CHLORPROMAZINE 50MG/2ML INJECTION

Indications

• Schizophrenia
• Bipolar disorder

Mechanism of action

Chlorpromazine acts as an antagonist on various postsynaptic receptors, including dopaminergic receptors (D1, D2, D3, and D4), serotonergic receptors (5-HT1 and 5-HT2), histaminergic receptors (H1), alpha-adrenergic receptors (alpha1 and alpha2), and muscarinic (cholinergic) M1/M2 receptors. This blockade results in a range of effects, including alleviation of positive and negative symptoms of schizophrenia, sedation, antiemetic effects, and modulation of extrapyramidal side effects. It also weakly inhibits dopamine reuptake, which may provide mild antidepressant and antiparkinsonian effects.

Pharmacodynamics

Chlorpromazine primarily exerts its pharmacologic effects at subcortical levels of the central nervous system. Its actions include strong antiadrenergic effects, sedative properties, and antiemetic activity. Chlorpromazine also has peripheral anticholinergic activity, which is relatively mild, along with slight antihistaminic and antiserotonin activity, contributing to its complex side effect profile. The drug may induce sedation, hypotension, and weight gain, while also potentially leading to extrapyramidal symptoms depending on the balance of receptor interactions.

Pharmacokinetics

Chlorpromazine is well-absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 2 to 4 hours after oral administration. It has a long half-life, ranging from 30 to 40 hours, allowing for once or twice daily dosing. The drug is extensively metabolized in the liver, primarily via the cytochrome P450 system, and is excreted mainly in urine as metabolites. The drug's effects can be influenced by hepatic function and other medications that affect the CYP enzyme system.

Adverse effects

• sedation
• weight gain
• hypotension
• extrapyramidal symptoms
• anticholinergic effects
• sexual dysfunction
• blurred vision
• dry mouth
• constipation
• tachycardia
• ECG changes
• memory loss

Interactions

• chlorpromazine+metyrapone: Severe (decreases effects)
• mexiletine+chlorpromazine: Unknown (increases exposure)
• osilodrostat+chlorpromazine: Unknown (increases exposure)
• chlorpromazine+antiepileptics: Unknown (decreases concentration)
• chlorpromazine+phenobarbital: Unknown (decreases concentration)
• chlorpromazine+primidone: Unknown (decreases concentration)
• chlorpromazine+desmopressin: Unknown (increases risk of hyponatraemia)
• rucaparib+chlorpromazine: Unknown (increases exposure)
• ssris+chlorpromazine: Unknown (increases exposure)
• vemurafenib+chlorpromazine: Unknown (increases exposure)

Pregnancy

Chlorpromazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is important to consider alternative treatments.

Breast-feeding

Chlorpromazine is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• tablets
• oral liquid
• injectable solution

Indications

• Schizophrenia
• Other psychoses
• Mania
• Adjunctive management of severe anxiety
• Short-term management of psychomotor agitation
• Nausea and vomiting in palliative care
• Intractable hiccup

Dosage

Adults: Initially

Mechanism of action

Chlorpromazine exerts its therapeutic effects by antagonizing dopamine D2 receptors in the central nervous system. This blockade reduces dopaminergic activity, which is often elevated in conditions like schizophrenia. Chlorpromazine also has affinity for various other receptors, including serotonin, histamine, and adrenergic receptors, contributing to its antipsychotic and sedative effects. Additionally, it may affect the cholinergic system, which can help manage extrapyramidal side effects associated with dopamine antagonism.

Pharmacodynamics

The pharmacodynamics of chlorpromazine involves its ability to modulate neurotransmitter activity in the brain. By blocking D2 receptors, chlorpromazine decreases the symptoms of psychosis, such as hallucinations and delusions. Its sedative properties arise from blockade of histamine H1 receptors, which can lead to drowsiness. Chlorpromazine may also influence mood and anxiety through its effects on serotonin receptors. It has a wide range of side effects due to its action on multiple receptor systems, including extrapyramidal symptoms, sedation, and metabolic effects.

Pharmacokinetics

Chlorpromazine is well-absorbed when administered orally, with peak plasma concentrations typically occurring within 2 to 4 hours. It is highly protein-bound (approximately 90%), and its volume of distribution is large, indicating extensive tissue uptake. The drug undergoes extensive hepatic metabolism, primarily via the cytochrome P450 system, and is excreted in urine and feces. The elimination half-life ranges from 30 to 100 hours, influenced by factors such as age, hepatic function, and concurrent medications.

Contra-indications

• CNS depression
• comatose states
• hypothyroidism
• phaeochromocytoma

Adverse effects

• Agitation
• Amenorrhoea
• Arrhythmias
• Constipation
• Dizziness
• Drowsiness
• Dry mouth
• Erectile dysfunction
• Fatigue
• Galactorrhoea
• Gynaecomastia
• Hyperglycaemia
• Hyperprolactinaemia
• Hypotension (dose-related)
• Insomnia
• Leucopenia
• Movement disorders
• Muscle rigidity
• Neutropenia
• Parkinsonism
• Postural hypotension (dose-related)
• QT prolongation
• Sudden death withdrawal syndrome

Precautions

• Drowsiness may affect performance of skilled tasks, especially at the start of treatment
• Patients should avoid direct sunlight due to potential photosensitisation
• Caution in patients with cardiovascular disease
• Monitor prolactin concentrations at the start of therapy and periodically thereafter
• Regular physical health monitoring for patients with schizophrenia

Pregnancy

Extrapyramidal effects and withdrawal syndrome have been reported in neonates when antipsychotic drugs are taken during the third trimester. Neonates should be monitored for symptoms such as agitation, hypertonia, hypotonia, tremor, drowsiness, feeding problems, and respiratory distress following maternal use.

Breast-feeding

There is limited information available on the short- and long-term effects of antipsychotic drugs on the breast-fed infant. Chronic treatment with antipsychotic drugs while breast-feeding should be avoided unless absolutely necessary.

Storage

Store below 25°C. Protect from light. Keep out of reach of children.

Formulations

• Oral tablets
• Oral liquid
• Deep intramuscular injection

Mechanism of action

Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). The principal pharmacologic effects of chlorpromazine are similar to those of other propylamino derivatives of phenothiazine. Chlorpromazine has strong anticholinergic and sedative effects and moderate extrapyramidal effects. Chlorpromazine has strong antiemetic and adrenergic blocking activity and weak ganglionic blocking, antihistaminic, and antiserotonergic 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 nervous system are complex and unpredictable because the drugs exhibit varying degrees of alpha-adrenergic blocking, muscarinic blocking,

Pharmacodynamics

Chlorpromazine is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity.