APRESIN TABLET

Indications

• Schizophrenia
• Other psychotic disorders

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations for paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations for adults.

Mechanism of action

Fluphenazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain. This action decreases the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system, thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

Pharmacodynamics

Fluphenazine, as a trifluoro-methyl phenothiazine derivative, is primarily effective in managing schizophrenia and similar psychotic disorders. Its efficacy is linked to its ability to modulate dopaminergic activity in the brain, which is crucial for regulating mood and behavior. However, it has not demonstrated effectiveness in managing behavioral complications associated with mental retardation.

Pharmacokinetics

Fluphenazine is well-absorbed and undergoes extensive metabolism in the liver, with a half-life that can vary significantly among individuals. It is excreted primarily in urine and has active metabolites that contribute to its effects. The pharmacokinetics can be influenced by individual patient factors, including age, liver function, and potential interactions with other medications.

Contra-indications

• Hypersensitivity to fluphenazine or any component of the formulation
• Comatose states
• Severe central nervous system depression
• Bone marrow depression

Adverse effects

• Drowsiness
• Extrapyramidal symptoms (EPS)
• Tardive dyskinesia
• Agranulocytosis
• Hepatotoxicity
• Weight gain
• Anticholinergic effects

Interactions

• May enhance the effects of other CNS depressants
• Antihypertensive agents may have additive effects
• May affect the metabolism of drugs metabolized by CYP450 enzymes

Precautions

• Monitor for signs of agranulocytosis and hepatotoxicity
• Use with caution in patients with a history of seizures
• Caution in elderly patients and those with cardiovascular disease
• Gradual withdrawal is recommended to avoid withdrawal symptoms

Pregnancy

Fluphenazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is categorized as Pregnancy Category C.

Breast-feeding

Fluphenazine is excreted in breast milk; caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Oral tablets
• Intramuscular injection
• Depot injection

Indications

• Depressive illness
• Neuropathic pain

Dosage

Children: For children aged 12–17 years, treatment should begin at a low dose, increasing if necessary to 30–50 mg daily in divided doses or alternatively taken once daily. The maximum dose is 150 mg per day.

Adults: Initially, 10 mg once daily, preferably at night, which may be increased to 75 mg daily if necessary, with the maximum dose being 150 mg per day.

Mechanism of action

Nortriptyline is thought to inhibit the reuptake of serotonin and norepinephrine at neuronal membranes, with a more selective action on norepinephrine. This action enhances mood and alleviates depressive symptoms. Additionally, it interacts with various other receptors including muscarinic acetylcholine receptors and histamine receptors, which may contribute to both its therapeutic effects and side effects.

Pharmacodynamics

Nortriptyline exhibits antidepressant effects primarily through the inhibition of serotonin and norepinephrine reuptake, leading to increased levels of these neurotransmitters in the synaptic cleft. It also has antimuscarinic properties which can lead to side effects such as dry mouth and urinary retention. The drug's affinity for multiple receptors may influence its overall therapeutic efficacy and side effect profile.

Pharmacokinetics

Nortriptyline is well absorbed following oral administration, with peak plasma concentrations typically occurring within 4 to 8 hours. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, and has a half-life of about 18 to 44 hours. The drug is mostly excreted as metabolites in the urine. Dosing adjustments may be necessary in patients with hepatic impairment. Regular monitoring of plasma levels may be warranted in patients receiving higher doses.

Contra-indications

• Arrhythmias during the manic phase of bipolar disorder
• Heart block
• Immediate recovery period after myocardial infarction

Adverse effects

• Dry mouth
• Drowsiness
• Constipation
• Urinary retention
• Hypotension
• Cardiac conduction defects
• Arrhythmias
• Dilated pupils
• Suicidal tendencies
• Neurological effects
• Increased risk of fracture
• Photosensitivity reaction
• Respiratory disorders
• Thrombocytopenia
• Anticholinergic syndrome

Interactions

• Severe: dacomitinib increases exposure
• Moderate: eliglustat increases exposure
• Unknown: valproate increases concentration

Precautions

• Caution in patients with cardiovascular disease
• Caution in patients with chronic constipation
• Caution in patients with diabetes
• Caution in patients with epilepsy
• History of bipolar disorder
• History of alcohol dependence
• History of hyperthyroidism (risk of arrhythmias)
• Elderly patients may be particularly susceptible to side effects

Pregnancy

Use only if potential benefit outweighs risk.

Breast-feeding

The amount secreted into breast milk is too small to be harmful.

Storage

Store in a cool, dry place away from light.

Formulations

• Nortriptyline (as Nortriptyline hydrochloride) 10 mg/5 ml oral solution
• Nortriptyline tablets 10 mg
• Nortriptyline tablets 25 mg
• Nortriptyline capsules 10 mg
• Nortriptyline capsules 25 mg

Mechanism of action

Fluphenazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. Agranulocytosis and the release of transaminase enzymes from liver cells are known consequences of neuroleptic drug use. These effects are most common with low potency neuroleptic drugs. It has been hypothesized that these effects are due to the direct toxic action of these drugs on blood and liver cells. The purpose of this study is to compare the cytotoxic effects of eight neuroleptic drugs in five different biological test systems. In all of the test systems, thioridazine, chlorpromazine, trifluoperazine, fluphenzine and thiothixene (group one drugs) were the most toxic drugs and molindone was the least toxic. Thioridazine was between 25 and 84 times more toxic than molindone. Loxapine was significantly more toxic than molindone, but less toxic than the group one drugs. Haloperidol was intermediate in toxicity between the group one drugs and loxapine. /It was/ concluded that the difference in cytotoxicity of the neuroleptic drugs observed in these experiments accounts in part for the increase in agranulocytosis and hepatotoxicity with thioridazine and chlorpromazine and for the lower incidence of these side effects with less toxic drugs. The possibility that tardive dyskinesia may be due to the cytotoxic effects of neuroleptic drugs is discussed and an experiment to test this hypothesis is suggested. The principal pharmacologic effects of fluphenazine are similar to those of chlorpromazine. Fluphenazine is more potent on a weight basis than chlorpromazine. Fluphenazine has weak anticholinergic and sedative effects and strong extrapyramidal effects. Fluphenazine has weak antiemetic activity. The development of phenothiazine derivatives as psychopharmacologic agents resulted from the observation that certain phenothiazine antihistaminic compounds produced sedation. In an attempt to enhance the sedative effects of these drugs, promethazine and chlorpromazine were synthesized. Chlorpromazine is the pharmacologic prototype of the phenothiazines. The pharmacology of phenothiazines is complex, and because of their actions on the central and autonomic nervous systems, the drugs affect many different sites in the body. Although the actions of the various phenothiazines are generally similar, these drugs differ both quantitatively and qualitatively in the extent to which they produce specific pharmacologic effects. /Phenothiazine General Statement/ In the CNS, phenothiazines act principally at the subcortical levels of the reticular formation, limbic system, and hypothalamus. Phenothiazines generally do not produce substantial cortical depression; however, there is minimal information on the specific effects of phenothiazines at the cortical level. Phenothiazines also act in the basal ganglia, exhibiting extrapyramidal effects. The precise mechanism(s) of action, including antipsychotic action, of phenothiazines has not been determined, but may be principally related to antidopaminergic effects of the drugs. There is evidence to indicate that phenothiazines antagonize dopamine-mediated neurotransmission at the synapses. There is also some evidence that phenothiazines may block postsynaptic dopamine receptor sites. However, it has not been determined whether the antipsychotic effect of the drugs is causally related to their antidopaminergic effects. Phenothiazines also have peripheral and/or central antagonistic activity against alpha-adrenergic, serotonergic, histaminic (H1-receptors), and muscarinic receptors. Phenothiazines also have some adrenergic activity, since they block the reuptake of monoamines at the presynaptic neuronal membrane, which tends to enhance neurotransmission. The effects of phenothiazines on the autonomic nervo

Pharmacodynamics

Fluphenazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Fluphenazine has not been shown effective in the management of behaviorial complications in patients with mental retardation.

Mechanism of action

Though prescribing information does not identify a specific mechanism of action for nortriptyline, is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at the level of the beta-adrenergic receptors. It displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake. As with other tricyclics, nortriptyline displays affinity for other receptors including mACh receptors, histamine receptors, 5-HT receptors, in addition to other receptors. The mechanism of adverse imipramine-induced reactions ... was investigated by precipitating such reactions in rats with three injections (ip) of imipramine (5-40 mg/kg) at 24, 5, and 1 hr before testing, and comparing their occurrence with comparable treatments using specific noradrenergic and serotonergic reuptake inhibitors (nortriptyline (10 or 30 mg/kg, ip), citalopram (0.5-5.0 mg/kg, ip)). This initial study indicated that these reactions were mediated by imipramine's noradrenergic effects. The effect of equal-dose regimens of amitriptyline and nortriptyline on the concn of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline incr to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs incr serotonin levels but decr cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential incr in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an incr in dopamine turnover particularly in brain areas assoc with motor function and posture which may account for tricyclic antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition. Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through beta2-adrenoceptors (beta2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor a (TNFa) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on beta2-ARs expressed by non-neuronal satellite cells. This stimulation of beta2-ARs decreases the neuropathy-induced production of membrane-bound TNFa, resulting in relief of neuropathic allodynia. This indirect anti-TNFa action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the beta2-AR agonist terbutali

Pharmacodynamics

Nortriptyline exerts antidepressant effects likely by inhibiting the reuptake of serotonin and norepinephrine at neuronal cell membranes. It also exerts antimuscarinic effects through its actions on the acetylcholine receptor.