Flupenthixol
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Flupentixol ( INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a
typical antipsychotic Typical antipsychotics (also known as major tranquilizers, and first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia). Typical antipsychotics m ...
drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
of the
thioxanthene Thioxanthene is a chemical compound in which the oxygen atom in xanthene is replaced with a sulfur atom. It is also related to phenothiazine. Several of its chemical derivative, derivatives are used as typical antipsychotics in the treatment of sc ...
class. It was introduced in 1965 by
Lundbeck H. Lundbeck A/S, commonly referred to as Lundbeck, is a Denmark, Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products ar ...
. In addition to single drug preparations, it is also available as flupentixol/melitracen—a combination product containing both melitracen (a
tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...
) and flupentixol (marketed as Deanxit). Flupentixol is not approved for use in the United States. It is, however, approved for use in the UK,
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Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...
, and various other countries.


Medical uses

Flupentixol's main use is as a long-acting injection given once in every two or three weeks to individuals with
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
who have poor compliance with medication and have frequent relapses of illness, though it is also commonly given as a tablet. There is little formal evidence to support its use for this indication but it has been in use for over fifty years. Flupentixol is also used in low doses as an
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
. There is tentative evidence that it reduces the rate of deliberate
self-harm Self-harm refers to intentional behaviors that cause harm to oneself. This is most commonly regarded as direct injury of one's own skin tissues, usually without suicidal intention. Other terms such as cutting, self-abuse, self-injury, and s ...
, among those who self-harm repeatedly.


Adverse effects

Adverse effect incidence ;Common (>1% incidence) adverse effects include: * Extrapyramidal side effects such as: (which ''usually'' become apparent soon after therapy is begun or soon after an increase in dose is made) ** Muscle rigidity **
Hypokinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sy ...
** Hyperkinesia **
Parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...
** Tremor **
Akathisia Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those a ...
**
Dystonia Dystonia is a neurology, neurological Hyperkinesia, hyperkinetic Movement disorders, movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed po ...
* Dry mouth * Constipation * Hypersalivation – excessive salivation * Blurred vision * Diaphoresis – excessive sweating * Nausea * Dizziness *
Somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...
* Restlessness * Insomnia * Overactivity * Headache * Nervousness *
Fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
*
Myalgia Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...
* Hyperprolactinemia and its complications such as: (''acutely'') ** Sexual dysfunction ** Amenorrhea – cessation of menstrual cycles ** Gynecomastia – enlargement of breast tissue in males ** Galactorrhea – the expulsion of breast milk that's not related to breastfeeding or pregnancy : and if the hyperprolactinemia persists ''chronically'', the following adverse effects may be seen: :* Reduced bone mineral density leading to
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
(brittle bones) :* Infertility * Dyspepsia – indigestion * Abdominal pain * Flatulence * Nasal congestion * Polyuria – passing more urine than usual ;Uncommon (0.1–1% incidence) adverse effects include: * Fainting * Palpitations ;Rare (<0.1% incidence) adverse effects include: * Blood dyscrasias (abnormalities in the cell composition of blood), such as: **
Agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing neutropenia in the circulating blood. I ...
– a drop in white blood cell counts that leaves one open to potentially life-threatening infections **
Neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
– a drop in the number of neutrophils (white blood cells that specifically fight bacteria) in one's blood **
Leucopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * sk ...
– a less severe drop in white blood cell counts than agranulocytosis **
Thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...
– a drop in the number of platelets in the blood. Platelets are responsible for blood clotting and hence this leads to an increased risk of bruising and other bleeds *
Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...
– a potentially fatal condition that appear to result from central D2 receptor blockade. The symptoms include: **
Hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...
** Muscle rigidity ** Rhabdomyolysis ** Autonomic instability (e.g.,
tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
, diarrhea, diaphoresis, etc.) ** Mental status changes (e.g., coma, agitation, anxiety, confusion, etc.) ;Unknown incidence adverse effects include: * Jaundice * Abnormal liver function test results *
Tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
– an often incurable movement disorder that usually results from years of continuous treatment with antipsychotic drugs, especially typical antipsychotics like flupenthixol. It presents with repetitive, involuntary, purposeless and slow movements; TD can be triggered by a fast dose reduction in any antipsychotic. * Hypotension * Confusional state * Seizures *
Mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...
*
Hypomania Hypomania (literally "under mania" or "less than mania") is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome characterized essentially by an apparently non-contextual elevation of Mood (psychology), mood (i.e., euphoria) th ...
* Depression * Hot flush * Anergia * Appetite changes * Weight changes * Hyperglycemia – high blood glucose (sugar) levels * Abnormal glucose tolerance * Pruritus – itchiness * Rash * Dermatitis * Photosensitivity – sensitivity to light * Oculogyric crisis * Accommodation disorder * Sleep disorder * Impaired concentration * Tachycardia * QTc interval prolongation – an abnormality in the electrical activity of the heart that can lead to potentially fatal changes in heart rhythm (only in
overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.
or <10 ms increases in QTc) * Torsades de pointes * Miosis – constriction of the pupil of the eye * Paralytic ileus – paralysis of the bowel muscles leading to severe constipation, inability to pass wind, etc. * Mydriasis *
Glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...


Interactions

It should not be used concomitantly with medications known to prolong the QTc interval (e.g.,
5-HT3 antagonist The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With th ...
s, tricyclic antidepressants,
citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soci ...
, etc.) as this may lead to an increased risk of QTc interval prolongation. Neither should it be given concurrently with
lithium (medication) Certain lithium compounds, also known as lithium salts, are used as psychiatric medication, primarily for bipolar disorder and for major depressive disorder. Lithium is taken orally (by mouth). Common side effects include increased urinati ...
as it may increase the risk of lithium toxicity and
neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...
. It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as
neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...
. It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates.


Contraindications

It should not be given in the following disease states: *
Pheochromocytoma Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they relea ...
* Prolactin-dependent tumors such as pituitary
prolactinoma A prolactinoma is a tumor (adenoma) of the pituitary gland that produces the hormone prolactin. It is the most common type of functioning pituitary tumor. Symptoms of prolactinoma are due to abnormally high levels of prolactin in the blood ( hyp ...
s and
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
*
Long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainti ...
* Coma * Circulatory collapse * Subcortical brain damage * Blood dyscrasia * Parkinson's disease *
Dementia with Lewy bodies Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior change (individual), behavior, cognition, movement, and dysautonomia, regulation of automatic bodily functions. Unlike some other dementias, mem ...


Pharmacology


Pharmacodynamics

Binding profile Acronyms used:
HFC – Human frontal cortex receptor
MB – Mouse brain receptor
RC – Cloned rat receptor A study measuring the
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
receptor occupancies of 13 schizophrenic patients treated with 5.7 ± 1.4 mg/day of flupentixol found 50-70% receptor occupancy for D2, 20 ± 5% for D1, and 20 ± 10% for 5-HT2A. Its antipsychotic effects are predominantly a function of D2 antagonism. Its antidepressant effects at lower doses are not well understood; however, it may be mediated by
functional selectivity Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the end ...
and/or preferentially binding to D2
autoreceptor An autoreceptor is a type of Receptor (biochemistry), receptor located in the cell membrane, membranes of neuron, nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or ...
s at low doses, resulting in increased postsynaptic activation via higher dopamine levels. Flupentixol's demonstrated ability to raise dopamine levels in mice and flies lends credibility to the supposition of autoreceptor bias. Functional selectivity may be responsible through causing preferential autoreceptor binding or other means. The effective dosage guideline for an antipsychotic is very closely related to its receptor residency time (i.e., where drugs like aripiprazole take several minutes or more to disassociate from a receptor while drugs like quetiapine and clozapine—with guideline dosages in the hundreds of milligrams—take under 30s) and long receptor residency time is strongly correlated with likehood of pronounced functional selectivity; thus, with a maximum guideline dose of only 18 mg/day for schizophrenia, there is a significant possibility of this drug possessing unique signalling characteristics that permit counterintuitive dopaminergic action at low doses.


Pharmacokinetics


History

In March 1963 the Danish pharmaceutical company Lundbeck began research into further agents for schizophrenia, having already developed the thioxanthene derivatives clopenthixol and chlorprothixene. By 1965 the promising agent flupenthixol had been developed and trialled in two hospitals in Vienna by Austrian psychiatrist Heinrich Gross. The long- acting decanoate preparation was synthesised in 1967 and introduced into hospital practice in Sweden in 1968, with a reduction in relapses among patients who were put on the depot.


References

{{Tricyclics Typical antipsychotics Antidepressants Trifluoromethyl compounds Piperazines Thioxanthene antipsychotics