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Rauwolfia Alkaloids (Systemic)

This monograph includes information on the following:

1) Deserpidine  
2) Rauwolfia Serpentina 
3) Reserpine

VA CLASSIFICATION
Primary: CV409

Commonly used brand name(s): Harmonyl1; Novoreserpine3; Raudixin2; Rauval2; Rauverid2; Reserfia3; Serpalan3; Serpasil3; Wolfina2.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihypertensive—

vasospastic therapy adjunct—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hypertension (treatment)—Rauwolfia alkaloids are indicated in the treatment of hypertension .
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

[Raynaud"s phenomenon (treatment) ]1—Reserpine has also been used to treat Raynaud"s phenomenon.

Unaccepted
Rauwolfia alkaloids have been used for relief of symptoms in agitated psychotic states such as schizophrenia; however, use as antipsychotics and sedatives has been superseded by use of more effective, safer agents.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Information (except physicochemical characteristics) available only for reserpine.


Physicochemical characteristics:
Molecular weight—
    Reserpine: 608.69

pKa—
    Deserpidine: 5.67
    Reserpine: 6.6

Mechanism of action/Effect:

Acts at postganglionic sympathetic nerve endings; depletes tissue and central nervous system (CNS) stores of catecholamines and serotonin; antihypertensive activity thought to be due to reduced cardiac output and possibly some decrease in peripheral resistance.

Absorption:

Reserpine is readily absorbed after oral administration.

Protein binding:

None (bound to sites involved with storage of biogenic amines; may persist in body for several days).

Biotransformation:

Hepatic.

Half-life:


Normal:

Initial: 4.5 hours.

Terminal: 45 to 168 hours.



Anuric:

Terminal: 87 to 323 hours.


Onset of action:

Antihypertensive—Oral: Several days to 3 weeks (multiple doses).

Catecholamine depletion—Within 1 hour (single dose).

Time to peak effect

Antihypertensive—Oral: 3 to 6 weeks (multiple doses).

Catecholamine depletion—Within 24 hours (single dose).

Duration of action:

Antihypertensive—Oral: 1 to 6 weeks.

Elimination:
    Fecal—More than 60%, mainly unchanged, in 4 days.
    Renal—8%, less than 1% unchanged, in 4 days.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one rauwolfia alkaloid may be sensitive to other rauwolfia alkaloids also.

Carcinogenicity/Tumorigenicity

The suggestion that long-term use of reserpine (and also, presumably, other rauwolfia alkaloids) may increase the risk of breast cancer in postmenopausal women has been controversial. A few epidemiologic studies have suggested a slightly increased risk of breast cancer in women who have used reserpine. However, other studies have not confirmed this finding. {01} {02}

Studies in rats and mice at 100 to 300 times the usual human dose found an increased incidence of mammary fibroadenomas in females, and malignant tumors of the seminal vesicles and malignant adrenal medullary tumors in males. {01}

Pregnancy/Reproduction
Fertility—
Long-term animal studies have not been done with the rauwolfia alkaloids to determine their effect on fertility in males or females.

Pregnancy—
Rauwolfia alkaloids cross the placenta. Adequate and well-controlled studies have not been done in humans. However, possible adverse effects in infants of mothers who received rauwolfia alkaloids include increased respiratory secretions, nasal congestion, cyanosis and anorexia. {01} {02}

Reserpine was found to be teratogenic in rats given parenteral doses of up to 2 mg per kg of body weight (mg/kg) and was embryocidal in guinea pigs given parenteral doses of 0.5 mg per day.

FDA Pregnancy Category C.

Breast-feeding

Problems in humans have not been documented. However, rauwolfia alkaloids are distributed into breast milk. Possible adverse effects in infants of mothers who received rauwolfia alkaloids include increased respiratory secretions, nasal congestion, cyanosis, and anorexia.

Pediatrics

Appropriate studies on the relationship of age to the effects of the rauwolfia alkaloids have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of these medications in children are not expected.


Geriatrics


Although appropriate studies on the relationship of age to the effects of the rauwolfia alkaloids have not been performed in the geriatric population, the elderly may be more sensitive to the CNS depressant and hypotensive effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving rauwolfia alkaloids. A lower dose is recommended in the elderly.


Dental

Use of rauwolfia alkaloids may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol or
CNS depression–producing medications (See Appendix II )    (concurrent use may enhance the CNS depressant effects of either these medications or rauwolfia alkaloids)


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin    (antihypertensive effects of rauwolfia alkaloids may be reduced when used concurrently with these agents; indomethacin, and possibly other NSAIDs, may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained)


Anticholinergics or other medications with anticholinergic action (See Appendix II )    (concurrent use of rauwolfia alkaloids may antagonize the inhibitory action of these medications on gastric acid secretion)


Beta-adrenergic blocking agents, including ophthalmic beta-blockers absorbed systemically    (concurrent administration with beta-blockers may result in additive and possibly excessive beta-adrenergic blockade; although this effect is largely theoretical, close observation is recommended since bradycardia and hypotension may occur)


Bromocriptine    (reserpine may increase serum prolactin concentrations, and interfere with effects of bromocriptine; dosage adjustment of bromocriptine may be necessary)


Digitalis glycosides or
Quinidine    (concurrent use may result in cardiac arrhythmias; although this interaction is controversial and does not appear to be significant with usual doses, caution is recommended, especially when large doses of rauwolfia alkaloids are used in digitalized patients)


Extrapyramidal reaction–causing medications, other (See Appendix II )    (concurrent use with rauwolfia alkaloids may potentiate the extrapyramidal effects)


Hypotension-producing medications, other, except MAO inhibitors (See Appendix II )    (antihypertensive effects may be potentiated when these medications are used concurrently with rauwolfia alkaloids; although some combinations are frequently used for therapeutic advantage, when used concurrently dosage adjustments may be necessary)

    (concurrent use of guanadrel or guanethidine with rauwolfia alkaloids may cause an increased incidence of orthostatic hypotension or bradycardia)


Levodopa    (rauwolfia alkaloids may cause dopamine depletion and parkinsonian effects, decreasing the therapeutic effects of levodopa; dosage adjustments of either or both medications may be necessary)


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (when an MAO inhibitor is added to existing therapy with rauwolfia alkaloids, serious potentiation of CNS depressant effect may result; however, if a rauwolfia alkaloid is added to an MAO inhibitor regimen, excessive stimulation of receptors caused by the sudden release of accumulated norepinephrine and serotonin may result in moderate to sudden and severe hypertension and hyperpyrexia, which can reach crisis levels; administration of rauwolfia alkaloids is not recommended during and for 1 week following MAO inhibitor therapy)


Sympathomimetics
(antihypertensive effects of rauwolfia alkaloids may be reduced when used concurrently with these agents; the patient should be carefully monitored to confirm that the desired effect is being obtained)
Indirect-acting amines, such as amphetamines, phenylpropanolamine, pseudoephedrine, and tyramine, or
Direct- and indirect-acting (primarily indirect-acting) amines, such as ephedrine and mephentermine    (rauwolfia alkaloids inhibit the action of indirect-acting sympathomimetics by depleting catecholamine stores)


Direct-acting amines such as epinephrine or norepinephrine (levarterenol) or
Direct- and indirect-acting (primarily direct-acting) amines such as appetite suppressants (except fenfluramine), dobutamine, dopamine, metaraminol, methoxamine, and phenylephrine    (rauwolfia alkaloids may theoretically prolong the action of direct-acting sympathomimetics by preventing uptake into storage granules; a ``denervation supersensitivity'' response is also possible; although concurrent use with rauwolfia alkaloids is not known to produce severe adverse effects, a significant increase in blood pressure has been documented when phenylephrine ophthalmic drops have been administered to patients taking reserpine, and caution and close observation are recommended; on the other hand, concurrent use with fenfluramine may increase the hypotensive effects of rauwolfia alkaloids)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Urinary steroid colorimetric determinations by modified Glenn-Nelson technique or Holtorff Koch modification of Zimmerman reaction    (falsely low because rauwolfia alkaloids slightly decrease absorbance)

With physiology/laboratory test values
Catecholamine excretion, urinary    (an overall decrease is usually noted with chronic administration of rauwolfia alkaloids)


Prolactin concentrations, serum    (may be increased)


Vanillylmandelic acid (VMA), urinary excretion    (chronic administration of rauwolfia alkaloids results in an overall decrease)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Cardiac arrhythmias
Cardiac depression
Epilepsy
» Gallstones or
» Peptic ulcer or
» Ulcerative colitis    (rauwolfia alkaloids increase gastrointestinal motility and secretion; may precipitate biliary colic)


» Mental depression, or history of
Parkinsonism
Pheochromocytoma
Renal function impairment    (patients with renal insufficiency may adjust poorly to reduced blood pressure levels. However, dosage reduction is not necessary in these patients)


Respiratory problems
Sensitivity to the rauwolfia alkaloid prescribed
» Caution is required also in patients receiving electroconvulsive therapy, as well as in the severely debilitated.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements    (recommended at periodic intervals in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)




Side/Adverse Effects

Note: Side effects occur more frequently with high-dose administration.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible cause in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Dizziness

Incidence less frequent
    
Arrhythmias (irregular heartbeat)
    
black, tarry stools
    
bloody vomit, stomach cramps or pain
    
bradycardia (slow heartbeat)
    
chest pain
    
drowsiness or faintness
    
headache
    
impotence or decreased sexual interest
    
lack of energy or weakness
    
mental depression or inability to concentrate
    
nervousness or anxiety
    
shortness of breath
    
vivid dreams or nightmares or early-morning sleeplessness

Note: CNS effects are dose-related, occurring more frequently with doses exceeding 500 mcg (0.5 mg) per day.


Incidence rare
    
Painful or difficult urination
    
skin rash or itching
    
stiffness or trembling and shaking of hands and fingers
    
thrombocytopenia (unusual bleeding or bruising)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anorexia (loss of appetite)
    
diarrhea
    
dryness of mouth
    
nasal congestion (stuffy nose)
    
nausea and vomiting

Incidence less frequent
    
Edema, peripheral (swelling of feet and lower legs)



Those indicating the need for medical attention if they occur after medication is discontinued
    
Arrhythmias (irregular heartbeat)
    
bradycardia (slow heartbeat)
    
drowsiness or faintness
    
impotence or decreased sexual interest
    
lack of energy or weakness
    
mental depression or inability to concentrate
    
nervousness or anxiety
    
vivid dreams or nightmares or early-morning sleeplessness

Note: Mental depression may have an insidious onset, may be severe enough to cause suicide, and may persist for several months following withdrawal of this medication.





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Dizziness or drowsiness, severe
    
flushing of skin
    
pinpoint pupils of eyes
    
slow pulse


Treatment of overdose
Immediate evacuation of the stomach and instillation of an activated charcoal slurry.

Supportive, symptomatic treatment.

If treatment with a vasopressor is necessary, one with a direct action on smooth muscle (phenylephrine, norepinephrine, metaraminol) should be used.

The patient should be observed for at least 72 hours.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rauwolfia Alkaloids (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any of the rauwolfia alkaloids

Pregnancy—Teratogenic in animals





Breast-feeding—Distributed into breast milk





Use in the elderly—May be more sensitive to the CNS depressant and hypotensive effects





Dental—May decrease or inhibit salivary flow
Other medications, especially monoamine oxidase (MAO) inhibitors
Other medical problems, especially gallstones, peptic ulcer, ulcerative colitis, or mental depression

Proper use of this medication
Possible need for control of weight and diet, especially sodium intake

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure but helps control hypertension; possible need for lifelong therapy; serious consequences of untreated hypertension

Compliance with therapy; taking medication at the same time(s) each day to maintain the therapeutic effect

Caution in taking combination therapy; taking each medication at the right time

Taking with meals or milk to reduce gastrointestinal irritation

» Proper dosing
Missed dose: Not taking missed dose at all and not doubling doses

» Proper storage

Precautions while using this medication
Making regular visits to physician to check progress

» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required

» Caution if depression or changes in sleep pattern occur

» Caution in taking alcohol or other CNS depressants

» Caution when driving or doing things requiring alertness because of possible drowsiness or dizziness

Possible dryness of mouth; using sugarless candy or gum, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

Nasal stuffiness may occur; nasal decongestants or other OTC preparations containing sympathomimetics should not be used without first consulting physician or pharmacist


Side/adverse effects
Dizziness, arrhythmias, bradycardia, black, tarry stools, bloody vomit, chest pain, drowsiness or faintness, headache, impotence or decreased sexual interest, lack of energy or weakness, mental depression or inability to concentrate, nervousness or anxiety, vivid dreams or nightmares or early-morning sleeplessness, shortness of breath


General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response, with the lowest effective dosage being utilized in order to minimize problems with mental depression, orthostatic hypotension, and other side effects.

Rauwolfia alkaloids are usually used in combination with a diuretic to prevent sodium and water retention.

A lower dose is recommended in the elderly or severely debilitated.

Doses higher than the recommended dose should be used with caution because of the risk of severe mental depression.

Antihypertensive effects of rauwolfia alkaloids may not be observed for a few days to several weeks after oral administration and may persist for 1 to 6 weeks after withdrawal of the medication. It is recommended that adjustments in dosage be made every 7 to 14 days to allow the full effects of the preceding dose to occur.

It is recommended that this medication be withdrawn at the first sign of despondency, early-morning insomnia, loss of appetite, impotence, or self-deprecation.

It is recommended that rauwolfia alkaloids be withdrawn 2 weeks before electroconvulsive therapy is employed.

Recent evidence suggests that withdrawal of catecholamine-depleting antihypertensive therapy prior to surgery is not necessary, but that the anesthesiologist must be aware of such therapy. Administration of atropine prior to induction may prevent excessive bradycardia. If a hypotensive episode occurs, use of a weak direct-acting sympathomimetic agent is recommended.

Diet/Nutrition
It is recommended that these medications be taken with food or milk to minimize gastrointestinal upset.

DESERPIDINE


Oral Dosage Forms

DESERPIDINE TABLETS

Usual adult dose
Antihypertensive
Oral, 250 to 500 mcg (0.25 to 0.5 mg) a day as a single dose or in two divided daily doses.


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


250 mcg (0.25 mg) (Rx) [Harmonyl]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight container. Protect from light.

Auxiliary labeling:
   • Take with meals or milk.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



RAUWOLFIA SERPENTINA


Oral Dosage Forms

RAUWOLFIA SERPENTINA TABLETS USP

Usual adult dose
Antihypertensive
Oral, 50 to 200 mg a day as a single dose or in two divided daily doses.


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg (Rx) [Raudixin] [Rauval] [Rauverid][Generic]


100 mg (Rx) [Raudixin] [Rauval] [Wolfina][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight, light-resistant container.

Auxiliary labeling:
   • Take with meals or milk.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



RESERPINE


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


RESERPINE TABLETS USP

Usual adult dose
Antihypertensive or
[Vasospastic therapy adjunct—Raynaud's phenomenon]1
Oral, 100 to 250 mcg (0.1 to 0.25 mg) a day.


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Antihypertensive
Oral, 5 to 20 mcg (0.005 to 0.02 mg) per kg of body weight or 150 to 600 mcg (0.15 to 0.6 mg) per square meter of body surface a day in one or two divided daily doses.


Strength(s) usually available
U.S.—


100 mcg (0.1 mg) (Rx) [Serpalan][Generic]


250 mcg (0.25 mg) (Rx) [Serpalan][Generic]


1 mg (Rx)[Generic]

Canada—


250 mcg (0.25 mg) (Rx) [Novoreserpine] [Reserfia] [Serpasil][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight, light-resistant container.

Auxiliary labeling:
   • Take with meals or milk.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.




Revised: 08/19/1998



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Harmonyl package insert (Abbott), Rev 8/90, Rec 5/92.
  1. Raudixin product information, PDR 1992.
  1. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153(2): 154-83.
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