Reserpine

Reserpine

Overview
Reserpine is an indole
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...

 alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

 and antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...

 drug that has been used for the control of high blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

 and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today. The antihypertensive actions of reserpine are a result of its ability to deplete catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...

s (among other monoamine neurotransmitters) from peripheral sympathetic nerve endings.
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Encyclopedia
Reserpine is an indole
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...

 alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

 and antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...

 drug that has been used for the control of high blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

 and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today. The antihypertensive actions of reserpine are a result of its ability to deplete catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...

s (among other monoamine neurotransmitters) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance.

Reserpine mediated depletion of monoamine neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

s in the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

s is often cited as evidence to the theory that depletion of the neurotransmitters causes subsequent depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

 in humans (c.f. monoamine hypothesis). However, this claim is not without controversy. The reserpine-induced depression is considered by some researchers to be a myth, while others claim that teas made out of the plant roots containing reserpine have a calming, sedative action that can actually be considered antidepressant. Though this remains to be demonstrated in the clinic, it is worth noting that reserpine was the first compound shown to be an effective antidepressant in a randomized placebo-controlled trial.

Moreover, reserpine has a peripheral action in many parts of the body, resulting in a preponderance of the cholinergic part of the nervous system (GI tract, smooth muscles vessels).

Mechanism of Action


Reserpine irreversibly blocks the vesicular monoamine transporter
Vesicular monoamine transporter
The vesicular monoamine transporter is a transport protein integrated into the membrane of intracellular vesicles of presynaptic neurons. It acts to transport monoamines into the synaptic vesicles.-Monoamines:...

 (VMAT). This normally transports free norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

, and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 from the cytoplasm of the presynaptic nerve terminal into storage vesicles for subsequent release into the synaptic cleft ("exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...

"); unprotected neurotransmitters are metabolized by MAO
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...

 (as well as by COMT) in the cytoplasm and therefore never reach the synapse.

It could take days to weeks by the body to replenish the depleted VMAT and hence reserpine's effects are long-lasting.

Biosynthetic pathway


Tryptophan is the starting material in the biosynthetic pathway of reserpine, and is converted to tryptamine by tryptophan decarboxylase enzyme. Tryptamine is combined with secologanin in the presence of strictosidine synthetase enzyme and yields strictosidine. Various enzymatic conversion reactions lead to the synthesis of reserpine from strictosidine.

History


Reserpine was isolated in 1952 from the dried root of Rauwolfia serpentina
Rauwolfia serpentina
Rauvolfia serpentina, or 'snakeroot' or 'sarpagandha' is a species of flowering plant in the family Apocynaceae.-Medicinal uses:It is one of the 50 fundamental herbs used in traditional Chinese medicine, where it has the name shégēn mù or yìndù shémù .Rauwolfia serpentina contains a number of...

 (Indian snakeroot), (which had been known as Sarpaganda and had been used for centuries in India for the treatment of insanity, as well as fever and snakebites — even Mahatma Gandhi
Mahatma Gandhi
Mohandas Karamchand Gandhi , pronounced . 2 October 1869 – 30 January 1948) was the pre-eminent political and ideological leader of India during the Indian independence movement...

 used it as a tranquilizer
Tranquilizer
A tranquilizer, or tranquilliser , is a drug that induces tranquility in an individual.The term "tranquilizer" is imprecise, and is usually qualified, or replaced with more precise terms:...

. It was first used in the United States by Robert Wallace Wilkins
Robert Wallace Wilkins
Robert Wallace Wilkins was an American medical investigator and educator, made many contributions in the research of hypertension and cardiovascular disease...

 in 1950. Its molecular structure was elucidated in 1953 and natural configuration published in 1955. It was introduced in 1954, two years after chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...

. The first total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...

 was accomplished by R. B. Woodward in 1958.

Reserpine almost irreversibly blocks the uptake (and storage) of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 (i.e. noradrenaline) and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 into synaptic vesicles by inhibiting the Vesicular Monoamine Transporters (VMAT).

Reserpine has been discontinued in the UK for some years due to its numerous interactions and side effects.

Reserpine was also highly influential in promoting the thought of a biogenic amine
Biogenic amine
-Examples:Some prominent examples of biogenic amines include:* Histamine - a substance derived from the amino acid histidine that acts as a neurotransmitter mediating arousal and attention, as well as a pro-inflammatory signal released from mast cells in response to allergic reactions or tissue...

 hypothesis of depression - see Everett & Tolman, 1959.

Uses today



Reserpine is one of the few antihypertensive medications that have been shown in randomized controlled trials to reduce mortality: The Hypertension Detection and Follow-up Program, the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents, and the Systolic Hypertension in the Elderly Program.

Reserpine is rarely used in the management of hypertension today. Reserpine is listed as an option by the JNC 7. Reserpine is a second-line adjunct agent for patients who are uncontrolled on a diuretic when cost is an issue.

It is also used to treat symptoms of dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

 in patients suffering from Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...

.

In some countries reserpine is still available as part of combination drugs for the treatment of hypertension, in most cases they contain also a diuretic and/or a vasodilator like hydralazine
Hydralazine
Hydralazine is a direct-acting smooth muscle relaxant used to treat hypertension by acting as a vasodilator primarily in arteries and arterioles...

. These combinations are currently regarded as second choice drugs. The daily dose of reserpine in antihypertensive treatment is as low as 0.1 to 0.25 mg. The use of reserpine as an antipsychotic drug had been nearly completely abandoned, but more recently it made a comeback as adjunctive treatment, in combination with other antipsychotics, so that more refractory patients get dopamine blockade from the other antipsychotic, and dopamine depletion from reserpine. Doses for this kind of adjunctive goal can be kept low, resulting in better tolerability. Originally, doses of 0.5 mg to 40 mg daily were used to treat psychotic diseases. Doses in excess of 3 mg daily often required use of an anticholinergic drug to combat excessive cholinergic activity in many parts of the body as well as parkinsonism. For adjunctive treatment, doses are typically kept at or below 0.25 mg twice a day. Reserpine may be used as a sedative for horses.

Side effects


At doses of less than 0.2 mg/day, reserpine has few side effects, the most common of which is nasal congestion.

There has been much concern about reserpine causing depression leading to suicide. However, this was reported in uncontrolled studies using doses averaging 0.5 mg per day.

Reserpine can cause: nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps and diarrhea are noted. The drug causes hypotension and bradycardia and may worsen asthma. Congested nose and erectile dysfunction are other consequences of alpha-blockade. Depression can occur at any dose and may be severe enough to lead to suicide. Other central effects are a high incidence of drowsiness, dizziness, and nightmares. Parkinsonism occurs in a dose dependent manner. General weakness or fatigue is quite often encountered. High dose studies in rodents found reserpine to cause fibroadenoma of the breast and malignant tumors of the seminal vesicles among others. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. It may also cause hyperprolactinemia.

Reserpine passes into breast milk
Breast milk
Breast milk, more specifically human milk, is the milk produced by the breasts of a human female for her infant offspring...

and is harmful to breast-fed infants, and should therefore be avoided during breastfeeding if possible.

Footnotes

  1. アルカロイド (Alkaloids) (T-Z). 2004.
  2. "Indole Alkaloids" Major Types Of Chemical Compounds In Plants & Animals Part II: Phenolic Compounds, Glycosides & Alkaloids. Wayne's Word: An On-Line Textbook of Natural History. 2005.
  3. Forney, Barbara. Reserpine for Veterinary Use Wedgewood Pharmacy. 2001-2002.
  4. Rauwolfia Dorlands Medical Dictionary. Merck Source. 2002.
  5. Lopez-Munoz F, Bhatara VS, Alamo C, Cuenca E. (2004): "[Historical approach to reserpine discovery and its introduction in psychiatry]" [Article in Spanish] Actas Esp Psiquiatr. 32(6):387-95. PMID 15529229 Fulltext in English and Spanish
  6. Schuldiner, S. et al. (1993): J. Biol. Chem. 268(1) 29-34. PMID 8416935

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