Product Details

PIZOTIFEN

Pizotifen belongs to the class of antamines and is related to Cyproheptadine. It is a potent serotonin and tryptamine antagonist that has been used for migraine prevention for many years. It exhibits weak anticholinergic, antihistamine, and antikinin actions in addition to sedative and appetite-stimulating properties. Some patients receiving pizotifen treatment developed tolerance with the prolonged use of the drug. Numerous studies have revealed the potential antidepressant effects of pizotifen, which are independent of its antimigraine action. While it is suggested that pizotifen may act similarly to the classic tricyclic antidepressants, its full mechanism of antidepressant action is not fully elucidated.

Indication

Indicated for the prophylactic management of migraines.

Associated Conditions

• Migraines

Pharmacodynamics

Various studies have shown pizotifen to be effective in the prophylaxis of migraines in reducing the frequency and severity of vascular headaches [3]. 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 [5]. It is an antagonist at histamine H1 receptors, and is weakly anticholinergic [9]. It also binds to α1- and α2-adrenergic receptors, and dopamine receptors [9]. Pizotifen elicits a minimal effect as an epinephrine or bradykinin antagonist [10]. 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 [10]. In dogs, intravenous administration of pizotifen cause rapid hypotension but was reversed to normal within 30 minutes [10]. 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 [2]. In contrast, pizotifen demonstrated a venoconstrictor activity in vivo when orally or intravenously administered to saphenous veins in conscious dogs [4]. Pizotifen has the potential to stimulate the appetite and may cause weight gain upon treatment [2].

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 [1]. This indicates that pizotifen may potentially improve the symptoms of patients with depressions in conjunction with migraines [1].

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 [6]. 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 [6]. However these effects being reflected in vivo are not established.

Mechanism of action

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 [10]. By blocking 5-HT receptors, pizotifen attenuates the signalling of serotonin in causing cranial vasoconstriction, as well as serotonin-enhanced platelet function and aggregation [7, 9]. There is evidence that it also inhibits the peripheral actions of bradykinin [2]. Pizotifen may inhibit serotonin reuptake by blood platelets, which affects the tonicity and decreases passive distension of extracranial arteries [10]. 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.

Absorption

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% [10].

Volume of distribution

The volume of distribution in an adult male is 833L for pizotifen and 70L for the N-glucuronide conjugate [10].

Protein binding

Plasma protein binding of pizotifen is > 90% [10].

Metabolism

Pizotifen is extensively metabolized in the liver, where it primarily undergoes N-glucuronidation to form the main metabolite, N-glucuronide conjugate [10]. N-glucuronide conjugate accounts for at least 50% of the plasma and 60-70% of the urinary-excreted radioactivity [10].

• Pizotifen
   
  Pizotifen glucuronide

Route of elimination

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 [10].

Half life

The elimination half-life for pizotifen and N-glucuronide conjugate is about 23 hours [10].

Clearance

Not Available

Toxicity

The oral Lowest published toxic dose (TDLo) is 12.86 mg/kg in man [MSDS]. Oral LD50 ranges from 410 to 1500 mg/kg in rat [MSDS]. Oral LD50 in mouse and rabbit is 880 mg/kg and 700 mg/kg, respectively [10]. The LD50 following intravenous administration in rat was 17 mg/kg [10].

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 [10]. 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 [10]. 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 [10]. 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 [10].

As pizotifen has the potential to cause tachycardia, an ECG should be performed and attention directed at the QRS and QT intervals [10]. Excitatory states or convulsions induced by pizotifen may be treated with short-acting barbiturates or benzodiazepines. However analeptics should be avoided.

SOURCE:DRUGBANK