease than in MSA. In modern practice, levodopa is administered in combination with a dopa decarboxylase inhibitor.

Levodopa/Carbidopa (Sinemet, Parcopa)

In this combination, levodopa is administered with a dopa decarboxylase inhibitor. When levodopa is administered alone, it is largely decarboxylated by the intestinal mucosa or other peripheral sites rich in monoamine oxidase (MAO), and little reaches the cerebral circulation and CNS.


Antiparkinson Agents, Dopamine Agonists

Class Summary

These agents are used as alternatives to levodopa therapy in the late phase of the movement disorder. They selectively act on different subtypes of dopamine receptors throughout the brain. The mechanism through which dopaminergic agonists act is independent of the functional capacities of the striatonigral neurons and may be more effective than those of other drugs.

Bromocriptine (Parlodel, Cycloset)

Bromocriptine is a strong agonist of D2 and a partial agonist of D1 striatal dopamine receptors.


Amantadine may alter dopamine release or reuptake and actions at glutamate receptors.


Antiparkinson Agents, Anticholinergics

Class Summary

These agents were widely used before levodopa was discovered.


Trihexyphenidyl is an anticholinergic receptor agent affecting structures in the neostriatum.

Benztropine mesylate (Cogentin)

Benztropine mesylate is an anticholinergic receptor agent affecting structures in the neostriatum.


Urinary Antispasmodic Agents

Class Summary

When detrusor hyperreflexia is the cause of a patient's urinary incontinence, peripherally acting anticholinergic agents (eg, oxybutynin chloride [Ditropan], tolterodine [Detrol], propantheline [Pro-Banthine]) can be applied.

Oxybutynin chloride (Ditropan XL, Gelnique, Oxytrol)

Oxybutynin chloride, a tertiary amine muscarinic receptor antagonist, is a nonspecific relaxant on smooth muscles.

Tolterodine (Detrol, Detrol LA)

Tolterodine is a competitive muscarinic receptor antagonist for overactive bladder. It differs from other anticholinergics by being selective for the urinary bladder over the salivary glands. Tolterodine has high specificity for muscarinic receptors and has minimal activity or affinity for other neurotransmitter receptors and other potential targets (eg, calcium channels).


Propantheline blocks the action of acetylcholine at postganglionic parasympathetic receptor sites.


Prokinetic Agents

Class Summary

If a special bulk-forming diet fails, lactulose occasionally is helpful. In rare cases, cisapride (Propulsid) may promote bowel movements, but this agent has been removed from the US market because of risk of cardiac rhythm disturbances.

Erythromycin (E.E.S., Ery-Tab, Erythrocin)

Erythromycin is a macrolide antibiotic that duplicates the action of motilin. By binding to and activating motilin receptors, it is responsible for migrating motor complex activity. IV administration enhances the emptying rate of liquids and solids. The effect can also be seen with oral erythromycin. The enteric-coated form may be the most tolerable. However, erythromycin's benefit as a prokinetic agent is usually marginal in MSA.


Agents for Erectile Dysfunction

Class Summary

MSA may respond to yohimbine with BP elevation, but male erectile dysfunction only occasionally improves. Yohimbine (Yohimex, Yocon) should be given at a dose of 5.4 mg 3 times a day for the purposes of blood pressure elevation. Yohimbine has a very limited ability to improve erectile dysfunction in MSA and can dangerously elevate blood pressure when given with acetylcholinesterase inhibitors such as pyridostigmine. If adverse effects are a problem, the dose can be reduced to half a tablet 3 times a day and gradually increased to 1 tablet 3 times a day. The effect of sildenafil (Viagra) has not been determined in patients with autonomic failure. Other approaches include the use of mechanical devices, pumps, penile prostheses, or implants.

Yohimbine (Yohimex)

Yohimbine blockades alpha2 receptors in the pontomedullary region of the CNS, increasing sympathetic outflow.



Class Summary

Specific agents in this class have salt-retaining (mineralocorticoid) properties.


Fludrocortisone has been a mainstay of pressor therapy for the last 50 years. It is a powerful mineralocorticoid that is largely devoid of a glucocorticoid effect when it is administered in low to moderate doses (0.1-0.3 mg). This agent can initially increase blood volume, which tends to normalize after the first week. Most patients gradually (over 2 wk) gain weight (usually 5-8 lb), with mild ankle edema occurring as a result of sodium retention, primarily in the extravascular compartment.

Much of the drug's benefit depends on support from tissue edema to the venous capacitance bed in the lower abdomen and extremities. With edema, the venous bed accommodates only a low volume of blood in the upright posture. The effect, in turn, improves blood return to the heart and, therefore, functional capacity. In addition to its direct effect through extravascular fluid accumulation, fludrocortisone increases alpha1-adrenoreceptor sensitivity by about 50%. During therapy, the renin-angiotensin system is suppressed (as expected).


Alpha1 Agonists

Class Summary

These agents may reduce sympathetic outflow, which may reduce muscle tone.


Midodrine is a prodrug with activity as an alpha1-adrenoreceptor agonist. This agent is widely used to treat orthostatic hypotension in MSA. Midodrine acts directly on the vasculature to increase BP and avoids electrolyte abnormalities associated with fludrocortisone. However, supine hypertension is a significant problem and limits the enhancement of functional capacity in MSA. Midodrine has often caused an unpleasant sensation in the scalp (due to piloerection).


Alpha/Beta Adrenergic Agonists

Class Summary

These agents augment coronary and cerebral blood flow. Agents such as ephedrine have been used in patients with MSA and share with midodrine the possible complication of excessive supine hypertension. The advantage of these short-acting vasopressors is that they can be given during the day if the patient does not lie down for 3-4 hours after taking them. A late-afternoon dose should be avoided if possible.

Droxidopa (Northera)

Droxidopa is an oral norepinephrine precursor that is directly metabolized to norepinephrine by dopa-decarboxylase which is extensively distributed throughout the body. Peak droxidopa plasma concentrations are associated with increases in systolic and diastolic blood pressures. Droxidopa has no clinically significant effect on standing or supine heart rates in patients with autonomic failure. It is indicated for symptomatic neurogenic orthostatic hypotension (NOH) in patients with primary autonomic failure caused by diseases and conditions (eg, Parkinson disease, multiple system atrophy, and pure autonomic failure, dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy).


Ephedrine is a sympathomimetic amine. It is an alpha- and a beta-adrenergic agonist and a peripheral vasoconstrictor.


Hematopoietic Growth Factors

Class Summary

These agents correct anemia associated with MSA.

Epoetin alfa (Epogen, Procrit)

This is a recombinant EPO that has been shown to increase the functional capacity of patients with MSA, particularly those with characteristic mild anemia. Up to 38% of patients with severe autonomic failure have anemia. A lack of sympathetic stimulation may lead to decreased EPO production and anemia. Sympathetic impairment and low plasma norepinephrine levels are correlated with the severity of anemia.

Even low doses (25-50 U/kg SC 3 times weekly) of epoetin alfa have successfully corrected anemia and improved upright BP. The drug's biologic activity mimics that of human urinary EPO, which stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the bloodstream.


Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Indomethacin (Indocin)

Indomethacin inhibits vasodilator prostaglandin synthesis.



Class Summary

These agents prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.

Diphenhydramine (Benadryl, Diphenhist)

Diphenhydramine is a first-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and body. It competitively blocks histamine from binding to H1 receptors.

Diphenhydramine affects structures in the neostriatum. It has significant antimuscarinic activity and penetrates the CNS, giving the drug a pronounced tendency to induce sedation. Approximately half of patients treated with conventional doses have some somnolence.