Continuing Education Activity

Haloperidol is a first-generation (typical) antipsychotic that is a commonly used drug worldwide. Haloperidol is used to manage positive symptoms of schizophrenia, such as hallucinations and delusions. It is FDA-approved for treating schizophrenia, Tourette syndrome, severe behavioral disorders in children (combative and explosive hyperexcitability), and hyperactivity in children (impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance). This activity will highlight the mechanism of action, administration, adverse event profile, toxicity, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to the interprofessional team members for the use of haloperidol appropriately for management of various indications.

Objectives:

• Identify the mechanism of action of haloperidol.
• Describe the adverse effects of haloperidol.
• Summarize the appropriate monitoring of haloperidol.
• Review some interprofessional team strategies for improving care coordination and communication to advance haloperidol and improve outcomes.

Indications

Haloperidol is a first-generation (typical) antipsychotic medication used widely around the world. It is a typical antipsychotic because it works on positive symptoms of schizophrenia, such as hallucinations and delusions.[1][2]

Haloperidol has numerous FDA-approved and off-label clinical uses.

FDA-approved Clinical Uses[3]

• Schizophrenia[4]

• Tourette syndrome: Control of tics and vocal utterances in children and adults.[5]

• Severe behavioral disorders in children: Haloperidol is effective for treating combative and explosive hyperexcitability (which cannot be accounted for by immediate provocation). Haloperidol should be reserved for children only after failure to respond to psychotherapy or medications other than antipsychotics.

• Hyperactivity: Haloperidol is effective for children with excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. Haloperidol should be reserved for children only after failure to respond to psychotherapy or medications other than antipsychotics.[6]

Off-label Clinical Uses

• Agitation-associated with psychiatric disorders[7]

• Acute mania[8]

• Chemotherapy-induced nausea and vomiting[9]

• Management of intractable hiccups[10]

Mechanism of Action

Haloperidol is a first-generation (typical antipsychotic) which exerts its antipsychotic action by blocking dopamine D2 receptors in the brain. When 72% of dopamine receptors are blocked, this drug achieves its maximal effect.[11] Haloperidol is not selective for the D2 receptor. It also has noradrenergic, cholinergic, and histaminergic blocking action. The blocking of these receptors is associated with various adverse drug reactions.[12]

Administration

Haloperidol is used widely in different countries. It is available in various formulations. For oral administration, it is available in tablets ( 0.5 mg, 1 mg, 2 mg, 5 mg, and 10 mg ) and oral concentrate ( 2 mg/mL ). It is also available in a nasal spray formulation. Haloperidol lactate is available in a short-acting parenteral solution (5 mg/mL) injected intramuscularly. Haloperidol decanoate is available for long-acting intramuscular preparation.[11]

• Psychosis: In this instance, the oral and intramuscular forms can be administered. For moderate symptomology: 0.5 to 2 mg 2 to 3 times a day orally. Up to 30 mg/day may be necessary in some resistant cases. For prompt control of acute agitation, an intramuscular injection can be given as a 2 to 5 mg dose every 4 to 8 hours. The maximum intramuscular dose is 20 mg/day.[13]

• Schizophrenia: In moderately severe patients, dosing is 0.5 to 2 mg haloperidol orally 2 to 3 times a day. It should not exceed 30 mg daily in case of severe cases. To control acute agitation in a schizophrenic patient, dosing is 2 to 5 mg haloperidol intramuscularly every 4 to 8 hours. 

• Tourette syndrome: Dosing is 0.5 to 2 mg orally 2 to 3 times a day in moderately symptomatic cases, and for severe cases, it can be higher: 3 to 5 mg, 2 to 3 times a day. 

Specific Patient Population

• Pediatric considerations: Haloperidol is no longer routinely used as initial therapy for behavioral disorders but may be necessary in refractory or complex cases. Dosing of haloperidol is 0.05 to 0.075 mg/kg/day. 

• Geriatric considerations:  Haloperidol is identified as a high-risk medication according to Beer criteria; hence lowest effective dose should be used for the shortest duration possible.[14] 

• Pregnancy Considerations: There are no well-controlled studies for haloperidol use in pregnant women. But there are several reports of limb malformations in newborns whose mothers used haloperidol, but causal relationships were not appropriately established. Since these experiences do not exclude the possibility of a fetal anomaly due to haloperidol, this drug should be used only if the benefit outweighs the potential risk to the fetus.[15]

• Breastfeeding Considerations: As haloperidol gets excreted in human breast milk, lactating women taking haloperidol should not nurse their infants.

• Hepatic Impairment: Haloperidol plasma levels may increase in patients with liver impairment because it is primarily metabolized by the liver.

Drug Interactions

• CYP3A4 inhibitors and/or CYP2D6 Inhibitors: The haloperidol plasma concentrations and hence adverse reactions increases when CYP3A4 inhibitors and/or CYP2D6 inhibitors are coadministered with haloperidol. Monitor patients taking these medicines concomitantly, and if signs and symptoms of increased haloperidol pharmacologic effects appear, then reduce the dose for haloperidol as clinically needed.
  • CYP3A4 inhibitors – alprazolam, ketoconazole, itraconazole, ritonavir, nefazodone.
  • CYP2D6 inhibitors – chlorpromazine; promethazine, paroxetine, quinidine, sertraline, and venlafaxine.
  • CYP3A4 and CYP2D6 inhibitors – fluvoxamine, fluoxetine, and ritonavir.
  • QTc prolongation was observed when haloperidol was administered with a combination of the metabolic inhibitors paroxetine (20 mg/day) and ketoconazole (400 mg/day).

• CYP3A4 Inducers: Coadministration of potent enzyme inducers of CYP3A4 (carbamazepine, phenobarbital, phenytoin, rifampin, St John's Wort) with haloperidol may gradually decrease the serum concentrations of haloperidol which can decrease its efficacy. In this scenario, patients are recommended to be monitored and increase the haloperidol dose as required. In addition, after stopping the CYP3A4 inducer treatment, haloperidol concentration may gradually increase, and hence it may be needed to reduce the dose or adjust the dosage interval for haloperidol.

• Effect of Haloperidol on Other Drugs: Being an inhibitor of the CYP2D6 enzyme, it may increase plasma concentrations of tricyclic antidepressants (desipramine or imipramine) when co-administered with haloperidol.

Adverse Effects

Typical antipsychotic medications such as haloperidol have correlations with extrapyramidal symptoms due to the blockade of the dopamine pathway in the brain.[11][3]

Extrapyramidal Symptoms[16]

• Acute Dystonia - (Develops within hours to days of initiation. Maybe presented as muscle spasm, stiffness, oculogyric crisis)
• Akathisia - (Develops within days to months of use of haloperidol - characterized by restlessness.)
• Neuroleptic malignant syndrome - (NMS; infrequent but severe condition. May present as high fever, muscle rigidity)
• Parkinsonism - (Develops after days to month use of haloperidol)
• Tardive dyskinesia - (Develops after years, presents as a chore, especially orofacial region)

Common

• Anticholinergic effects - (Elevated temperature, dry mouth, drowsiness or sedation, constipation, urinary retention)
• Sedation
• Weight gain
• Erectile dysfunction in male
• Oligomenorrhea or amenorrhea in female

Less Common

• Orthostatic hypotension - (After IM injection of haloperidol), tachycardia, palpitation
• Agitation, generalized anxiety, cerebral edema, new-onset depression, dizziness, euphoric mood, headache, sleeplessness, poikilothermia, restlessness, generalized weakness, confusion
• Anorexia, constipation, dyspepsia, ileus, decreased gag reflex.
• Lens opacities - (If used for a prolonged time)

Uncommon

• ECG changes - (QT prolongation, torsades de pointes)[17]
• Photosensitivity reaction
• Generalized pruritus
• Diarrhea, gastrointestinal distress
• Blood dyscrasia
• Ejaculatory problems

Rare

• Seizure[18]
• Cholestatic jaundice
• Priapism

Contraindications

Haloperidol is contraindicated if there is documented hypersensitivity to this drug, patients with Parkinson disease, dementia with Lewy body, comatose patients, in any condition with a severely depressed central nervous system (CNS). Since many drugs (barbiturates, benzodiazepines, and opioids) can cause depression in CNS, concurrent use of haloperidol should be avoided or used with great caution.[11]

Box Warning

There is an increased risk of mortality (1.6 to 1.7 times) in elderly patients with dementia-related psychosis. In seventeen placebo-controlled controlled trials, patients using atypical antipsychotic drugs for 10-weeks, death was reported in 4.5% of patients for drug-treated patients compared to  2.6% in the placebo group. Hence haloperidol is not FDA-approved for the treatment of patients with dementia-related psychosis.

Warnings/Precautions

Cardiovascular Effects

Intravenous administration or higher than recommended doses of any haloperidol formulation is associated with a higher risk of QTc interval-prolongation, Torsades de Pointes, and sudden death. Special care should be taken in patients with electrolyte imbalances (particularly hypokalemia or hypomagnesemia), hypothyroidism, underlying cardiac abnormalities, concomitant drugs known to increase QTc and familial long QT-syndrome.[19]

Cerebrovascular Adverse Reactions

Antipsychotic use is associated with an increased risk of transient ischemic attack, stroke, and death, in elderly patients with dementia-related psychosis. Hence exercise caution when used in patients with increased risk for cerebrovascular adverse reactions.

Tardive Dyskinesia

A syndrome consisting of involuntary, irreversible, and dyskinetic movements may develop in patients administered antipsychotic drugs. The risk is highest among older women. The risk of developing TD and being irreversible is proportional to treatment duration and total cumulative dose for antipsychotic medicine. Although rarely, TD can develop after relatively short treatment periods and low doses. Hence, antipsychotic drugs, including haloperidol, should be prescribed in a way that is most likely to minimize the occurrence of TD. Chronic antipsychotic medicine should generally be reserved for patients with chronic illness when it is known to respond to those antipsychotic medicines and for patients for whom alternative or equally effective and potentially less toxic treatments are unavailable or inappropriate. In patients when chronic treatment is required, clinicians should recommend the smallest possible dose and the shortest treatment duration of treatment, generating a reasonable clinical response. Health care providers should reassess the need for continued treatment periodically, and if any signs of TD appear, discontinuation of haloperidol should be considered.

Neuroleptic Malignant Syndrome (NMS)

NMS clinically manifests as muscle rigidity, hyperpyrexia, altered mental status (including catatonic signs), and evidence of autonomic instability (tachycardia, irregular pulse or blood pressure, diaphoresis, and cardiac arrhythmias). Additionally, patients can have elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. NMS should be managed by 1) an immediate cessation of antipsychotic drugs and other drugs not essential to concurrent treatment, 2) symptomatic treatment and medical monitoring for the patient, and 3) treatment of serious medical issues where specific treatments are available. If a patient requires antipsychotic medicine treatment after recovery from NMS, the potential reintroduction of haloperidol should be cautiously considered. The patient should be closely monitored as recurrences of NMS are reported. Heatstroke and hyperpyrexia not associated with the NMS have also been reported with haloperidol.[16]

Falls

somnolence, motor instability, and orthostatic hypotension are reported with the antipsychotics, including haloperidol, which may lead to falls, fractures, and/or other fall-related injuries. For older adults with conditions or medications which could exacerbate these effects, the risk of falls needs to be assessed at the initiation of antipsychotic treatment and throughout the treatment duration.

Monitoring

Patients require monitoring due to the potential adverse drug reactions, especially when receiving haloperidol in the intramuscular form. It can be easily monitored by taking blood levels. It has a therapeutic range of 2 to 15 ng/ml in serum. Therefore, clinicians should monitor blood levels of haloperidol at 12-hour or 24-hour intervals or after the last dose of haloperidol.[20]

Toxicity

Toxicities are the exaggerated symptoms of known pharmacologic effects and adverse drug reactions. The most prominent toxicities of haloperidol are 1) severe extrapyramidal symptoms, hypotension, and sedation. The patient may appear comatose with severe respiratory depression or shock from hypotension. The extrapyramidal symptoms include akathisia, rigidity, bradykinesia, tremor, and acute dystonia. Haloperidol overdose is also associated with ECG changes known as torsade de pointes, which may cause arrhythmia or cardiac arrest.[17]

Since there is no specific antidote, supportive treatment is the mainstay of haloperidol toxicity. If a patient develops signs and symptoms of toxicities, the clinician should consider gastric lavage or induction of emesis as soon as possible, followed by the administration of activated charcoal. Maintenance of Airway, Breathing, and circulation are critical factors for survival. A patent airway is ensured by using an oropharyngeal airway or endotracheal tube. Comatose patients with a difficult airway or upper airway obstruction require a tracheostomy. Supplemental oxygen is administered via nasal prongs or facemask. Patients with refractory hypoxia often require intubation and mechanical ventilation. Hypotension and circulatory collapse need aggressive treatment with intravenous fluids, concentrated albumin, and vasopressor agents such as norepinephrine or phenylephrine. Epinephrine should not be used as it can decrease blood pressure. 

Extrapyramidal reactions such as acute dystonia are treated with benztropine. ECG and vital signs require regular monitoring, especially for signs of torsades de Pointes or QT prolongation, or dysrhythmias. Cardiac monitoring should be in place until the ECG becomes normal. If the patient develops arrhythmias, which could be life-threatening, prompt management should commence with appropriate anti-arrhythmic measures.[21]

Enhancing Healthcare Team Outcomes

Haloperidol is one of the most commonly used antipsychotics in this world. However, since the drug can cause several side effects and is related to several toxicities after initiation, the healthcare workers must be familiar with its pharmacology, signs, and symptoms of toxicity, and management of adverse effects. In addition, a proper history and physical examination are necessary before the initiation of haloperidol in any patient. Therefore, recommended course of action when prescribing haloperidol is as follows:

• The clinicians(MD, PA, NP) prescribe haloperidol for appropriate indication.

• Psychiatrists are responsible for the overall care of patients on haloperidol therapy.

• Pharmacists should ensure proper dosing and report back to clinicians if there are potential drug interactions. 

• Specialty-trained nurses should review the medicine administration record to ensure there were no administration errors.

• Emergency department physicians and triage nurses are the first to respond in case of acute haloperidol overdose.

• Intensivist ensures proper ICU care and monitoring while in hospital.

• Severe cases of haloperidol toxicity require the consultation of a medical toxicologist.

As depicted above, close interprofessional coordination between providers (MDs, DOs, NPs, PAs), nurses, pharmacists, and other healthcare workers is necessary to improve patient outcomes and decrease adverse events when using haloperidol therapy. The above illustrated interprofessional healthcare team approach makes haloperidol therapy more effective, with fewer adverse events, and improves patient outcomes. [Level 5]