Bethanechol

DESCRIPTION

Bethanechol chloride, a cholinergic agent, is a synthetic ester which is structurally and pharmacologically related to acetylcholine. It is designated chemically as 2-[(aminocarbonyl)oxy]- N, N, N-trimethyl-1-propanaminium chloride. The molecular formula is: C₇H₁₇ClN₂O₂ with a molecular weight of 196.68.

It is a white, hygroscopic crystalline powder having a slight amine-like odor, freely soluble in water. Bethanechol chloride is supplied as 5 mg, 10 mg, 25 mg and 50 mg tablets for oral use.

Bethanechol chloride tablets for oral administration contain the following inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium starch glycolate.

The 25 mg and 50 mg tablets also contain: D&C Yellow No. 10 and FD&C Yellow No. 6.

CLINICAL PHARMACOLOGY

Bethanechol chloride acts principally by producing the effects of stimulation of the parasympathetic nervous system. It increases the tone of the detrusor urinae muscle, usually producing a contraction sufficiently strong to initiate micturition and empty the bladder. It stimulates gastric motility, increases gastric tone, and often restores impaired rhythmic peristalsis.

Stimulation of the parasympathetic nervous system releases acetylcholine at the nerve endings. When spontaneous stimulation is reduced and therapeutic intervention is required, acetylcholine can be given, but it is rapidly hydrolyzed by cholinesterase, and its effects are transient. Bethanechol chloride is not destroyed by cholinesterase and its effects are more prolonged than those of acetytcholine.

Effects on the GI and urinary tracts sometimes appear within 30 minutes after oral administration of bethanechol chloride, but more often 60-90 minutes are required to reach maximum effectiveness. Following oral administration, the usual duration of action of bethanechol is one hour, although large doses (300-400 mg) have been reported to produce effects for up to six hours. Subcutaneous injection produces a more intense action on bladder muscle than does oral administration of the drug.

Because of the selective action of bethanechol, nicotinic symptoms of cholinergic’stimulation are usually absent or minimal when orally or subcutaneously administered in therapeutic doses, while muscarinic effects are prominent. Muscarinic effects usually occur within 5-15 minutes after subcutaneous injection, reach a maximum in 15-30 minutes, and disappear within two hours. Doses that stimulate micturition and defecation and increase peristalsis do not ordinarily stimulate ganglia or voluntary muscles. Therapeutic test doses in normal human subjects have little effect on heart rate: blood pressure, or peripheral circulation.

Bethanechol chloride does not cross the blood-brain barrier because of its charged quaternary amine moiety. The metabolic fate and mode of excretion of the drug have not been elucidated.

A clinical study¹ was conducted on the relative effectiveness of oral and subcutaneous doses of bethanechol chloride on the stretch response of bladder muscle in patients with urinary retention. Results showed that 5 mg of the drug given subcutaneously stimulated a response that was more rapid in onset and of larger magnitude than an oral dose of 50 mg, 100 mg or 200 mg. All the oral doses, however, had a longer duration of effect than the subcutaneous dose. Although the 50 mg oral dose caused little change in intravesical pressure in this study, this dose has been found in other studies to be clinically effective in the rehabilitation of patients with decompensated bladders.

INDICATIONS

For the treatment of acute postoperative and postpartum nonobstructive (functional) urinary retention and for neurogenic atony of the urinary bladder with retention.

DOSAGE AND ADMINISTRATION

Dosage must be individualized, depending on the type and severity of the condition to be treated. Preferably give the drug when the stomach is empty. If taken soon after eating, nausea and vomiting may occur.

Oral

The usual adult oral dosage ranges from 10 to 50 mg three or four times a day. The minimum effective dose is determined by giving 5 or 10 mg initially and repeating the same amount at hourly intervals until satisfactory response occurs or until a maximum of 50 mg has been given. The effects of the drug sometimes appear within 30 minutes and usually within 60 to 90 minutes. They persist for about an hour.

If necessary, the effects of the drug can be abolished promptly by atropine (see OVERDOSAGE).

HOW SUPPLIED

Bethanechol Chloride Tablets, USP 5 mg are 14/ 32”, bisected, round, white tablets imprinted “DAN DAN” and “5370” supplied in bottles of 100 and 1000.

Bethanechol Chloride Tablets, USP 10 mg are 14/ 32”, bisected, round, white tablets imprinted “DAN DAN” and “5369” supplied in bottles of 100 and 1000.

Bethanechol Chloride Tablets, USP 25 mg are 14/ 32”, bisected, round, yellow tablets imprinted “DAN DAN” and “5402” supplied in bottles of 100 and 1000.

Bethanechol Chloride Tablets, USP 50 mg are 15/ 32”, bisected, round, yellow tablets imprinted “DAN DAN” and “5515” supplied in bottles of 100, 500 and 1000.

Dispense in tight container with child-resistant closure.

Store at controlled room temperature 15°-30° C (59°-86° F).

CAUTION: Federal law prohibits dispensing without prescription.

REFERENCES

1. Diokno, A. C.; Lapides, J., Urol. n2 23- 24, July 1977.

SIDE EFFECTS

Adverse reactions are rare following oral administration of bethanechol, but are more common following subcutaneous injection. Adverse reactions are more likely to occur when dosage is increased. The following adverse reactions have been observed:

Body as a Whole: malaise;

Digestive: abdominal cramps or discomfort, colicky pain, nausea and belching, diarrhea, borborygmi, salivation;

Renal: urinary urgency;

Nervous System: headache;

Cardiovascular: a fall in blood pressure with reflex tachycardia, vasomotor response;

Skin: flushing producing a feeling of warmth, sensation of heat about the face, sweating;

Respiratory: bronchial constriction, asthmatic attacks;

Special Senses: lacrimation, miosis.

Causal Relationship Unknown

The following adverse reactions have been reported, and a causal relationship to therapy with bethanechol chloride has not been established:

Body as a Whole: malaise;

Nervous System: seizures.

DRUG INTERACTIONS

Special care is required if this drug is given to patients receiving ganglion blocking compounds because a critical fall in blood pressure may occur. Usually, severe abdominal symptoms appear before there is such a fall in the blood pressure.

WARNINGS

No information provided.

PRECAUTIONS

General

In urinary retention, if the sphincter fails to relax as bethanechol chloride contracts the bladder, urine may be forced up the ureter into the kidney pelvis. If there is bacteriuria, this may cause reflux infection.

Carcinogenesis, Mutagenesls, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenic or carcinogenic potential of bethanechol chloride.

Pregnancy

Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with bethanechol chloride. It is also not known whether bethanechol chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bethanechol chloride should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions from bethanechol chloride in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.