Reserpine: plant-derived rauwolfia alkaloid
Reserpine is an indole alkaloid from the root of Rauwolfia serpentina, an Indian shrub used in Ayurvedic medicine for thousands of years. In 1952 reserpine was first isolated as a pure substance and was regarded in the 1950s and 1960s as a breakthrough antihypertensive. It also has a place in psychiatric history: it was one of the first substances with antipsychotic properties and shaped research on biogenic amines in the CNS.
Today reserpine is on the German market only as a component of a few combination preparations against hypertension and is rarely used due to its unfavourable side-effect profile. In some countries, especially in Asia, it is still used. In research, reserpine serves as a pharmacological tool for studying monoaminergic systems and as an animal model for depression and Parkinson's disease.
Mechanism of action
Reserpine irreversibly inhibits the vesicular monoamine transporter 2 (VMAT 2), which transports noradrenaline, dopamine, serotonin and to a lesser extent histamine into synaptic vesicles. When vesicular storage is blocked, monoamines in the cytoplasm are degraded by monoamine oxidase (MAO). The result is depletion of presynaptic stores and a lack of releasable neurotransmitters.
The effect develops slowly: reserpine accumulates in presynaptic vesicles and only reaches its full effect after several days to weeks. Offset is also delayed, since the effect is only reversed by synthesis of new vesicles and transporters.
Clinically this pharmacology produces:
- Antihypertensive effect via reduced sympathetic tone and decreased catecholamine release
- Antipsychotic action through reduced dopaminergic neurotransmission
- Sedative and mood-altering effects
- Characteristic induction of depressive symptoms in predisposed patients
Indications
- Arterial hypertension: historically important indication, today reserve therapy, mostly only in fixed combination with diuretics and dihydralazine in Briserin or similar products
- Symptomatic treatment of severe treatment-resistant schizophrenia: rarely off-label, since modern antipsychotics are almost always superior
- Movement disorders: tardive dyskinesia, tic disorders off-label
- Pharmacological tool in research: animal model for Parkinson and depression
In practice, reserpine is rarely prescribed in Germany today and mostly continued in legacy combination preparations when a patient has been well controlled for decades and a switch seems unwise.
Dosing and administration
Antihypertensive therapy: 0.1 to 0.25 mg daily as a single dose. Maximum dose: 0.5 mg per day, exceptionally, with markedly increased risk of side effects.
In combination preparations: often 0.1 mg reserpine combined with a diuretic (hydrochlorothiazide) and dihydralazine.
Take in the morning, ideally with a meal, to reduce gastrointestinal complaints. Full effect appears only after days to weeks; rapid dose changes are not useful.
Side effects
Very common: fatigue, drowsiness, depressive mood, nightmares, nasal congestion, dry mouth, bradycardia, orthostatic hypotension.
Common: abdominal pain, increased gastric secretion (up to ulcers), diarrhoea, sexual dysfunction, weight gain, fluid retention.
Uncommon: marked depression with suicidality, parkinsonism (extrapyramidal symptoms), confusion, bronchospasm, allergic skin reactions.
Rare: hyperprolactinaemia with galactorrhoea or gynaecomastia, pancreatitis, breast cancer (disputed link from older studies), agranulocytic reactions.
Important points:
- Frequent depressive mood is the classic textbook phenomenon and the main reason this substance has been pushed back
- Patients with a history of depression should not receive reserpine
- If suicidal thoughts arise abruptly, stop immediately and seek psychiatric assessment
- Gastric ulcer risk requires caution in patients with prior ulcer history
- Because of irreversible VMAT 2 inhibition, reserpine continues to act for days after discontinuation
Interactions
- MAO inhibitors: risk of hypertensive crisis from initial release of stored monoamines, combination contraindicated; minimum 14-day interval
- Tricyclic antidepressants and SSRIs: antagonistic effect and increased risk of hypertensive reactions
- Sympathomimetics (direct-acting, e.g. adrenaline): increased effect via receptor sensitisation
- Sympathomimetics (indirect-acting, e.g. tyramine, pseudoephedrine): attenuated effect, since stores are depleted
- Levodopa: loss of effect through reduced dopaminergic storage, avoid combination
- Other antihypertensives: additive blood pressure lowering
- Alcohol: increased sedation
- Digitalis glycosides: potentiated bradycardia
Special considerations
Pregnancy: only on strict indication, since reserpine crosses the placenta and can cause nasal obstruction, feeding difficulties and respiratory disorders in the newborn.
Breastfeeding: passage into milk, avoid use if possible.
Contraindications: active depression or suicidality, Parkinson's disease, peptic ulcer, severe renal impairment, phaeochromocytoma, marked bradycardia or conduction disorders, third-trimester pregnancy.
Older patients: increased sensitivity, risk of orthostatic hypotension and falls. The PRISCUS list classifies reserpine as potentially inappropriate.
Therapy switch: when changing to modern antihypertensives, taper slowly, since the prolonged residual effect can cause unexpectedly low blood pressure.
Emergency surgery: for elective surgery, reserpine is ideally paused 1 to 2 weeks beforehand to prevent intraoperative circulatory issues. For emergency surgery, inform the anaesthesia team.
Related substances
- Clopidogrel as modern cardiovascular protection
- Enalapril, ACE inhibitor as today's standard antihypertensive
- Propranolol, classic beta-blocker
- Levodopa, key substance in Parkinson's disease
Frequently asked questions
Why is reserpine rarely used today?
Safer and better-tolerated antihypertensives (ACE inhibitors, sartans, calcium channel blockers, beta-blockers) have displaced reserpine. Especially the cluster of depressive moods, induction of parkinsonism and the poorly controllable slow pharmacokinetics make this substance a reserve.
Can reserpine really cause depression?
Yes, this is well documented. Up to 10 % of patients develop depressive symptoms, some of them severe. Observations from the 1950s were a major impetus for the monoamine hypothesis of depression. In patients with prior depression, reserpine is contraindicated.
How long does reserpine continue to act after discontinuation?
Because reserpine inhibits VMAT 2 irreversibly, the effect persists until new vesicles and transporters are synthesised. Clinically this means residual action over days to weeks. This must be considered when switching therapy and before surgery.
Does reserpine still play a role in research?
Yes. In pharmacological research reserpine is used as a tool to investigate the role of monoamines in the CNS. Classic animal models of depression and Parkinson's use reserpine-induced store depletion.
Sources
- BfArM Federal Institute for Drugs and Medical Devices
- EMA European Medicines Agency
- AWMF guideline hypertension
- Gelbe Liste reserpine monograph
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