What is the mechanism of action and uses of chlorpromazine and levomepromazine?

Mechanism of Action and Uses of Chlorpromazine and Levomepromazine

Both chlorpromazine and levomepromazine are phenothiazine antipsychotics that primarily act as dopamine receptor antagonists with additional effects on multiple neurotransmitter systems, making them useful for treating psychosis, nausea/vomiting, and providing sedation in palliative care settings.

Mechanism of Action

Chlorpromazine

• Primary mechanism: Dopamine D2 receptor antagonism in the central nervous system 1
• Additional receptor activity:
  • Antiadrenergic (strong) - blocks alpha-adrenergic receptors
  • Anticholinergic (weaker) - blocks muscarinic receptors
  • Antihistaminic - blocks H1 receptors
  • Antiserotonergic - blocks 5-HT receptors
  • Slight ganglionic blocking action 1

Levomepromazine

• Primary mechanism: Antipsychotic phenothiazine with broader receptor profile than chlorpromazine 2
• Receptor binding profile:
  • Significantly greater binding affinity for alpha-1 adrenergic receptors than chlorpromazine 3
  • Significantly greater binding affinity for serotonin-2 (5-HT2A) receptors than chlorpromazine 3
  • Greater binding to alpha-2 adrenergic sites than chlorpromazine 3
  • Some analgesic effect (unique among typical antipsychotics) 2

Clinical Uses

Chlorpromazine

1. Psychotropic/Antipsychotic:

   • Treatment of schizophrenia 4
   • Management of acute psychotic states

2. Antiemetic:

   • Treatment of nausea and vomiting 5
   • Listed as an option for management of nausea in palliative care 5

3. Sedation:

   • Used for sedation in palliative care 2
   • Management of agitation in emergency settings 2

4. Dosing for sedation in palliative care:

   • Starting dose: 12.5 mg IV/IM every 4-12 hours, or 3-5 mg/h IV, or 25-100 mg rectally every 4-12 hours
   • Usual effective dose: Parenteral 37.5-150 mg/day, rectal 75-300 mg/day 2

Levomepromazine

1. Antipsychotic:

   • Treatment of schizophrenia, including treatment-resistant cases 6
   • Comparative studies show it may have a modest advantage over chlorpromazine in treatment-resistant schizophrenia 6

2. Palliative Care:

   • Management of refractory symptoms at end of life 2
   • Particularly useful for delirium in palliative care settings 2
   • Has analgesic properties in addition to antipsychotic effects 2

3. Sedation:

   • Palliative sedation for terminal patients 2
   • Management of agitation in delirium 2

4. Dosing for palliative sedation:

   • Starting dose: 12.5-25 mg or 50-75 mg continuous infusion
   • Usual effective dose: 12.5 or 25 mg every 8 hours and every 1 hour PRN for breakthrough agitation, or up to 300 mg/day continuous infusion 2

Comparative Efficacy and Side Effects

Efficacy Comparison

• Both medications are effective for treating schizophrenia 4, 6
• Levomepromazine may have a modest advantage over chlorpromazine in treatment-resistant schizophrenia based on longitudinal analysis 6
• Response rates in treatment-resistant schizophrenia: 10/19 for levomepromazine vs. 8/19 for chlorpromazine 6

Side Effect Profile (Both Medications)

• Orthostatic hypotension (significant risk)
• Extrapyramidal symptoms (including akathisia, dystonia)
• Anticholinergic effects (dry mouth, blurred vision, urinary retention)
• Paradoxical agitation
• Sedation/somnolence 2

Important Clinical Considerations

• Dosing considerations: Lower doses may be more effective than very high doses for antipsychotic effects. In one study, 9 of 18 responders with treatment-resistant schizophrenia responded to 200-700 mg/day of either phenothiazine 6

• Metabolic differences: Chlorpromazine loses its 5-HT2A blocking activity in vivo, while levomepromazine maintains stronger serotonergic and alpha-adrenergic blocking properties 3, 7

• Route of administration flexibility:

  • Chlorpromazine: Oral, IV, IM, rectal 2
  • Levomepromazine: Oral, IV, SC, IM 2

• Caution: Both medications can cause significant sedation and hypotension, requiring careful monitoring especially in elderly patients or those with cardiovascular disease 2

Practical Applications

• For acute agitation in delirium: Either agent can be effective, but levomepromazine may be preferred when analgesia is also needed 2

• For treatment-resistant schizophrenia: Consider levomepromazine as it may have advantages over chlorpromazine in this population 6, 3

• For palliative sedation: Both are effective options, with dosing tailored to symptom severity 2

• For nausea and vomiting: Chlorpromazine is an established antiemetic option, particularly when other agents have failed 5