B A S I C S

BASICS OF COMPOUNDING for

Raynauds Disease
Andrew Glasnapp, BS, PharmD, FIACP
Professional Compounding Centers of America
Houston, Texas

Introduction
Raynauds disease (RD) is idiopathic, paroxysmal bilateral
cyanosis of the digits due to arterial or arteriolar contraction.
First described by Maurice Raynaud in 1883, it remains a medical mystery to this day. 1 Raynauds phenomenon (RP) is a syndrome manifested by attacks of pallor (paleness of the skin)
and cyanosis (bluish discoloration of the skin) of the digits in
response to cold or emotion; when the attack subsides, redness
replaces the paleness and bluish discoloration of the digits. 2
RD is idiopathic and can only be diagnosed when secondary
causes have been excluded; 1 whereas RP is due to secondary
causes. RD is the most common cause of RP, accounting for
60% of such cases. 2 Although RD can begin at any age, it is
most common between the ages of 20 and 40 years and is more
common among women than men.

Etiology
Raynaud believed that RD was caused by increased sympathetic nerve activity. However, it has been reported that sympathetic nerve traffic in the median nerve is no different in
patients with RD than in normal individuals and that attacks
of RP could be induced after interruption of the sympathetic
nerves. 2 It has also been concluded that the cause of the disorder is a fault in the arterial wall that renders the vessels hyperresponsive to the vasoconstrictive effects of cold. 2 It has been
proposed that accelerated destruction of platelets and release
of agents such as serotonin or thromboxane A 2 are the cause of
vasoconstriction in some patients with RP. 2 However, it is not
known whether platelet destruction is the cause of spasms in
patients or a consequence of them. In one study, 2 26% of patients with angina pectoris were found to have migraine; and
24% were found to have RP. Some patients with RP may have
a generalized defect that predisposes arteries in many regions
to vasospasm. An association of RP with idiopathic pulmonary
hypertension has also been suggested. This association may reect a very high level of peripheral vascular tone secondary to
the severe reduction in cardiac output.
RP is observed frequently and may be caused by:
Occlusive arterial disease
Note: Occlusive arterial disease may be caused by arteriosclerosis
obliterans, Buergers disease, arterial embolism vasculitis or arterial thrombosis.
Connective-tissue diseases

288

International Journal of Pharmaceutical Compounding

Vol. 7 No. 4 July/August 2003

Note: Connective-tissue diseases may be caused by scleroderma

(almost all patients with scleroderma develop RP during the
course of their illness 2 ).
Vascular injury
Neurogenic causes
Note: Included in neurogenic causes are carpal tunnel syndrome,
sympathetic causalgia and spinal-cord diseases.
Drugs
Exposure to chemicals, or intravascular coagulation or
aggregation
Rheumatoid arthritis
Systemic lupus erythematosus
RP may be the presenting manifestation in connective-tissue
diseases and may precede the appearance of other manifestations by several years. 2 Smoking, beta-adrenergic blocking
agents, ergots, sympathomimetics, imipramine or clonidine
exposure may precipitate an RP attack. The most common
chemical precipitating factors are smoking and the use of betablockers. Trauma to the digital areas, frequent use of the hands
or use of heavy, vibrating machinery are other commonly associated conditions or contributing factors to RP. 1

Pathophysiology
The pallor of the skin during an attack of RP is explained by
intense vasoconstriction or spasm of the digital arteries. This
Continuing Education
GOALS AND OBJECTIVES
Basics of Compounding for Raynauds Disease
Goal: The goal of this presentation is to provide compounding pharmacists with supportive information on Raynauds disease (RD) and
Raynauds phenomenon (RP) and to provide compounded medications that may benet the treatment of RD and RP.
Objectives: After reading and studying the article, the reader will be
able to:
1. Describe RD and RP and their typical symptomatology.
2. Discuss the etiology of RD and RP.
3. List the typical screening questions related to RP.
3. Describe the prognosis of RD.
4. Discuss the treatment recommendations for RD and RP.
5. List the drugs of choice for the treatment of RD and RP,
including those that can be compounded.
To complete this continuing education program, go to www.ijpc.com. The
program is presented by the IJPC in partnership with P*ceutics Institute @
PCCA, which is accredited by the American Council on Pharmaceutical
Education as a provider of continuing pharmaceutical education. Upon
successful completion of 70 percent of the questions and completion
of the evaluation, an ACPE statement of credit for one (0.1 CEUs)
credit will be immediately available for printing. The cost is $15.

B A S I C S

Table 1. Drugs of Choice for the Treatment of RD and/or RP.

Drug

Recommended Dosage

Comments

Diltiazem

Oral dose of 60 mg
3 or 4 times daily
Oral dose of 10 mg to 20 mg
3 or 4 times daily; may also
be applied topically in
a transdermal vehicle
High doses of nitroglycerin
ointment (3.5 inches)
3 times daily for 6 weeks
Oral dose of 1 mg
3 times daily

Diltiazem may be substituted if nifedipine is not well tolerated or if side effects (ie, headache,
dizziness, peripheral edema) occur from the use of nifedipine.
Nifedipine has been found to be effective and beneficial for two thirds of patients
undergoing treatment for RD or RP. If side effects (ie, headaches, dizziness or peripheral
edema) occur or if nifedipine is not well tolerated, diltiazem may be substituted for nifedipine.

Nifedipine

Nitroglycerin

Nitroglycerin is a direct-acting vasodilator and has been applied to the hands of Raynauds
patients since the mid-1940s. 1 The preferred dosage shown has resulted in fewer and less
severe attacks. However, side effects severely limit the use of nitroglycerin.
Prazosin
Prazosin is an adrenergic antagonist that has been used as a treatment for RD patients.
Prazosin may produce moderate benefit in two thirds of RD patients, but the drug has significant
side effects (ie, dizziness, edema, fatigue, orthostasis). 1
Reserpine
Oral dose of 0.1 to 0.5 mg
Reserpine is the most-studied of a group of drugs that interferes with the function of the
daily
adrenergic nervous system. Nasal congestion, postural hypotension, and fatigue are some of
the possible side effects associated with this group of drugs.
Triiodothyronine
75 g daily
The administration of triiodothyronine induces vasodilation in the digits via the iatrogenic
induction of hyperthyroidism. The resultant hypermetabolism elicits thermoregulatory reflex
cutaneous vasodilation. This therapy should be reserved for patients who have frequent attacks
with active painful ulcers and who have not responded to other therapies.
RD = Raynauds disease
RP = Raynauds phenomenon
mg = milligram
g - microgram

vasoconstriction or spasm results in severe reduction in blood

ow. In a later stage of the attack, the vasoconstriction becomes less severe, the capillaries and veins are partially lled
with blood and hemoglobin becomes markedly deoxygenated.
This accounts for the cyanosis. Upon rewarming of the skin,
cyanosis is replaced by an intense red color, which is associated
with reactive hyperemia. Between attacks, blood ow to the
digits is usually reduced, especially in patients who have trophic changes (a result of the interruption of nerve supply), but
blood ow may be normal in some patients. In those patients
without trophic changes, blood ow to the hand during maximum vasodilation is the same as in normal individuals but is
severely reduced in those with trophic changes, which is a reection of structural changes in the blood vessels. 2 In the early
stages of RP, the digital vessels are histologically normal. In
long-standing cases, the intima becomes thickened; and the
media may be hypertrophied. In severe progressive cases, complete obstruction from thrombosis may occur; and gangrene of
the tips of the digits may ensue. 2

Clinical Manifestations
The onset of RD is usually gradual. The patient notices an
occasional mild, short-lasting attack during the winter months.
Over succeeding years, the severity and duration of the attacks
may increase. A wide variation in severity is present. Most
commonly, the attacks are provoked by exposure to cold. In
some patients, attacks are also precipitated by emotion. The
attacks may be terminated by rewarming, or they may abate
spontaneously. Between attacks, in a warm environment, the
patient is asymptomatic; and physical examination shows no

abnormalities. However, some patients complain of chronically

cold hands and feet; and they may have cold ngers with
cyanosis on examination. In a typical attack of RP, the digits
become pale. Usually, all digits are affected symmetrically. The
pallor is sharply demarcated at the level of the metacarpophalangeal joints, which is a reection of spasm of the digital arteries. At a later stage during the attack, pallor is replaced by
cyanosis. The patient may have feelings of coldness; numbness; and, occasionally, pain. Upon rewarming of the skin, the
cyanosis is replaced by intense redness, and the patient may
feel tingling or throbbing. Most commonly, only the hands are
affected. Frequently, both the hands and the feet are affected.
Rarely are the nose, cheeks, chin or ears affected.

Diagnosis
RP can usually be diagnosed on the basis of the history of vasospastic attacks in the digits, precipitated by cold and relieved
by warming. Pharmacists may wish to ask their patients a few
screening questions, such as:
Are your ngers unusually sensitive to cold?
Do your ngers change color when they are exposed to cold
temperatures?
Do your ngers turn white, or blue or both white and blue?
The diagnosis of RP is conrmed by a positive response to
all three questions. 3
Differentiating RD from RP is based mainly on the exclusion
of disorders known to cause RP. Pharmacists may wish to review the patients medication prole to exclude the use of
chemotherapeutic agents, interferon, estrogen, nicotine,
narcotics, sympathomimetic agents, cyclosporine, cocaine,

International Journal of Pharmaceutical Compounding

289
Vol. 7 No. 4 July/August 2003

B A S I C S

Table 2. Nutritional Supplements That May Safely Reduce the Severity and Frequency of Attacks Resulting From RD and/or RP.
Drug

Recommended Dosage

Comments

Calcium

1500 mg daily

Coenzyme Q 10

100 to 200 mg daily 4

Lecithin

1200 mg 3 times daily,

taken with meals
750 mg daily 4

Calcium may be taken to reduce the severity and frequency of attacks. Calcium protects the
arteries from stress caused by sudden blood-pressure changes.
Coenzyme Q 10 is an over-the-counter drug that, when taken at proper dosages, improves
tissue oxygenation.
Lecithin helps lower blood lipid levels.

Magnesium
Vitamin E

Zinc

Magnesium may be taken to reduce the severity and frequency of attacks. Magnesium protects
the arteries from stress caused by sudden blood-pressure changes.
Vitamin E improves circulation and acts as an anticoagulant.

200 IU daily to begin,

increased slowly to
1000 IU daily 4
50 mg daily 4

Zinc is among a group of other important supplements that may be included in a patients
therapy to reduce the severity and frequency of attacks. Zinc protects the arteries from stress
caused by sudden blood-pressure changes. 4
RP = Raynauds phenomenon
IU = international units

RD = Raynauds disease
mg = milligram

polyvinyl chloride, ergotamine derivatives or clonidine. 3

The patient should also be questioned about environmental
exposure and possible injury such as frostbite, repetitive

Ductless Fume Hoods and

Laminar Flow Workstations
Maximum protection from
powders and vapors

NO DUC
NO INSTATWORK
LLAT
COSTS

ION

Safe
Portable
Cost effective

MISONIX
1-800-645-9846

1938 New Highway

Farmingdale, NY 11735
www.misonix.com

290

International Journal of Pharmaceutical Compounding

Vol. 7 No. 4 July/August 2003

occupational stress (hand-arm vibration syndrome) and carpal

tunnel syndrome. Patients who have normal ndings on review
of their medical history and physical examination, no digital
lesions or gangrene and normal nail-fold capillaries do not
need to undergo specialized studies and can be diagnosed with
RD. 3 Other patients should be referred to their physician for
further studies and subsequent diagnosis.

Prognosis
The prognosis of patients with RD is good. There is no mortality associated with the disease, and morbidity is low; it is
generally limited to the loss of portions of digits as a result of
ulcerations. In approximately 50% of patients with RD, the
disorder improves and may disappear completely after several
years. 2 In fewer than 1% of patients diagnosed with RD, an
amputation is necessary. 2 Approximately 15% of patients diagnosed with RP eventually develop a connective-tissue disorder,
particularly scleroderma.

Treatment
The management of patients with RP must be tailored to the
individual needs of the patient, and the frequency and severity
of the attacks should be taken into consideration. These patients should be taught to recognize and terminate attacks. All
patients benet from protective measures against exposure to
cold. RP patients should:
Limit the duration of exposure to cold as much as possible.
Wear heavy clothing to protect not only the hands and feet
but also the face and trunk, especially when there is a cold
wind. This is important because exposure to cold of other
portions of the body may induce vasoconstriction in the
digits and precipitate RP.
When prolonged exposure to cold is unavoidable, the use
of electrically powered or solid fuel-powered hand and foot
warmers is advisable. If the patient has been unavoidably

B A S I C S

exposed to cold temperatures, he or she should:

Return promptly to a warm environment.
Place the hands in warm water (110F), which will
induce vasodilation and has been reported 2 to raise skin
temperature and minimize the severity of attacks of RP, or
use a hair dryer to warm the hands rapidly.
These simple measures will usually suffice for patients with
infrequent or mild attacks. However, when RP is more frequent or more severe, and when the disease has resulted in
trophic changes or ulcerations, these measures need to be supplemented by drug therapy. The goal of drug therapy is to induce vascular smooth-muscle relaxation, which should relieve
spasms, raise resting blood ow and limit the degree of ischemia during attacks. For most patients, the drug of choice is
a calcium antagonist. Table 1 lists the drugs of choice for the
treatment of RD and/or RP and furnishes comments and preferred dosages. Reserpine, guanethidine and methyldopa are
among the group of drugs that interfere with the function
of the adrenergic nervous system. Reserpine is the best studied
(see Table 1). This group of drugs causes signicant side
effects, including nasal congestion, postural hypotension
and fatigue.
It is uncertain whether niacin is benecial in the treatment
of RD and/or RP, as the benets are dependent upon the patients concomitant disease state. For example, a patient who is
being treated for hypercholesterolemia and RP will likely have
dual benet from the addition of the vasodilating effects of
niacin. In contrast, a patient with diabetes mellitus may not
benet from niacin treatment due to the risk of losing glucose
control. Topical prostaglandin E 2 (PGE 2 ) has been found to be
effective in RP. 2 The topical application is advantageous because the local relaxant action is not counteracted by reex
vasoconstriction, secondary to changes in blood pressure that
may occur when PGE 2 is given systemically. 2
Nutritional supplementation may play a safe and important
role in reducing the severity and frequency of RD and/or
RP attacks. Table 2 provides a list of the nutritional supplementations that may be more benecial. Other nutritional
supplementation that may be taken to reduce the severity and
frequency of RD and/or RP attacks are dimethylglycine,
axseed oil, inositol and vitamin B complex. 4 Table 3 provides
sample formulations for the treatment of RD.

Recommendations
There are no formal guidelines for the evaluation and
treatment of patients with RP. However, any patient who presents with RP should be assessed for signs and symptoms suggestive of a secondary cause. 2 Patients presenting before the
age of 20 years who have no symptoms or signs of a secondary
cause can be followed without undergoing other specialized
tests. Initial management should include the avoidance of cold
temperatures. Drug therapy should be added only if the attacks
are poorly controlled and disabling. Calcium-channel blockers
are the rst line of therapy. Nifedipine is the drug of choice
and may be given orally or transdermally. 2 Doses should be
increased until benet is noted or until a maximal tolerated
dose is reached. Treatment of any underlying autoimmune

Table 3. Sample Formulations for the Treatment of RD.

Nifedipine in PLO Gel
Rx
For 100 mL
Nifedipine
Propylene glycol
Lecithin:isopropyl palmitate (1:1)
Pluronic F127, 20% gel
qs
Nitroglycerin 0.2% Ointment
Rx
For 100 g
Nitroglycerin 2% ointment
Lanolin, anhydrous
White petrolatum
Coenzyme Q 10 100 mg-in-Oil Capsules
Rx
For 100 capsules
Coenzyme Q 10
Olive oil
Size No. 1 locking capsule
Zinc, Magnesium, Calcium and Vitamin D 3 Oral Liquid
Rx
For 100 mL
Zinc gluconate
Magnesium oxide
Calcium phosphate dibasic
Vitamin D 3
Polysorbate 80
Glycerin
Flavor
Methylparaben
Purified water
qs
RD = Raynauds disease
PLO = Pluronic lecithin organogel

qs
qs
22 mL
100 mL

10 g
30 g
60 g

10 g
38 mL

2.32 g
2.77 g
37.16 g
4,320 units
2 mL
20 mL
qs
200 mg
100 mL

disease may reduce the frequency and severity of attacks of RP,

although the pattern or pace of attacks is often independent of
overall disease activity.

References
1. Lawrence D, Weart C. Peripheral vascular disorders. In: Young L,
Koda-Kimble MA, eds. Applied Therapeutics: The Clinical Use of Drugs.
6th ed. Vancouver, WA:Applied Therapeutics, Inc.; 1995:(11-2)-(11-7).
2. Kontos H. Vascular diseases of the limbs. In: Wyngaarden J, Smith L,
eds. Cecils Textbook of Medicine. 18th ed. Philadelphia:WB Saunders
Co.:1988;1:375-377, 382, 601, 1561-1565, 2015, 2018-2037.
3. Wigley FM. Clinical practice. Raynauds phenomenon. N Engl J Med
2002;347:1001-1003.
4. Balch JF, Balch PA. Prescription for Nutritional Healing. 2nd ed. Garden
City Park, NY:Avery Publishing Group; 1998:458.

Address correspondence to: Andrew Glasnapp, BS, PharmD,

FIACP, Professional Compounding Centers of America,
9901 South Wilcrest, Houston, TX 77099.
E-mail: glasnapp@pccarx.com

International Journal of Pharmaceutical Compounding

291
Vol. 7 No. 4 July/August 2003