Mephentermine Sulfate
Indications: Hypotension, secondary to ganglionic blockade; Hypotension, secondary to spinal anesthesia
DESCRIPTION:
Mephentermine sulfate is a synthetic sympathomimetic drug which is intended for intramuscular or intravenous administration. In addition to the stated quantity of the active ingredient (15 or 30 mg/ml), each ml of the sterile injection solution is buffered to a pH of 5 (pH range of 4 to 6.5) with sodium acetate, and contains not more than 1.8 mg of methylparaben and 0.2 mg of propylparaben.
Mephentermine sulfate occurs as white, usually odorless crystals. It is soluble in water and slightly soluble in alcohol.
The chemical name of mephentermine sulfate is N,alpha,alpha-trimethylbenzeneethanamine sulfate (2:1).
CLINICAL PHARMACOLOGY:
Mephentermine sulfate is a sympathomimetic amine that acts indirectly by releasing norepinephrine. Cardiac contraction is enhanced, and cardiac output and systolic and diastolic pressures are usually increased. The pressor response also involves peripheral vasoconstriction. The change in heart rate is variable, depending on the degree of vagal tone; large doses can depress the heart. In some cases the net vascular effect may be vasodilation, which appears not to involve beta-adrenergic receptors. Coronary blood flow is increased, forearm blood flow is reduced, and venous tone is increased. Marked mucosal vasoconstriction can be produced by local application of the drug. CNS effects may occur with large doses of mephentermine. The main effect of therapeutic doses of mephentermine is cardiac stimulation.
Mephentermine is metabolized in the liver by N-demethylation to normephentermine (or phentermine) with subsequent p-hydroxylation to p-hydroxynormephentermine (or p-hydroxyphentermine). The excretion rate of the drug and its metabolites is more rapid in an acidic urine and is only slightly influenced by urine output.
The half-life in humans is reported to be between 17 and 18 hours.
A pressor response occurs almost immediately and persists for 15 to 30 minutes following intravenous injection of therapeutic doses of mephentermine sulfate. Pressor activity occurs within 5 to 15 minutes following intramuscular administration and persists for 1 to 4 hours.
INDICATIONS AND USAGE:
Mephentermine sulfate is indicated in the treatment of hypotension secondary to ganglionic blockade and that occurring with spinal anesthesia.
CONTRAINDICATIONS:
Mephentermine sulfate should not be used in patients with a past history of sensitivity to the drug.
Mephentermine sulfate, like epinephrine and ephedrine, is contraindicated in the treatment of hypotension induced by chlorpromazine, since the sympathomimetic amines will act to potentiate, rather than correct, the hypotension secondary to the adrenolytic effects of chlorpromazine.
Mephentermine sulfate should not be administered in combination with any monoamine-oxidase inhibitor.
WARNINGS:
Persistent hypotension during or after surgery usually indicates hypovolemia and should be treated by replacement of blood volume, rather than with a sympathomimetic such as mephentermine sulfate.
Cyclopropane and halothane are known to sensitize the heart to the arrhythmic action of catecholamines. Serious ventricular arrhythmias may occur in patients under general anesthesia with these agents if sympathomimetic drugs, such as mephentermine, are given to control hypotension.
PRECAUTIONS:
General
Patients with hyperthyroidism may show an increased responsiveness to vasopressor agents.
Mephentermine sulfate must be used with caution in patients with known cardiovascular diseases and in chronically ill patients, since the drug's action on the cardiovascular system may be profound.
If mephentermine sulfate is to be given to known hypertensives, careful monitoring of the blood pressure is advisable.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of mephentermine sulfate, nor are there relevant data with regard to mutagenicity or impairment of fertility.
Pregnancy Category C
It is not known whether mephentermine sulfate crosses the placental barrier.
Teratogenic Effects: Animal reproduction studies have not been conducted with mephentermine sulfate. It is not known whether mephentermine sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Mephentermine sulfate should be given to a pregnant woman only if clearly needed.
Nonteratogenic Effects: Mephentermine sulfate may increase uterine contractions especially during the third trimester of pregnancy.
Labor And Delivery
Animal studies indicated that mephentermine sulfate, used during labor, caused a decrease in uterine blood flow. Fetal hypoxia from decreased uterine blood flow secondary to uterine blood flow secondary to uterine vasoconstriction may occur. Transient fetal hypertension (mean arterial blood pressure more than 20% of control) has also been reported with mephentermine sulfate in animal experiments.
Nursing Mothers
It is not known whether mephentermine sulfate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mephentermine sulfate is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of mephentermine sulfate in children have not been established.
DRUG INTERACTIONS:
Administration of mephentermine sulfate to patients who are receiving cyclopropane or halogenated hydrocarbon general anesthetics which increase cardiac irritability may result in serious ventricular arrhythmias. The possibility that digitalis or mercurial diuretics can also sensitize the myocardium to the effects of sympathomimetic drugs should also be considered.
Phenothiazines, including chlorpromazine, may antagonize the pressor effects of mephentermine.
Monoamine-oxidase-inhibitors may potentiate the pressor effects of mephentermine by inhibiting the metabolism of catecholamines.
Drugs such as reserpine and guanethidine, which reduce the quantity of norepinephrine in sympathetic nerve endings, may significantly reduce the pressor response to mephentermine.
ADVERSE REACTIONS:
Adverse reactions to mephentermine sulfate may be especially likely to occur in patients with cardiovascular diseases, hypertension, hyperthyroidism, or other chronic illnesses.
Following the administration of recommended doses of mephentermine sulfate, CNS stimulating effects may result in nervousness and anxiety.
Mephentermine sulfate may produce arrhythmias, including transient extrasystoles, AV block, and hypertension.
OVERDOSAGE:
Effects of overdosage are an extension of the pharmacological activity of mephentermine. In therapy with mephentermine sulfate, cardiac contractility, cardiac output, systolic and diastolic blood pressure are usually raised. The increase in heart rate is variable depending on vagal tone. Large doses may depress the heart. Doses in the range of 3 mg/kg of body weight may alter myocardial conduction by decreasing conduction time and shortening the refractory period. Tachycardia may also be present. Central-nervous-system effects may occur with large doses: hyperexcitability, prolonged wakefulness, weeping, incoherence, convulsions, flushing, tremor, and hallucinations.
Treatment: Therapy of overdosage is symptomatic and supportive. Side effects, in general, disappear rapidly on withdrawal of the drug. Sedation may help to control CNS hyperexcitability. Blood pressure should be followed closely, and cardiac excitability should be monitored by EKG.
Convulsions or cardiac arrhythmias should be treated promptly if they occur. Since arrhythmias produced by mephentermine sulfate may be due to excessive beta-adrenergic stimulation, a beta-blocking agent such as propranolol may be considered.
DOSAGE AND ADMINISTRATION:
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Mephentermine sulfate can be administered intramuscularly without fear of irritation or abnormal tissue reaction. Pressor response is evident 5 to 15 minutes after intramuscular injection and has a duration of 1 to 2 hours. Injection of an undiluted parenteral solution of mephentermine sulfate, containing 30 mg/ml, or a continuous infusion of a solution of mephentermine sulfate, in 5% dextrose in water with a concentration of approximately 1 mg/ml, directly into the vein, is the preferred route for treatment of shock. Intravenous administration of undiluted mephentermine sulfate does not produce vascular irritation and, should extravasation occur, no untoward tissue reaction will develop. Dosage of mephentermine sulfate used in the treatment of shock and hypotension is based on experimental observations that 0.5 mg/kg produces a positive inotropic action, the pharmacologic action of mephentermine sulfate responsible for the pressor effect.
Treatment of hypotension occurring following spinal anesthesia is accomplished by the administration of 30 to 45 mg mephentermine sulfate intravenously in a single injection. Doses of 30 mg may be repeated as necessary to maintain the desired level of blood pressure. An immediate response and maintenance of blood pressure can be accomplished by the continuous intravenous infusion of a 0.1% solution of mephentermine sulfate in 5% dextrose in water (1 mg mephentermine sulfate/ml solution). The rate of flow and duration of this intravenous therapy should be regulated according to the response of the patient.
Treatment of hypotension secondary to spinal anesthesia in the obstetrical patient undergoing Caesarean section, who is known to react more positively to drugs, is accomplished by the administration of an initial dose of 15 mg of mephentermine sulfate intravenously. This dose may be repeated if the response is not adequate.
Prevention of hypotension attendant to spinal anesthesia can be accomplished by the administration of 30 to 45 mg mephentermine sulfate intramuscularly 10 to 20 minutes prior to anesthesia, operation, or termination of the operative procedure.
Preparation Of Intravenous Solution: The 0.1% solution of mephentermine sulfate recommended for continuous intravenous administration can be conveniently prepared in the approximate concentration (0.115%) by adding two 10-ml vials of mephentermine sulfate, 30 mg/ml, to 500 ml of 5% dextrose in water.
Store at room temperature, approximately 25Β°C (77Β°F).