Reserpine

Reserpine is an antihypertensive and antipsychotic agent belonging to the adrenergic neuron blocker class.

Reserpine is approved for the treatment of Hypertension and psychiatric disorder.

Reserpine gets absorbed through the GI tract with 50% bioavailability, where distribution occurs after crossing the placenta and blood-brain barrier and entering breast milk. The plasma protein binding of Reserpine was found to be 96%. It gets extensively metabolized in the liver with >90%. Reserpine gets excreted via feces while keeping 60% of the drug as unchanged and through urine (approx 8% as metabolites).

The common side effects associated with Reserpine include nausea, vomiting, diarrhea, loss of appetite, headache, dizziness, drowsiness; breast tenderness or swelling, itching or rash; stuffy nose, nosebleeds, weight gain; or impotence, etc.

Reserpine is available in the form of dosage forms as tablets

Reserpine is available in India, the UK, Egypt, and Australia.

Reserpine, belonging to the adrenergic neuron blocker, acts as an antihypertensive and antipsychotic agent. Reserpine works by slowing the activity of the nervous system, causing the heartbeat to slow and the blood vessels to relax. Reserpine is used to treat high blood pressure. It is also used to treat severe agitation in patients with mental disorders.

Reserpine irreversibly blocks VMAT-2 (vesicular monoamine transporter-2) in the adrenergic neurotransmission pathway. The inhibition of catecholamine pumps results in the blockage of the uptake of serotonin, norepinephrine, and dopamine into presynaptic storage vesicles. This action will then lead to their depletion by the cytoplasmic monoamine oxidase from peripheral and central synapses.

The onset of action of Reserpine occurs within 3-6 days.

The Duration of Action for Reserpine in the body is 2-6 weeks.

The Tmax was found within 2.5 hours following the administration of Reserpine and the Cmax was about 1.1 ng/ml.

Reserpine is available in the form of tablets and Injections

Tablets:

Reserpine tablets to be swallowed whole with water. Reserpine comes as a tablet to be taken by mouth. It is usually taken two times a day.

Reserpine is an antihypertensive and antipsychotic agent belonging to the adrenergic neuron blocker class.

Reserpine is approved for the treatment of Hypertension and psychiatric disorder.

Reserpine inhibits the ATP/Mg²⁺ pump which is responsible for sequestering neurotransmitters into storage vesicles located in the presynaptic neuron. The neurotransmitters that are not sequestered in the storage vesicle are readily metabolized by monoamine oxidase (MAO) causing a reduction in catecholamines.

Reserpine is approved for use in the following clinical indications.

• Hypertension:

Management of mild to moderate Hypertension.

Note: Not recommended for the initial treatment of Hypertension.

• Psychiatric disorder.

Treatment of agitated psychotic states (schizophrenia)

Reserpine is available in the form of tablets and injections.

Hypertension:

• Initial Dosage

On average patients do not receive other antihypertensive agents, the usual initial dosage is 0.5 mg daily for 1 or 2 weeks.

• Maintenance Dosage

For maintenance, reduce to 0.1–0.25 mg daily.

Higher dosages should be used cautiously because the occurrence of serious mental depression and other side effects may increase considerably.

Psychiatric Disorders:

The usual initial dosage is 0.5 mg daily but may range from 0.1 mg to 1.0 mg. Adjust dosage upward or downward according to the patient's response.

Reserpine is also useful as adjunctive therapy with other antihypertensive agents in the more severe forms of Hypertension; relief of symptoms in agitated psychotic states (e.g., schizophrenia), primarily in those individuals unable to tolerate phenothiazine derivatives or in those who also require antihypertensive medication.

Reserpine can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Reserpine is available in various dosage strengths as 0.1 mg, 0.25 mg, 2.5 mg/ml

Reserpine is approved for the treatment of Hypertension and psychiatric disorder.

• Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

• Psychiatric Disorder: Avoid High consumption of red and/or processed meat, refined grains, sweets, high-fat dairy products, butter, potatoes, and high-fat gravy, and low intakes of fruits and vegetables.

The dietary restriction should be individualized as per patient requirements.

Reserpine may be contraindicated in the following

Absolute contraindications for reserpine use include the presence of :

• Active peptic ulcer

• Ulcerative colitis

• Electroconvulsive therapy
• Pregnancy

• Parkinson’s disease

• Rauwolfia alkaloid hypersensitivity

• Psychiatric depression

• Pheochromocytoma

Caution is necessary when administering Reserpine to patients with a history of peptic ulcer or gastroesophageal reflux disease (GERD) due to a possible side effect of increased gastric acid secretion. At higher doses, Reserpine may cause a significant incidence of mental depression, anxiety, or psychosis. The FDA categorizes Reserpine as a Pregnancy C class drug.

Relative contraindications for reserpine use include the presence of:

• Cardiac arrhythmias

• Myocardial infarction

• Renal insufficiency

• Asthma

• Elderly patients

For relative contraindications, reserpine use should be approached with caution and begin with lower doses.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

• Extreme caution should be exercised in treating patients with a history of mental depression. Reserpine may cause mental depression. Recognition of depression may be difficult because this condition may often be disguised by somatic complaints (masked depression). The drug should be discontinued at first signs of depression such as despondency, early morning insomnia, loss of appetite, impotence, or self-deprecation. Drug-induced depression may persist for several months after drug withdrawal and may be severe enough to result in suicide.

Precautions

General

• Since Reserpine increases gastrointestinal motility and secretion, it should be used cautiously in patients with a history of peptic ulcer, ulcerative colitis, or gallstones (biliary colic may be precipitated).
• Caution should be exercised when treating hypertensive patients with renal insufficiency since they adjust poorly to lowered blood pressure levels.
• Preoperative withdrawal of Reserpine does not assure that circulatory instability will not occur. It is important that the anesthesiologist be aware of the patient’s drug intake and consider this in the overall management since hypotension has occurred in patients receiving rauwolfia preparations. Anticholinergic and/or adrenergic drugs (e.g., metaraminol, norepinephrine) have been employed to treat adverse vagocirculatory effects.

There are some food warnings for the drug reserpine mentioned below:

Ginseng: Intake of ginseng while taking Reserpine will reduce the effectiveness of Reserpine. Ginseng is found to increase blood pressure and therefore should be avoided with antihypertensive medications.

The adverse reactions related to the molecule Reserpine can be categorized as

Common Adverse effects:

Bradycardia, headache, Dizziness, fatigue, etc.

Less Common adverse effects:

Nervousness, Elevated liver enzymes, joint paint, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesias, bradycardia, cold extremities, hypotension, palpitations, syncope, Anxiety, lethargy, diarrhea, vomiting, Pruritus, drug-induced Parkinson’s disease

Rare adverse effects:

Heart failure, optic atrophy, bronchospasm, depression, decreased exercise tolerance, Gynecomastia, etc.

The clinically relevant drug interactions of Reserpine are briefly summarized here

• Acebrophylline: May enhance the tachycardic effect of Reserpine. Risk C: Monitor therapy
• Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
• Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
• Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
• Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
• Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
• Cannabinoid: Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
• Carbidopa: This May enhance the hypotensive effect of Reserpine. Reserpine may diminish the therapeutic effect of Carbidopa. Risk X: Avoid combination
• Cardiac Glycosides: Reserpine may enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy
• Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
• Chlorphenesin Carbamate: This May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
• CNS Depressants: This May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
• Levodopa: Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
• Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy.

The common side of Reserpine includes the following

Nasal Congestion, upset stomach, headache, depression, dizziness, nausea, etc.

The use of Reserpine should be prudent in the following group of special populations:

Pregnancy

Pregnancy Category (FDA):

Pregnancy Category C

• Reserpine administered parenterally has been shown to be teratogenic in rats at doses up to 2 mg/kg and to have an embryocidal effect in guinea pigs given dosages of 0.5 mg daily.

• There are no adequate and well-controlled studies of Reserpine in pregnant women. Reserpine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

• Reserpine crosses the placental barrier, and increased respiratory tract secretions, nasal congestion, cyanosis, and anorexia may occur in neonates of reserpine-treated mothers.

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on the usage of Reserpine in women who are pregnant.

• Labor and Delivery

There is no FDA guidance on the use of Reserpine during labor and delivery.

• Nursing Mothers

Reserpine is excreted in maternal breast milk, and increased respiratory tract secretions, nasal congestion, cyanosis, and anorexia may occur in breast-fed infants. Because of the potential for adverse reactions in nursing infants and the potential for tumorigenicity shown for Reserpine in animal studies, 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.

• Race

There is no FDA guidance on the use of Reserpine with respect to specific racial populations.

• Symptoms:

Impaired consciousness ranges from drowsiness to coma, flushing, conjunctival injection, pupillary constriction, hypotension, hypothermia, central resp depression, bradycardia, increased salivary and gastric secretion, and diarrhea.

• Management:

Symptomatic and supportive treatment. Administer activated charcoal w/in 1 hour of ingestion. Place the patient in a supine position with feet raised for severe hypotension or give direct-acting sympathomimetics.

Pharmacodynamics:

Reserpine has been shown to block the vesicular storage of monoamines (including dopamine). Consequently, these neurotransmitters remain longer in the cytoplasm and are more likely to be destroyed by monoamine oxidase, the enzyme that destroys all monoamine neurotransmitters. As a result, depletion of monoamines becomes evident in central and peripheral neurons, and levels of monoamine neurotransmitters released with each neuronal action are significantly decreased. In addition, the effects of this action seem evident a few days to a few weeks after discontinuation of the supplement.

Raw rauwolfia extract seems to have a broader binding profile, and may also be a GABA and alpha 2 noradrenergic antagonist. This appears to change its pharmacodynamics and allows the compound to address a wider variety of symptoms. This also seems to reduce the adverse effects, although this property may be the result of lower reserpine levels in raw rauwolfia extracts.

Pharmacokinetics:

• Absorption:

The reported bioavailability is approximately 50% to 70% after oral ingestion. Absorption is relatively rapid, with peak concentrations achieved approximately 1 to 2 hours after administration.

• Distribution:

• Metabolism:

It gets extensively metabolized in the liver with >90%.

• Excretion:

Reserpine gets excreted via feces while keeping 60% of the drug as unchanged and through urine (approx 8% as metabolites).

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