Medication Guide App

Trimethaphan (Systemic)


VA CLASSIFICATION
Primary: CV409

Commonly used brand name(s): Arfonad.

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



Category:


Antihypertensive—

Indications

Accepted

Hypotension, controlled (induction and maintenance)—Trimethaphan is indicated for production of controlled hypotension during surgery to reduce bleeding into the surgical field. {01}

Hypertension (treatment)—Trimethaphan is indicated for rapid reduction of blood pressure in the treatment of hypertensive emergencies, especially in patients with acute dissecting aneurysm, and in the emergency treatment of pulmonary edema in patients with pulmonary hypertension associated with systemic hypertension. {01}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    596.80 {02}

Mechanism of action/Effect:

Ganglionic blocking agent {01} {03} {04}; prevents stimulation of postsynaptic receptors by competing with acetylcholine for these receptor sites {01} {03}; additional effects may include direct peripheral vasodilation and release of histamine. {01} Trimethaphan's hypotensive effect is due to reduction in sympathetic tone and vasodilation, and is primarily postural {03}. Cardiac output may increase in patients with cardiac failure or decrease in patients with normal cardiac function. {03}

Biotransformation:

Exact metabolic fate unknown; however, possibly by pseudocholinesterase. {11}

Onset of action:

Immediate. {05}

Duration of action:

10 to 15 minutes {05}.

Elimination:
    Renal, mostly unchanged. {03}


Precautions to Consider

Carcinogenicity/Mutagenicity

Adequate studies have not been done. {01}

Pregnancy/Reproduction

Pregnancy—
Trimethaphan crosses the placenta. Its ganglionic blocking effects may decrease gastrointestinal motility in the fetus, resulting in meconium ileus or neonatal paralytic ileus. Furthermore, trimethaphan-induced hypotension may have other serious adverse effects on the fetus. Risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used. {01}

FDA Pregnancy Category D.

Breast-feeding

It is not known whether trimethaphan is distributed into breast milk. Because of the potential for serious adverse effects in nursing infants, it is recommended that mothers who require trimethaphan refrain from nursing. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of trimethaphan have not been performed in the pediatric population. However, caution may be required in pediatric patients. {01}


Geriatrics


No information is available on the relationship of age to the effects of trimethaphan in geriatric patients. However, elderly patients may be more sensitive to the hypotensive effects of trimethaphan. Furthermore, these patients may have age-related renal function impairment, which may require caution in patients receiving trimethaphan.

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.

» Ambenonium or
» Neostigmine or
» Pyridostigmine    (concurrent use may interfere with the antimyasthenic effect of ambenonium, neostigmine, or pyridostigmine, leading to weakness and sudden inability to swallow)


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin    (antihypertensive effects of trimethaphan may be reduced when it is 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)


Hypotension-producing medications, other (see Appendix II ){01}    (concurrent use with trimethaphan may result in enhanced hypotension; individual dosage adjustment is important; halothane may also reduce or prevent trimethaphan-induced tachycardia)

    (preanesthetic and anesthetic agents used in surgery, especially spinal anesthetics, may potentiate the hypotensive response to trimethaphan, with increased risk of severe hypotension, shock, and cardiovascular collapse during surgery)


Neuromuscular blocking agents{01}    (effects may be prolonged, especially by administration of large doses of trimethaphan, since trimethaphan appears to have a slight curare-like effect; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade)


Sympathomimetics    (trimethaphan may enhance the pressor response to sympathomimetic pressor amines, and the hypotensive effect of trimethaphan may be decreased or reversed by all sympathomimetics)



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 physiology/laboratory test values
Glucose, blood, concentrations{01}    (trimethaphan prevents surgically induced increase)


Potassium, serum{01}    (concentrations may be slightly decreased)


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
» Addison's disease
Allergies, history of    (trimethaphan liberates histamine and has been reported to cause a histamine-like reaction along the vein where administered)


» Anemia, uncorrected or
» Asphyxia or
» Hypovolemia or
» Shock, frank or incipient    (for use in producing controlled hypotension during anesthesia only; additional hypotension may result in hypoxia of vital organs)


Bladder neck obstruction or
Prostatic hypertrophy or
Urethral stricture    (possible urinary retention caused by trimethaphan)


» Cardiovascular insufficiency, including coronary insufficiency or
» Cerebrovascular insufficiency or
» Myocardial infarction, recent    (ischemia may be aggravated by hypotension)


» Degenerative disease of the central nervous system (CNS)
» Diabetes mellitus
Glaucoma
» Hepatic function impairment    (the decrease in blood pressure secondary to trimethaphan administration may decrease hepatic perfusion and worsen this condition {11} {12})


Pyelonephritis, chronic    (condition may be aggravated by urinary retention caused by trimethaphan)


» Renal function impairment    (increased effects due to reduced excretion of trimethaphan)


» Respiratory insufficiency, uncorrected    (aggravation of hypoxemia by trimethaphan)


Sensitivity to trimethaphan
» Caution is required also in debilitated patients and those also receiving steroids.

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 determinations{01}    (should be made frequently)


Respiratory function determinations{01}    (recommended at periodic intervals, especially with large doses of trimethaphan, since respiratory arrest has been reported rarely with its use)




Side/Adverse Effects

Note: Most side/adverse effects are due to parasympathetic blockade and respond to dosage reduction or withdrawal of trimethaphan.
Overdosage may result in profound hypotension and respiratory arrest.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive: {01}

Incidence dose-related
    
Anorexia, nausea, and vomiting
    
constipation
    
cycloplegia and mydriasis
    
dryness of mouth
    
impotence
    
itching, urticaria
    
orthostatic hypotension
    
paralytic ileus
    
precipitation of angina
    
tachycardia
    
urinary retention, short-term

Note: Increased risk of paralytic ileus when the infusion is continued for longer than 48 hours.
Mydriasis is common and does not necessarily indicate anoxia or depth of anesthesia.





General Dosing Information
Trimethaphan Camsylate Injection USP must be diluted and administered by intravenous infusion. {01}

To achieve optimal reduction in blood pressure, it is recommended that trimethaphan infusion be administered intravenously by means of an infusion pump, a micro-drip regulator, or a similar device to allow precise adjustment of the flow rate. Tilting the head of the bed up may enhance the hypotensive effect {05}; the patient should be positioned to avoid cerebral anoxia. {01}

For use as an antihypertensive only
It is recommended that patients receiving trimethaphan be in an intensive care unit and that blood pressure be monitored frequently.

It is recommended that oral antihypertensive therapy be instituted as soon as possible while the patient is receiving trimethaphan and that trimethaphan be withdrawn as soon as the blood pressure has stabilized. Patients receiving concomitant antihypertensive medication require lower doses of trimethaphan.

Pseudotolerance to the effects of trimethaphan occurs in some patients; tachyphylaxis may develop within 24 to 72 hours. Pseudotolerance with prolonged use may be prevented by use of a diuretic. {07}

For use to produce controlled hypotension during surgery only
It is recommended that trimethaphan infusion be discontinued prior to wound closure to allow blood pressure to return to normal. {01}


Parenteral Dosage Forms

TRIMETHAPHAN CAMSYLATE INJECTION USP

Usual adult dose
Controlled hypotension during surgery
Initial: Intravenous infusion, 3 to 4 mg per minute, adjusted according to response. {01}

Maintenance: Intravenous infusion, 300 mcg (0.3 mg) to 6 mg per minute. {01}

Hypertensive emergency
Initial: Intravenous infusion, 500 mcg (0.5 mg) to 1 mg per minute, adjusted according to response.

Maintenance: Intravenous infusion, 1 to 5 mg per minute. {05} {09}


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


Usual pediatric dose
Initial—Intravenous infusion, 50 mcg (0.05 mg) to 150 mcg (0.15 mg) per kg per minute, adjusted according to response. {10} {13}

Strength(s) usually available
U.S.—


50 mg per mL (Rx) [Arfonad]

Canada—


50 mg per mL (Rx) [Arfonad]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Protect from freezing (to avoid ampul breakage).

Preparation of dosage form:
Trimethaphan Camsylate Injection USP is prepared for intravenous infusion by diluting the contents of a 500-mg ampul in 500 mL of 5% dextrose injection only to produce a solution containing 1 mg of trimethaphan camsylate per mL.

Stability:
Intravenous solutions should be freshly prepared; unused portions should be discarded. After preparation, intravenous infusion solution is stable for 24 hours at room temperature.

Auxiliary labeling:
   • Dilute before using.

Note: Must be diluted before use.




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. Arfonad package insert (Roche Laboratories), Rev 2/88, Rec 11/91.
  1. USAN and the USP dictionary of drug names. 29th ed. United States Pharmacopeial Convention, Inc. 1992; 631.
  1. Taylor P. Agents acting at the neuromuscular junction and autonomic ganglia. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, editors. The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, Inc. 1990; 179, 181-4.
  1. Knight PR, Lane GA, Hensinger RN, Bolles RS, Bjoraker DG. Catecholamine and renin-angiotensin response during hypotensive anesthesia induce by sodium nitroprusside or trimethaphan camsylate. Anesthesiology 1983; 59(3): 248-53.
  1. Stumpf JL. Drug therapy of hypertensive crises. Clin Pharm 1988; 7: 582-91.
  1. Handbook on injectable drugs. Trissel LA. 5th ed. American Society of Hospital Pharmacists. 1988; 678.
  1. Smith CB, Flower LW, Reinhardt CE. Control of hypertensive emergencies. Postgrad Med 1991; 89(5): 111-7.
  1. Sanders AB. Hypertensive emergencies. Am Fam Physician 1991; 44(5): 1767-74.
  1. Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med 1990; 323(17): 1177-83.
  1. Fleischmann LE. Management of hypertensive crisis in children. Pediatr Ann 1977; 6(6): 410-4.
  1. Manufacturer comment.
  1. Panel comment.
  1. Panel comments.
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