Pizotifen

Pizotifen Uses, Dosage, Side Effects, Food Interaction and all others data.

Pizotifen is a tri-cyclic compound possessing structural similarities to cyproheptadine and tri-cyclic antidepressants. It is given orally for the prophylaxis of migraine and for the prevention of headache attacks during cluster periods. It is not effective in acute attacks of migraine.

The prophylactic effect of Pizotifen is associated with its ability to modify the humoral mechanisms of headache. It inhibits the permeability increasing effect of serotonin and histamine on the affected cranial vessels, thereby checking the transudation of plasmakinin so that the pain threshold of the receptor is maintained at "normal" levels. In the sequence of events leading to migraine attack, depletion of plasma serotonin contributes to loss of tone of extracranial vessels. Pizotifen inhibits serotonin re-uptake by the platelets, thus maintaining plasma serotonin and preventing the loss of tone and passive diffusion of the extracranial arteries.

Various studies have shown pizotifen to be effective in the prophylaxis of migraines in reducing the frequency and severity of vascular headaches . Evidence from studies in vivo and in vitro demonstrate antagonistic actions towards serotonin and histamine. Pizotifen blocks the postsynaptic 5-HT2 receptors, as supported by antagonism of several direct agonists of 5-HT receptors . It is an antagonist at histamine H1 receptors, and is weakly anticholinergic . It also binds to α1- and α2-adrenergic receptors, and dopamine receptors . Pizotifen elicits a minimal effect as an epinephrine or bradykinin antagonist . Pizotifen exhibits weak sedative properties in mouse and monkey studies, as indicated by inhibition of locomotion and potentiation of barbiturates, without changes in cardiac or respiratory rates . In dogs, intravenous administration of pizotifen cause rapid hypotension but was reversed to normal within 30 minutes . Pizotifen was shown to inhibit serotonin uptake in the isolated perfused cat spleen and, in vivo, inhibits serotonin-induced contractions in rat uterus and cat nictiating membrane . In contrast, pizotifen demonstrated a venoconstrictor activity in vivo when orally or intravenously administered to saphenous veins in conscious dogs . Pizotifen has the potential to stimulate the appetite and may cause weight gain upon treatment .

In a double-blind clinical study of patients with mild to moderate depression, treatment of pizotifen led to clinical improvement of the depressive symptoms. However, deterioration of the schizophrenic emotional symptoms was also observed in patients with depression and chronic schizophrenia . This indicates that pizotifen may potentially improve the symptoms of patients with depressions in conjunction with migraines .

Neuroprotective effect of pizotifen was investigated in vitro in a mouse cell model of Huntington's disease (HD). According to a chemical screen of a mouse HdhQ111/Q111 striatal cell model of HD, treatment of pizotifen was associated with increased ATP levels and decreased activation of caspase-3, leading to enhanced cell viability . Transient activation of ERK signalling pathway lasting for less than 3 hours was also observed. In the R6/2 transgenic mouse model of HD, rotarod performance of the mouse treated with pizotifen was seen, accompanied by an increase in DARPP-32 protein expression and restoration of striatal area . However these effects being reflected in vivo are not established.

Pizotifen
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Pizotifen
Generic	Pizotifen
Pizotifen Other Names	Pizotifen, pizotifeno, Pizotyline
Type	Tablets
Formula	C₁₉H₂₁NS
Weight	Average: 295.44 Monoisotopic: 295.139470854
Protein binding	Plasma protein binding of pizotifen is > 90% .
Groups	Approved
Therapeutic Class	Anti-histamine Preparations, Other drugs for migraine
Manufacturer	Rivopharm Uk Ltd, Accord-uk Ltd
Available Country	United Kingdom
Last Updated:	September 19, 2023 at 7:00 am

Uses

Pizotifen is chiefly used for the prophylactic treatment of vascular headaches of the migraine type such as classical migraine, common migraine and cluster headache.

Pizotifen is also used to associated treatment for these conditions: Migraine

How Pizotifen works

While the mechanism of action is not fully understood, it is proposed that pizotifen works by inhibiting the peripheral actions of serotonin and histamine in increasing the membrane permeability of cranial vessels and transudation of plasmakinin, while altering pain thresholds in migraines . By blocking 5-HT receptors, pizotifen attenuates the signalling of serotonin in causing cranial vasoconstriction, as well as serotonin-enhanced platelet function and aggregation . There is evidence that it also inhibits the peripheral actions of bradykinin . Pizotifen may inhibit serotonin reuptake by blood platelets, which affects the tonicity and decreases passive distension of extracranial arteries . The effects of pizotifen leading to appetite stimulation may be due to the drug acting at the metabolic level rather than a direct stimulation of the appetite centre .

Dosage

Pizotifen dosage

Adults: The initial adult dose is 1.5 mg daily, this may be taken at bed time as a single dose or in three divided doses. Dosage can be adjusted according to individual patients’ requirements up to a maximum of 4.5 mg daily. Up to 3 mg may be given as a single daily dose.

Children: Up to 1.5 mg daily, usually as a divided dose. Use of 1.5 mg at a time is not recommended, but up to 1 mg has been given as a single daily dose at night.

Side Effects

Drowsiness is the most common side effect and also increased appetite, which may lead to increase in body weight. Other side effects are, dizziness, dry mouth, nausea, constipation, which are rare. In children central nervous system (CNS) stimulation may occur.

Toxicity

The oral Lowest published toxic dose (TDLo) is 12.86 mg/kg in man . Oral LD50 ranges from 410 to 1500 mg/kg in rat . Oral LD50 in mouse and rabbit is 880 mg/kg and 700 mg/kg, respectively . The LD50 following intravenous administration in rat was 17 mg/kg .

In adults, the symptoms of overdosage include sedation, drowsiness (preceding excitement, convulsions, and postictal depression), dizziness, hypotension, dryness of the mouth, confusion, tachycardia, ataxia, nausea, vomiting, dyspnea, cyanosis, convulsions, coma, respiratory paralysis and CNS depression . Antihistamine toxicity of pizotifen in children may involve excitation, hallucinations, ataxia, incoordination, convulsions, fixed dilated pupils, flushed faces, and fever, leading to coma and cardiorespiratory collapse . The use of activated charcoal is recommended in the management of overdose. For drug recent uptake, induction of emesis or gastric lavage and diuresis should be performed . Supportive measures should be initiated to maintain effective respiration while closely monitoring vital signs. While severe hypotension must be corrected, the use of adrenaline may produce paradoxical effects .

As pizotifen has the potential to cause tachycardia, an ECG should be performed and attention directed at the QRS and QT intervals . Excitatory states or convulsions induced by pizotifen may be treated with short-acting barbiturates or benzodiazepines. However analeptics should be avoided .

Precaution

Patients should be cautioned about the possibility of drowsiness and informed of its significance in driving vehicles and operation of machineries. Pizotifen may enhance the central effects of sedatives, hypnotic, antihistamines and alcohol. Dose adjustment may be required in patients with renal insufficiency.

Interaction

Patients should be warned that their tolerance to alcohol may be lowered. Pizotifen may increase and prolong the drowsiness that occurs as an adverse effect of concurrently used tranquilizers, hypnotics and antidepressants. It should not be used in patients receiving monoamine oxidase inhibitors.

Food Interaction

Take with or without food. The absorption is unaffected by food.

Volume of Distribution

The volume of distribution in an adult male is 833L for pizotifen and 70L for the N-glucuronide conjugate .

Elimination Route

The absorption half-life of pizotifen following oral administration is 0.5 to 0.8 hours in an adult male with nearly complete absorption rate of 80%. Maximum blood levels are reached 5 hours post-administration and the absolute bioavailability is 78% .

Half Life

The elimination half-life for pizotifen and N-glucuronide conjugate is about 23 hours .

Elimination Route

About one third of the total orally administered dose is excreted into the feces. Less than 1% of the total dose is excreted in the urine as the unchanged parent drug, and up to 55% of the dose is excreted as its metabolites .

Pregnancy & Breastfeeding use

Information of using Pizotifen in pregnancy is limited, so it should only be used during pregnancy under compelling circumstances and it is not recommended to the nursing mother.

Contraindication

Although its anticholinergic activity is relatively weak, Pizotifen should probably not be administered in presence of narrow angle glaucoma or prostate hypertrophy. It should not be given in patients with hypersensitivity to this drug.