Prothipendyl
Low potency neuroleptic for agitation and sleep disorders
Prothipendyl is a low potency neuroleptic from the group of azaphenothiazines, marketed in Germany since 1961 under the brand name Dominal. The substance is today used predominantly for the dampening of agitation, insomnia and psychomotor excitement and rarely for long term antipsychotic therapy. Dominal forte and Dominal compact packages as well as generics are available in Germany as tablets and in a few other formulations.
Because of its pharmacological profile, prothipendyl is particularly common in older patients with agitated symptomatology, in dementia related restlessness and in sleep disorders in the inpatient setting. The pronounced sedative component outweighs the antipsychotic action, which is why the drug is used in many psychiatric hospitals as a second line sedative when benzodiazepines are to be avoided because of dependence risk.
Mechanism of Action
Prothipendyl blocks postsynaptic dopamine D2 receptors, with an affinity markedly lower than that of high potency neuroleptics such as haloperidol. More pronounced is the blockade of histamine H1 receptors, which explains the characteristic marked sedation. Additional effects at α1 adrenoceptors and muscarinic acetylcholine receptors lead to hypotension, tachycardia and anticholinergic side effects.
This receptor profile makes prothipendyl pharmacologically a low potency neuroleptic with predominantly sedative and anxiolytic properties and only weak antipsychotic activity. The substance dampens psychomotor excitement, reduces anxiety and promotes sleep. Extrapyramidal motor side effects are less frequent than with high potency neuroleptics, though tardive dyskinesia with long term therapy remains possible.
The half life is about 3 to 4 hours, which often requires multiple daily dosing. Metabolism is hepatic via sulfoxidation and glucuronidation; elimination is mainly renal. In older patients, elimination is slowed, so cautious dose titration is indicated.
Indications
- Psychomotor excitement in various psychiatric and neurological disorders
- Sleep disorders of psychiatric origin, as an alternative to benzodiazepines
- Anxiety and tension states
- Dementia related restlessness with cautious indication in view of the increased mortality risk in dementia patients
- Alcohol and substance withdrawal adjunctive sedation
- Augmentation of antipsychotics to strengthen sedation in acute situations
Dosage and Administration
Sleep disorders and agitation: 40 to 80 mg in the evening; for severe agitation during the day add 40 mg in the morning and at midday. For pronounced psychomotor excitement up to 320 mg per day in 3 to 4 divided doses.
Older patients: lower starting dose of 40 mg in the evening, slow titration, markedly reduced maximum dose because of increased delirium and fall risk. The Priscus list of potentially inappropriate medications for older people is critical of low potency neuroleptics, and strict indication is obligatory in this group.
Intake is with or without food; swallow tablets whole. Onset of action occurs within 30 to 60 minutes. With evening dosing allow at least 8 to 10 hours before waking to avoid hangover sedation.
Renal impairment: consider dose reduction in moderate impairment, cautious titration in severe impairment. Hepatic impairment: dose reduction in severe impairment because of slowed metabolism. Children and adolescents: not approved for children under 18 years.
Side Effects
Very common and common: sedation, dry mouth, lethargy, morning drowsiness, orthostatic hypotension, constipation, blurred vision, tachycardia, weight gain, urinary complaints.
Uncommon: extrapyramidal motor disorders (parkinsonism, akathisia, early dyskinesia), hyperprolactinaemia with galactorrhea or cycle disturbances, skin rash, photosensitivity, elevated liver enzymes.
Serious: neuroleptic malignant syndrome, tardive dyskinesia with long term therapy, agranulocytosis, QT prolongation with torsade de pointes, cerebrovascular events in dementia patients (Dear Doctor letter for the entire neuroleptic class), venous thromboembolism, seizures due to lowered seizure threshold.
Special considerations: in older patients with dementia there is increased risk of cerebrovascular events and all cause mortality. Use in this group requires strict indication, written information and regular reassessment; non pharmacological interventions (daily structure, light, movement, biography oriented communication) should be tried first.
Interactions
- Central depressants (alcohol, benzodiazepines, opioids, barbiturates, other neuroleptics): strongly enhanced sedation and respiratory depression
- Anticholinergics (tricyclic antidepressants, biperiden, scopolamine): additive anticholinergic effects up to anticholinergic delirium
- QT prolonging drugs (amiodarone, sotalol, macrolides, ondansetron, quinolones): additive torsade de pointes risk
- Antihypertensives: enhanced hypotension
- Levodopa, dopamine agonists: mutual action reversal
- Lithium: increased neurotoxicity possible
- CYP substrates and inhibitors: prothipendyl is only partly hepatically metabolised, interaction potential lower than with phenothiazines with strong CYP involvement
Special Notes
Contraindications: comatose states, acute intoxication with central depressants, narrow angle glaucoma, urinary retention in prostatic hypertrophy, severe bone marrow depression, Parkinson's disease, porphyria, known QT prolongation, pheochromocytoma.
Dementia related behavioural disorders: all antipsychotics carry an increased risk of cerebrovascular events and all cause mortality in this indication (Dear Doctor letter). Use is only justifiable after non pharmacological measures have been exhausted and in cases of clear harm to self or others, at the lowest effective dose for short duration with reassessment.
Pregnancy: experience is limited; use only under compelling indication. Newborns exposed in the third trimester may show withdrawal symptoms or extrapyramidal motor signs; neonatal observation is advisable. Lactation: passes into breast milk; breastfeeding under therapy is not recommended.
Monitoring: blood pressure, heart rate, ECG before therapy in at risk patients. Blood count, liver values every 3 to 6 months. In older patients regularly assess fall risk, cognitive function, oral hygiene and nutritional status. Tardive dyskinesia screening (AIMS) with long term therapy.
Driving: the substance markedly impairs reaction time and vigilance, especially during initiation and dose changes. Operating machinery and active driving should be avoided at the start and after dose increases.
You Might Also Be Interested In
- Chlorprothixene, thioxanthene in acute sedation
- Chlorpromazine, classical phenothiazine
- Levomepromazine, sedating phenothiazine in palliative care
- Fluanxol (flupentixol), thioxanthene with dual dose action
- Aripiprazole, atypical antipsychotic
Frequently Asked Questions
Why is Dominal used for sleep disorders?
Prothipendyl has pronounced sedation based on histamine H1 blockade. Unlike benzodiazepines it has no dependence potential, which makes the substance attractive in long term psychiatric situations. Its antipsychotic action is weak, so the drug is used primarily as a sedative rather than as an antipsychotic.
Is prothipendyl addictive?
Prothipendyl is not among substances with classical dependence potential such as benzodiazepines or opioids. Nevertheless, abrupt discontinuation after long term therapy is not advisable because recurrence of symptoms and sleep disturbance can be expected. Gradual tapering over days to weeks is usual.
Can my relative with dementia take prothipendyl?
Use is possible, but must be strictly indicated. In elderly dementia patients all antipsychotics carry an increased risk of cerebrovascular events and all cause mortality. Non pharmacological interventions such as daily structure, validating communication, pain management and sensory adaptation should be tried first. If prothipendyl is necessary, use the lowest dose for short duration with reassessment.
How long does morning drowsiness last?
Residual fatigue may be pronounced in the first hours after waking, especially after higher evening doses and in older patients. Evening intake 8 to 10 hours before planned waking is important. With marked morning dullness a dose reduction or switch to another substance should be considered.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guideline on Dementia and Sleep Disorders
- Gelbe Liste, Prothipendyl active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
Legal Notice and Disclaimer
The information provided on this page is for general informational purposes only and does not constitute medical advice, diagnosis or treatment recommendation. It does not replace consultation with a licensed physician or pharmacist. Medicines should only be taken on medical prescription or via a pharmacy. All information is based on product information and recognised scientific sources published at the time of creation; the manufacturer's current summary of product characteristics is always authoritative. Sanoliste assumes no liability for the completeness, timeliness or accuracy of the information presented. In a medical emergency, call the emergency number 112 (Europe).