Continuing Education Activity

Prochlorperazine is a first-generation antipsychotic. FDA indications include schizophrenia, schizoaffective, and other conditions presenting with symptoms of psychosis, as well as nausea and vomiting (post-chemotherapy, post-radiation therapy, pre- and post-operative setting, and other conditions). Non-FDA Indications include migraine headaches. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of prochlorperazine, so providers can direct patient therapy in treating conditions for which it is indicated as part of the interprofessional team.

Objectives:

• Summarize the mechanism of action of prochlorperazine.
• Identify the indications for initiating therapy with prochlorperazine.
• Review the potential adverse event profile of prochlorperazine.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with prochlorperazine.

Indications

FDA Indications

• It is for schizophrenia, schizoaffective, and other conditions presenting with symptoms of psychosis. Prochlorperazine can be used to treat both acute psychotic episodes and chronic mental illnesses. As a first-generation antipsychotic, the drug is better at treating positive symptoms than negative ones, including delusions, hallucinations, agitation, and disorganized speech and behavior.[1]      
• To treat nausea and vomiting (Post-chemotherapy, post-radiation therapy, pre- and post-operative setting, and other conditions). One review concluded that prochlorperazine was equally as effective as metoclopramide, ondansetron, promethazine, and droperidol in the emergency department (ED). Side effects for all the medications studied were generally mild.[2]

Non-FDA Indications

• Migraine
  • For adult migraines, the American Headache Society recommended prochlorperazine as well as metoclopramide and sumatriptan as first-line medications in the ED for treating migraines.[3]    
  • For pediatric migraines, ED physicians often prescribe a combination of a nonsteroidal anti-inflammatory drug and a dopamine antagonist.[4] One study examined three dopamine antagonists (prochlorperazine, metoclopramide, and promethazine) and compared their effectiveness with one another. Researchers found prochlorperazine to be the most effective in reducing the need for opioids and reducing pain by at least 50%.[5] The authors in another study confirmed that prochlorperazine was superior amongst dopamine antagonists but found that adding diphenhydramine (antihistamine) to a dopamine antagonist increased the chances of an ED revisit.[4]  

Mechanism of Action

As a first-generation antipsychotic, prochlorperazine mainly blocks D2 dopamine receptors in the brain. It can also block histaminergic, cholinergic, and noradrenergic receptors.[1] One study found that prochlorperazine also inhibits the P2X7 receptor in human macrophages but not in mouse cells, preventing a calcium ion influx.[6] This mechanism was independent of dopamine antagonism.  

Administration

Prochlorperazine administration can be oral, parenteral, intramuscular, and rectal.[1] All four routes can be given to control nausea and vomiting. For nausea and vomiting pre- and post-surgery, the intramuscular and parenteral routes are both viable options. For psychiatric conditions, the administration can be via both intramuscular and oral routes. For headaches, parenteral is the route used.[2]

Adult dosing by condition and formulation is as follows:

Oral Formulation (5 or 10 mg tablets)

• For severe nausea and vomiting (including migraine-associated): 5 to 10 mg orally every 6 to 8 hours; max dose is 40 mg per day. (Note - migraine dosing is off-label.)
• Non-psychotic anxiety: 5 to 10 mg orally every 6 to 8 hours. Max dose is 20 mg daily for 12 weeks.
• Schizophrenia: 5 to 10 mg orally every 6 to 8 hours. The dose may be increased 5 to 10 mg every 2 or 3 days. Max dose 150 mg daily.

Injectable Formulation (5 mg/ml)

• Severe nausea and vomiting: 5 to 10 mg IM every 3 to 4 hours; max dose 40 mg daily.
• Migraine-associated nausea and vomiting (off label): 5 to 10 mg IM or IV once.
• Nausea/vomiting - postoperative prophylaxis: 5 to 10 mg IM or IV once. Give IM dose 1 to 2 hours and IV 15 to 30 minutes before induction.
• Schizophrenia: 5 to 10 mg IM daily every 6 to 8 hours. The dose may be increased 5 to 10 mg every 2 or 3 days. Max dose 150 mg daily.

Rectal (25 mg suppositories)

• Severe nausea and vomiting: 25 mg rectally every 12 hours.
• Migraine-associated nausea and vomiting (off label): 25 mg rectally every 12 hours as needed.

Clinicians should discontinue the drug if ANC < 1000, and consider discontinuing if the patient exhibits an unexplained drop in WBC count.

Adverse Effects

As a first-generation antipsychotic, prochlorperazine can cause a variety of adverse effects.[1] Significant extrapyramidal symptoms, including acute dystonia, tardive dyskinesia, Parkinsonism, akathisia, and neuroleptic malignant syndrome. Anticholinergic side effects include anorexia, blurred vision, constipation, dry mucosa, and urinary retention. Antihistaminic side effects (blockage of H1 receptor) include sedation. Prochlorperazine can also lower the seizure threshold. It can also lead to prolonged QTc interval and cause other cardiac conduction abnormalities. Antiadrenergic effects (blockage of the alpha1-adrenergic receptor) can lead to orthostatic hypotension. Due to dopamine blockade in the tuberoinfundibular tract, hyperprolactinemia, amenorrhea, breast enlargement, and sexual dysfunction may also occur.[1]

Leukopenia, agranulocytosis, cholestatic jaundice, and fatty liver are other possible but rare side effects. A rare but very severe condition that can result from any antipsychotic use is neuroleptic syndrome. Symptoms occur over 24 to 72 hours and present with elevated vitals, agitation, confusion, severe muscle rigidity, increased white blood cell count, increased creatinine phosphokinase concentrations, abnormal liver function tests, myoglobinuria, and acute renal failure.[1]

Prochlorperazine may also exert negative effects on melanocytes. In one in-vitro study, the presence of the drug correlated with decreased cell viability as well as reduced melanin content and tyrosinase activity.[7]     

Prochlorperazine may have significant adverse effects on children. One study from 2009, examining treatment modalities for pediatric nausea and vomiting, noted that side effects of prochlorperazine are high in children; therefore, patients under two years of age should not use it, and patients over two years old should consider alternatives such as ondansetron (5-HT3 receptor antagonist).[8] A review/meta-analysis from 2016 examined 49 previous studies and recorded pediatric side effects from dopamine antagonist use. Sedation and extrapyramidal symptoms were the most common, whereas serious adverse effects such as seizure, tardive dyskinesia, neuroleptic malignant syndrome, and autonomic failure were rare.[9] Therefore, healthcare providers should exercise caution when prescribing prochlorperazine to children.

Contraindications

It is important to note that geriatric patients with dementia have a higher risk of death when treated with an antipsychotic, including prochlorperazine.

The following lists contraindications for prochlorperazine[1][8]

• History of allergy to prochlorperazine or the phenothiazine drug class
• Concomitant use of CNS depressants (opioids, benzodiazepines, and barbiturates) leading to sedation
• Concomitant use of anticholinergic medications (scopolamine, atropine, etc.)
• Pre-existing cardiac conduction abnormalities
• History of seizure/epilepsy (prochlorperazine lowers seizure threshold)
• Narrow-angle glaucoma
• Prostatic hypertrophy
• Past or current history of tardive dyskinesia
• Patients under two years of age

It is not a recommended agent for patients who are pregnant. Antipsychotics are generally not recommended in pregnant patients.[1] Also, there is a lack of evidence to suggest that prochlorperazine is clinically effective in treating nausea and vomiting during pregnancy, nor are the side effects completely understood.[10]     

Monitoring

For patients who take prochlorperazine on a short-term basis, there are no recommendations for monitoring. However, some monitoring parameters are recommended for patients with chronic mental illnesses who take the drug long-term.[11] Every physician visit should record the patient's weight, height, and BMI. Patients who are overweight or have other diabetes mellitus risk factors should have fasting plasma glucose, or hemoglobin A1C measured four months after starting an antipsychotic and then annually. Lipid plasma concentrations are indicated once every two years and once every six months if LDL-C > 130 mg/dl.[11]     

The concentration of prochlorperazine in the blood is not typically measured. When performed in cases such as suspected overdose, high-performance liquid chromatography/tandem mass spectrometry may be performed. The limit for quantifying the metabolite in the plasma is estimated to be around 0.20 ng/ml.[12] Oral prochlorperazine has high first-pass metabolism and poor absorption, so the exact concentration present in the body can be variable.[13]

The cytochrome P450 system metabolizes oral prochlorperazine, so monitoring a patient's full list of medications is essential.[14] If the patient takes medications that stimulate or inhibit cytochrome P450, the healthcare provider should consider adjusting the dose of prochlorperazine. One study examined the effects of three cytochrome P450 genotypes (CYP2C19, CYP2D6, and CYP3A5) and their effects on the concentrations of prochlorperazine and its metabolites; the authors found no significant differences amongst the three.[14]

Toxicity

There are varying treatments available for extrapyramidal symptoms. Parkinsonism is treatable with benztropine or amantadine. Benztropine or diphenhydramine can treat acute dystonia. Akathisia is treatable with beta-blockers, benztropine, or benzodiazepines. Tardive dyskinesia is treatable by switching to atypical antipsychotics such as clozapine. Tetrabenazine is another option. For neuroleptic malignant syndrome, the healthcare provider should immediately discontinue prochlorperazine and give dantrolene (0.8 to 2.5 mg/kg given four times per day; up to 10 mg/day may be provided).[1] Also, monitor white blood cell count and vitals, and cool and hydrate the patient as much as possible.

Enhancing Healthcare Team Outcomes

Prochlorperazine is a medication that can produce numerous side effects and drug-drug interactions. Therefore, close interprofessional coordination amongst clinicians (Mds, DOs, NPs, PAs), nurses, pharmacists, and other healthcare providers is necessary to monitor for signs and symptoms related to the above. Working together with team members and the patient is also essential to determine if prochlorperazine is the optimal therapeutic choice and increase medication adherence. As referenced above, prescribers should investigate cytochrome P450 enzyme status. Nurses can provide patient counsel on dosing, potential adverse events to watch for and answer patient questions. Pharmacists can perform medication reconciliation, paying particular attention to CYP450 inducers and inhibitors. This interprofessional team approach will drive better patient outcomes and preclude more serious adverse events. [Level 5]