Tag: Haloperidol

What is Neuroleptic Malignant Syndrome?

Published on by Andrew Marshall2 Comments

Introduction

Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fast heart rate. Complications may include rhabdomyolysis, high blood potassium, kidney failure, or seizures.

Any medications within the family of neuroleptics can cause the condition, though typical antipsychotics appear to have a higher risk than atypicals, specifically first generation antipsychotics like haloperidol. Onset is often within a few weeks of starting the medication but can occur at any time. Risk factors include dehydration, agitation, and catatonia.

Rapidly decreasing the use of levodopa or other dopamine agonists, such as pramipexole, may also trigger the condition. The underlying mechanism involves blockage of dopamine receptors. Diagnosis is based on symptoms.

Management includes stopping the offending medication, rapid cooling, and starting other medications. Medications used include dantrolene, bromocriptine, and diazepam. The risk of death among those affected is about 10%. Rapid diagnosis and treatment is required to improve outcomes. Many people can eventually be restarted on a lower dose of antipsychotic.

As of 2011, among those in psychiatric hospitals on neuroleptics about 15 per 100,000 are affected per year (0.015%). In the second half of the 20th century rates were over 100 times higher at about 2% (2,000 per 100,000). Males appear to be more often affected than females. The condition was first described in 1956.

Brief History

NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines. NMS was first described in 1960 by French clinicians who had been working on a study involving haloperidol. They characterized the condition that was associated with the side effects of haloperidol “syndrome malin des neuroleptiques”, which was translated to neuroleptic malignant syndrome.

Signs and Symptoms

The first symptoms of neuroleptic malignant syndrome are usually muscle cramps and tremors, fever, symptoms of autonomic nervous system instability such as unstable blood pressure, and sudden changes in mental status (agitation, delirium, or coma). Once symptoms appear, they may progress rapidly and reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.

Symptoms are sometimes misinterpreted by doctors as symptoms of mental illness which can result in delayed treatment. NMS is less likely if a person has previously been stable for a period of time on antipsychotics, especially in situations where the dose has not been changed and there are no issues of noncompliance or consumption of psychoactive substances known to worsen psychosis.

  • Increased body temperature >38 °C (>100.4 °F);
  • Confused or altered consciousness;
  • sweating;
  • Rigid muscles; and/or
  • Autonomic imbalance.

Causes

NMS is usually caused by antipsychotic drug use, and a wide range of drugs can result in NMS. Individuals using butyrophenones (such as haloperidol and droperidol) or phenothiazines (such as promethazine and chlorpromazine) are reported to be at greatest risk. However, various atypical antipsychotics such as clozapine, olanzapine, risperidone, quetiapine, and ziprasidone have also been implicated in cases.

NMS may also occur in people taking dopaminergic drugs (such as levodopa) for Parkinson’s disease, most often when the drug dosage is abruptly reduced. In addition, other drugs with anti-dopaminergic activity, such as the antiemetic metoclopramide, can induce NMS. Tetracyclics with anti-dopaminergic activity have been linked to NMS in case reports, such as the amoxapines. Additionally, desipramine, dothiepin, phenelzine, tetrabenazine, and reserpine have been known to trigger NMS. Whether lithium can cause NMS is unclear.

At the molecular level, NMS is caused by a sudden, marked reduction in dopamine activity, either from withdrawal of dopaminergic agents or from blockade of dopamine receptors.

Risk Factors

One of the clearest risk factors in the development of NMS is the course of drug therapy chosen to treat a condition. Use of high-potency neuroleptics, a rapid increase in the dosage of neuroleptics, and use of long-acting forms of neuroleptics are all known to increase the risk of developing NMS.

It has been purported that there is a genetic risk factor for NMS, since identical twins have both presented with NMS in one case, and a mother and two of her daughters have presented with NMS in another case.

Demographically, it appears that males, especially those under forty, are at greatest risk for developing NMS, although it is unclear if the increased incidence is a result of greater neuroleptic use in men under forty. It has also been suggested that postpartum women may be at a greater risk for NMS.

An important risk factor for this condition is Lewy body dementia. These patients are extremely sensitive to neuroleptics. As a result, neuroleptics should be used cautiously in all cases of dementia.

Pathophysiology

The mechanism is commonly thought to depend on decreased levels of dopamine activity due to:

  • Dopamine receptor blockade.
  • Genetically reduced function of dopamine receptor D2.

It has been proposed that blockade of D2-like (D2, D3 and D4) receptors induce massive glutamate release, generating catatonia, neurotoxicity and myotoxicity. Additionally, the blockade of diverse serotonin receptors by atypical antipsychotics and activation of 5HT1 receptors by certain of them reduces GABA release and indirectly induces glutamate release, worsening this syndrome.

The muscular symptoms are most likely caused by blockade of the dopamine receptor D2, leading to abnormal function of the basal ganglia similar to that seen in Parkinson’s disease.

However, the failure of D2 dopamine receptor antagonism, or dopamine receptor dysfunction, do not fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with atypical antipsychotic drugs with lower D2 dopamine activity. This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system) as a mechanism for NMS. Release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in the breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as typical neuroleptics, are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.

There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.

The raised white blood cell count and creatine phosphokinase (CPK) plasma concentration seen in those with NMS is due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue). The patient may suffer hypertensive crisis and metabolic acidosis. A non-generalized slowing on an EEG is reported in around 50% of cases.

The fever seen with NMS is believed to be caused by hypothalamic dopamine receptor blockade. The peripheral problems (the high white blood cell and CPK count) are caused by the antipsychotic drugs. They cause an increased calcium release from the sarcoplasmic reticulum of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal EEG, but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.

Diagnosis

Differential Diagnosis

Differentiating NMS from other neurological disorders can be very difficult. It requires expert judgement to separate symptoms of NMS from other diseases. Some of the most commonly mistaken diseases are encephalitis, toxic encephalopathy, status epilepticus, heat stroke, catatonia and malignant hyperthermia. Due to the comparative rarity of NMS, it is often overlooked and immediate treatment for the syndrome is delayed. Drugs such as cocaine and amphetamine may also produce similar symptoms.

The differential diagnosis is similar to that of hyperthermia, and includes serotonin syndrome. Features which distinguish NMS from serotonin syndrome include bradykinesia, muscle rigidity, and a high white blood cell count.

Treatment

NMS is a medical emergency and can lead to death if untreated. The first step is to stop the antipsychotic medication and treat the hyperthermia aggressively, such as with cooling blankets or ice packs to the axillae and groin. Supportive care in an intensive care unit capable of circulatory and ventilatory support is crucial. The best pharmacological treatment is still unclear. Dantrolene has been used when needed to reduce muscle rigidity, and more recently dopamine pathway medications such as bromocriptine have shown benefit. Amantadine is another treatment option due to its dopaminergic and anticholinergic effects. Apomorphine may be used however its use is supported by little evidence. Benzodiazepines may be used to control agitation. Highly elevated blood myoglobin levels can result in kidney damage, therefore aggressive intravenous hydration with diuresis may be required. When recognised early NMS can be successfully managed; however, up to 10% of cases can be fatal.

Should the affected person subsequently require an antipsychotic, trialling a low dose of a low-potency atypical antipsychotic is recommended.

Prognosis

The prognosis is best when identified early and treated aggressively. In these cases NMS is not usually fatal. In earlier studies the mortality rates from NMS ranged from 20%-38%, but by 2009 mortality rates were reported to have fallen below 10% over the previous two decades due to early recognition and improved management. Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.

Memory impairment is a consistent feature of recovery from NMS, and is usually temporary though in some cases may become persistent.

Epidemiology

Pooled data suggest the incidence of NMS is between 0.2%-3.23%. However, greater physician awareness coupled with increased use of atypical anti-psychotics have likely reduced the prevalence of NMS. Additionally, young males are particularly susceptible and the male-female ratio has been reported to be as high as 2:1.

Research

While the pathophysiology of NMS remains unclear, the two most prevalent theories are:

  • Reduced dopamine activity due to receptor blockade.
  • Sympathoadrenal hyperactivity and autonomic dysfunction.

In the past, research and clinical studies seemed to corroborate the D2 receptor blockade theory in which antipsychotic drugs were thought to significantly reduce dopamine activity by blocking the D2 receptors associated with this neurotransmitter. However, recent studies indicate a genetic component to the condition. In support of the sympathoadrenal hyperactivity model proposed, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS. This model of NMS strengthens its suspected association with malignant hyperthermia in which NMS may be regarded as a neurogenic form of this condition which itself is linked to defective calcium-related proteins.

The introduction of atypical antipsychotic drugs, with lower affinity to the D2 dopamine receptors, was thought to have reduced the incidence of NMS. However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves. NMS induced by atypical drugs also resembles “classical” NMS (induced by “typical” antipsychotic drugs), further casting doubt on the overall superiority of these drugs.

What is Haloperidol?

Published on by Andrew Marshall18 Comments

Introduction

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication.

Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks in people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent. Neuroleptic malignant syndrome and QT interval prolongation may occur. In older people with psychosis due to dementia it results in an increased risk of death. When taken during pregnancy it may result in problems in the infant. It should not be used in people with Parkinson’s disease.

Haloperidol was discovered in 1958 by Paul Janssen. It was made from pethidine (meperidine). It is on the World Health Organisation’s (WHO’s) List of Essential Medicines. It is the most commonly used typical antipsychotic. In 2017, it was the 296th most commonly prescribed medication in the United States, with more than one million prescriptions.

Brief History

Haloperidol was discovered by Paul Janssen. It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.

Haloperidol was approved by the US Food and Drug Administration (FDA) on 12 April 1967; it was later marketed in the US and other countries under the brand name Haldol by McNeil Laboratories.

Medical Uses

Haloperidol is used in the control of the symptoms of:

  • Acute psychosis, such as drug-induced psychosis caused by LSD, psilocybin, amphetamines, ketamine, and phencyclidine, and psychosis associated with high fever or metabolic disease.
    • Some evidence, however, has found haloperidol to worsen psychosis due to psilocybin.
  • Adjunctive treatment of alcohol and opioid withdrawal.
  • Agitation and confusion associated with cerebral sclerosis.
  • Alcohol-induced psychosis.
  • Hallucinations in alcohol withdrawal.
  • Hyperactive delirium (to control the agitation component of delirium).
  • Hyperactivity, aggression.
  • Otherwise uncontrollable, severe behavioral disorders in children and adolescents.
  • Schizophrenia.
  • Therapeutic trial in personality disorders, such as borderline personality disorder.
  • Treatment of intractable hiccups.
  • Treatment of neurological disorders, such as tic disorders such as Tourette syndrome, and chorea.
  • Treatment of severe nausea and emesis in postoperative and palliative care, especially for palliating adverse effects of radiation therapy and chemotherapy in oncology.

Haloperidol was considered indispensable for treating psychiatric emergency situations, although the newer atypical drugs have gained a greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.

In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone.

Pregnancy and Lactation

Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Reports in pregnant women revealed possible damage to the foetus, although most of the women were exposed to multiple drugs during pregnancy. In addition, reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential foetal risk.

Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.

Other Considerations

During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually. In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.

Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly. PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy. Patients responded with doses under even 2 mg in first-episode psychosis. For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.

Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.

The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks. The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.

Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.

Adverse Effects

As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects.

With more than 6 months of use 14 percent of users gain weight. Haloperidol may be neurotoxic.

  • Common (>1% incidence):
    • Extrapyramidal side effects including:
      • Akathisia (motor restlessness).
      • Dystonia (continuous spasms and muscle contractions).
      • Muscle rigidity.
      • Parkinsonism (characteristic symptoms such as rigidity).
    • Hypotension:
    • Anticholinergic side effects such as (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine):
      • Blurred vision.
      • Constipation.
      • Dry mouth.
    • Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis).
  • Unknown frequency:
    • Anaemia.
    • Headache.
    • Increased respiratory rate.
    • Orthostatic hypotension.
    • Prolonged QT interval.
    • Visual disturbances.
  • Rare (<1% incidence):
    • Acute hepatic failure.
    • Agitation.
    • Agranulocytosis.
    • Anaphylactic reaction.
    • Anorexia.
    • Bronchospasm.
    • Cataracts.
    • Cholestasis.
    • Confusional state.
    • Depression.
    • Dermatitis exfoliative.
    • Dyspnoea.
    • Oedema.
    • Extrasystoles.
    • Face oedema.
    • Gynecomastia.
    • Hepatitis.
    • Hyperglycaemia.
    • Hypersensitivity.
    • Hyperthermia.
    • Hypoglycaemia.
    • Hyponatremia.
    • Hypothermia.
    • Increased sweating.
    • Injection site abscess.
    • Insomnia.
    • Itchiness.
    • Jaundice.
    • Laryngeal oedema.
    • Laryngospasm.
    • Leukocytoclastic vasculitis.
    • Leukopenia.
    • Liver function test abnormal.
    • Nausea.
    • Neuroleptic malignant syndrome.
    • Neutropenia.
    • Pancytopenia.
    • Photosensitivity reaction.
    • Priapism.
    • Psychotic disorder.
    • Pulmonary embolism.
    • Rash.
    • Retinopathy.
    • Seizure.
    • Sudden death.
    • Tardive dyskinesia.
    • Thrombocytopenia.
    • Torsades de pointes.
    • Urinary retention.
    • Urticaria.
    • Ventricular fibrillation.
    • Ventricular tachycardia.
    • Vomiting.

Contraindications

  • Pre-existing coma, acute stroke.
  • Severe intoxication with alcohol or other central depressant drugs.
  • Known allergy against haloperidol or other butyrophenones or other drug ingredients.
  • Known heart disease, when combined will tend towards cardiac arrest.

Special Cautions

  • A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimer’s with mild behavioural problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.
  • Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients.
    • Most of the causes of death were either cardiovascular or infectious in nature.
    • It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients.
    • The drug bears a boxed warning about this risk.
  • Impaired liver function, as haloperidol is metabolised and eliminated mainly by the liver.
  • In patients with hyperthyroidism, the action of haloperidol is intensified and side effects are more likely.
  • IV injections: risk of hypotension or orthostatic collapse.
  • Patients at special risk for the development of QT prolongation (hypokalaemia, concomitant use of other drugs causing QT prolongation).
  • Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.
  • Pre-existing Parkinson’s disease or dementia with Lewy bodies.

Interactions

  • Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).
  • Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD.
  • Epinephrine: action antagonised, paradoxical decrease in blood pressure may result.
  • Guanethidine: antihypertensive action antagonised.
  • Levodopa: decreased action of levodopa.
  • Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.
  • Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects.
  • Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased.
    • In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
  • Other drugs metabolised by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels.
  • Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold).

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Overdose

Symptoms

Symptoms are usually due to side effects. Most often encountered are:

  • Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration).
  • Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock.
  • Hypotension or hypertension.
  • Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time.
  • Sedation.
  • Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.

Treatment

Treatment is mostly symptomatic and involves intensive care with stabilisation of vital functions. In early detected cases of oral overdose, induction of emesis, gastric lavage, and the use of activated charcoal can be tried. In the case of a severe overdose, antidotes such as bromocriptine or ropinirole may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists. ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.

Prognosis

In general, the prognosis of overdose is good, provided the person has survived the initial phase. An overdose of haloperidol can be fatal.

Pharmacology

Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. It has effects similar to the phenothiazines. The drug binds preferentially to D2 and α1 receptors at low dose (ED50 = 0.13 and 0.42 mg/kg, respectively), and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Given that antagonism of D2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT2 receptors on the negative symptoms, this characteristic underlies haloperidol’s greater effect on delusions, hallucinations and other manifestations of psychosis. Haloperidol’s negligible affinity for histamine H1 receptors and muscarinic M1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.

Haloperidol acts on these receptors: (Ki)

  • D1 (silent antagonist) – Unknown efficiency.
  • D5 (silent antagonist) – Unknown efficiency.
  • D2 (inverse agonist) – 0.7 nM.
  • D3 (inverse agonist) – 0.2 nM.
  • D4 (inverse agonist) – 5–9 nM.
  • σ1 (irreversible inactivation by haloperidol metabolite HPP+) – 3 nM.
  • σ2 (agonist): 54 nM.
  • 5HT1A receptor agonist – 1927 nM.
  • 5HT2A (silent antagonist) – 53 nM.
  • 5HT2C (silent antagonist) – 10,000 nM.
  • 5HT6 (silent antagonist) – 3666 nM.
  • 5HT7 (irreversible silent antagonist) – 377.2 nM.
  • H1 (silent antagonist) – 1,800 nM.
  • M1 (silent antagonist) – 10,000 nM.
  • α1A (silent antagonist) – 12 nM.
  • α2A (silent antagonist) – 1130 nM.
  • α2B (silent antagonist) – 480 nM.
  • α2C (silent antagonist) – 550 nM.
  • NR1/NR2B subunit containing NMDA receptor (antagonist; ifenprodil site): IC50 – 2,000 nM.

Pharmacokinetics

By Mouth

The bioavailability of oral haloperidol ranges from 60-70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.

Intramuscular Injections

The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours. The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.

Intravenous Injections

The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg. The duration of action is four to six hours.

Therapeutic Concentrations

Plasma levels of five to 15 micrograms per litre are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998). The determination of plasma levels is rarely used to calculate dose adjustments but can be useful to check compliance.

The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue, which may explain the slow disappearance of side effects when the medication is stopped.

Distribution and Metabolism

Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4.

Society and Culture

Cost

Haloperidol is relatively inexpensive, being up to 100 fold less expensive than newer antipsychotics.

Brand Names

Haloperidol is the INN, BAN, USAN, AAN approved name.

It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halol, Halosten, Keselan, Linton, Peluces, Serenace and Sigaperidol.

Veterinary Use

Haloperidol is also used on many different kinds of animals for nonselective tranquilisation and diminishing behavioural arousal, in veterinary and other settings including captivity management.

What is the Libby Zion Law?

Published on by Andrew Marshall1 Comment

Introduction

New York State Department of Health Code, Section 405, also known as the Libby Zion Law, is a regulation that limits the amount of resident physicians’ work in New York State hospitals to roughly 80 hours per week. The law was named after Libby Zion, who died in 1984 at the age of 18 under the care of what her father believed to be overworked resident physicians and intern physicians. In July 2003, the Accreditation Council for Graduate Medical Education adopted similar regulations for all accredited medical training institutions in the United States.

Although regulatory and civil proceedings found conflicting evidence about Zion’s death, today her death is widely believed to have been caused by serotonin syndrome from the drug interaction between the phenelzine she was taking prior to her hospital visit, and the pethidine administered by a resident physician. The lawsuits and regulatory investigations following her death, and their implications for working conditions and supervision of interns and residents, were highly publicised in both lay media and medical journals.

Death of Libby Zion

Libby Zion (November 1965 to 05 March 1984) was a freshman at Bennington College in Bennington, Vermont. She took a prescribed antidepressant, phenelzine, daily. A hospital autopsy revealed traces of cocaine, but other later tests showed no traces. She was the daughter of Sidney Zion, a lawyer who had been a writer for The New York Times. She had two brothers, Adam and Jed. Her obituary in The New York Times, written the day after her death, stated that she had been ill with a “flu-like ailment” for the past several days. The article stated that after being admitted to New York Hospital, she died of cardiac arrest, the cause of which was not known.

Libby Zion had been admitted to the hospital through the emergency room by the resident physician assigned to the ER on the night of 04 March. Raymond Sherman, the Zion family physician, agreed with their plan to hydrate and observe her. Zion was assigned to two residents, Luise Weinstein and Gregg Stone, who both evaluated her. Weinstein, a first-year resident physician (also referred to as intern or PGY-1), and Stone, a PGY-2 resident, were unable to determine the cause of Zion’s illness, though Stone tentatively suggested that her condition might be a simple overreaction to a normal illness. After consulting with Dr. Sherman, the two prescribed pethidine (meperidine) to control the “strange jerking motions” that Zion had been exhibiting when she was admitted.

Weinstein and Stone were both responsible for covering dozens of other patients. After evaluating Zion, they left. Luise Weinstein went to cover other patients, and Stone went to sleep in an on-call room in an adjacent building. Zion, however, did not improve, and continued to become more agitated. After being contacted by nurses by phone, Weinstein ordered medical restraints be placed on Zion. She also prescribed haloperidol by phone to control the agitation.

Zion finally managed to fall asleep, but by 6:30, her temperature was 107 °F (42 °C). Weinstein was once again called, and measures were quickly taken to try to reduce her temperature. However, before this could be done, Zion had a cardiac arrest and could not be resuscitated. Weinstein informed Zion’s parents by telephone.

Several years had gone by before a general agreement was reached regarding the cause of Zion’s death. Zion had been taking a prescribed antidepressant, phenelzine, before she was admitted to the hospital. The combination of that and the pethidine given to her by Stone and Weinstein contributed to the development of serotonin syndrome, a condition which led to increased agitation. This led Zion to pull on her intravenous tubes, causing Weinstein to order physical restraints, which Zion also fought against. By the time she finally fell asleep, her fever had already reached dangerous levels, and she died soon after of cardiac arrest.

Publicity and Trials

Grieving the loss of their child, Zion’s parents became convinced their daughter’s death was due to inadequate staffing at the teaching hospital. Sidney Zion questioned the staff’s competence for two reasons. The first was the administration of pethidine, which can cause fatal interactions with phenelzine, the antidepressant that Zion was taking. Said interaction was known to few clinicians at the time, though because of this case it is now widely known. The second issue was the use of restraints and emergency psychiatric medication. Sidney’s aggrieved words were: “They gave her a drug that was destined to kill her, then ignored her except to tie her down like a dog.” To the distress of the doctors, Sidney referred to his daughter’s death as a “murder”. Sidney also questioned the long hours that residents worked at the time. In a New York Times op-ed piece, he wrote: “You don’t need kindergarten to know that a resident working a 36-hour shift is in no condition to make any kind of judgment call—forget about life-and-death.” The case eventually became a protracted high-profile legal battle, with multiple abrupt reversals; case reports about it appeared in major medical journals.

State Investigation

In May 1986, Manhattan District Attorney Robert Morgenthau agreed to let a grand jury consider murder charges, an unusual decision for a medical malpractice case. Although the jury declined to indict for murder, in 1987 the intern and resident were charged with 38 counts of gross negligence and/or gross incompetence. The grand jury considered that a series of mistakes contributed to Zion’s death, including the improper prescription of drugs and the failure to perform adequate diagnostic tests. Under New York law, the investigative body for these charges was the Hearing Committee of the State Board for Professional Medical Conduct. Between April 1987 and January 1989, the committee conducted 30 hearings at which 33 witnesses testified, including expert witnesses in toxicology, emergency medicine, and chairmen of internal medicine departments at six prominent medical schools, several of whom stated under oath that they had never heard of the interaction between meperidine and phenelzine prior to this case. At the end of these proceedings, the committee unanimously decided that none of the 38 charges against the two residents were supported by evidence. Its findings were accepted by the full board, and by the state’s Health Commissioner, David Axelrod.

Under New York law, however, the final decision in this matter rested with another body, the Board of Regents, which was under no obligation to consider either the Commissioner’s or the Hearing Committee’s recommendations. The Board of Regents, which at the time had only one physician among its 16 members, voted to “censure and reprimand” the resident physicians for acts of gross negligence. This decision did not affect their right to practice. The verdict against the two residents was considered very surprising in medical circles. In no other case had the Board of Regents overruled the Commissioner’s recommendation. The hospital also admitted it had provided inadequate care and paid a $13,000 fine to the state. In 1991, however, the state’s appeals court completely cleared the records of the two doctors of findings that they had provided inadequate care to Zion.

Civil Trial

In parallel with the state investigation, Sidney Zion also filed a separate civil case against the doctors and the hospital. The civil trial came to a close in 1995 when a Manhattan jury found that the two residents and Libby Zion’s primary care doctor contributed to her death by prescribing the wrong drug, and ordered them to pay a total of $375,000 to Zion’s family for her pain and suffering. The jury also found that Raymond Sherman, the primary care physician, had lied on the witness stand in denying he knew that Libby Zion was to be given pethidine. Although the jury found the three doctors negligent, none of them were found guilty of “wanton” negligence, i.e. demonstrating utter disregard for the patient, as opposed to a simple mistake. Payouts for wanton negligence would not have been covered by the doctors’ malpractice insurance.

The emergency room physician, Maurice Leonard, as well as the hospital (as legal persona) were found not responsible for Zion’s death in the civil trial. The jury decided that the hospital was negligent for leaving Weinstein alone in charge of 40 patients that night, but they also concluded that this negligence did not directly contribute to Zion’s death. The trial was shown on Court TV.

Law and Regulations

After the grand jury’s indictment of the two residents, Axelrod decided to address the systemic problems in residency by establishing a blue-ribbon panel of experts headed by Bertrand M. Bell, a primary care physician at the Albert Einstein College of Medicine in the Bronx. Bell was well known for his critical stance regarding the lack of supervision of physicians-in-training. Formally known as the Ad Hoc Advisory Committee on Emergency Services, and more commonly known as the Bell Commission, the committee evaluated the training and supervision of doctors in the state, and developed a series of recommendations that addressed several patient-care issues, including restraint usage, medication systems, and resident work hours.

“In 1989, New York state adopted the Bell Commission’s recommendations that residents could not work more than 80 hours a week or more than 24 consecutive hours” and that attending physicians “needed to be physically present in the hospital at all times. Hospitals instituted so-called night floats, doctors who worked overnight to spell their colleagues, allowing them to adhere to the new rules.” Periodic follow-up audits have prompted the New York State Department of Health to crack down on violating hospitals. Similar limits have since been adopted in numerous other states. In July 2003 the Accreditation Council for Graduate Medical Education (ACGME) adopted similar regulations for all accredited medical training institutions in the United States.

What is a Typical Antipsychotic?

Published on by Andrew Marshall15 Comments

Introduction

Typical antipsychotics (also known as major tranquilisers, or first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia).

Advertisement for Thorazine (chlorpromazine) from the 1950s, reflecting the perceptions of psychosis, including the now-discredited perception of a tendency towards violence, from the time when antipsychotics were discovered.

Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the phenothiazines, namely chlorpromazine which was discovered serendipitously. Another prominent grouping of antipsychotics are the butyrophenones, an example of which is haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders in the latter.

Both generations of medication tend to block receptors in the brain’s dopamine pathways, but atypicals at the time of marketing were claimed to differ from typical antipsychotics in that they are less likely to cause extrapyramidal symptoms (EPS), which include unsteady Parkinson’s disease-type movements, internal restlessness, and other involuntary movements (e.g. tardive dyskinesia, which can persist after stopping the medication). More recent research has demonstrated the side effect profile of these drugs is similar to older drugs, causing the leading medical journal The Lancet to write in its editorial “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.” While typical antipsychotics are more likely to cause EPS, atypicals are more likely to cause adverse metabolic effects, such as weight gain and increase the risk for type II diabetes.

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic after an initial report in 1952. It was first used in psychiatric institutions because of its powerful tranquilising effect; at the time it was regarded as a non-permanent “pharmacological lobotomy” (Note that “tranquilizing” here only refers to changes in external behaviour, while the experience a person has internally may be one of increased agitation but inability to express it).

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was “neuroleptic”, followed by “major tranquilizer” and then “ataraxic”. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: “νεῦρον” (neuron, originally meaning “sinew” but today referring to the nerves) and “λαμβάνω” (lambanō, meaning “take hold of”). Thus, the word means taking hold of one’s nerves. It was often taken to refer also to common effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and harmful, they were, along with akathisia, considered a reliable sign that the drug was working. These terms have been largely replaced by the term “antipsychotic” in medical and advertising literature, which refers to the medication’s more-marketable effects.

Clinical Uses

Typical antipsychotics block the dopamine 2 receptor (D2) receptor, causing a tranquilising effect. It is thought that 60-80% of D2 receptors need to be occupied for antipsychotic effect. For reference, the typical antipsychotic haloperidol tends to block about 80% of D2 receptors at doses ranging from 2 to 5 mg per day. On the aggregate level, no typical antipsychotic is more effective than any other, though people will vary in which antipsychotic they prefer to take (based on individual differences in tolerability and effectiveness). Typical antipsychotics can be used to treat, e.g. schizophrenia or severe agitation. Haloperidol, due to the availability of a rapid-acting injectable formulation and decades of use, remains the most commonly used tranquilizer for chemical restraint in the emergency department setting (in the interests of hospital staff, not to meet a medical need of the patient).

Adverse Effects

Adverse effects vary among the various agents in this class of medications, but common effects include: dry mouth, muscle stiffness, muscle cramping, tremors, EPS and weight gain. EPS refers to a cluster of symptoms consisting of akathisia, parkinsonism, and dystonia. Anticholinergics such as benztropine and diphenhydramine are commonly prescribed to treat the EPS. 4% of users develop rabbit syndrome while on typical antipsychotics.

There is a risk of developing a serious condition called tardive dyskinesia as a side effect of antipsychotics, including typical antipsychotics. The risk of developing tardive dyskinesia after chronic typical antipsychotic usage varies on several factors, such as age and gender, as well as the specific antipsychotic used. The commonly reported incidence of TD among younger patients is about 5% per year. Among older patients incidence rates as high as 20% per year have been reported. The average prevalence is approximately 30%. There are few treatments that have consistently been shown to be effective for the treatment of tardive dyskinesia, though an VMAT2 inhibitor like valbenazine may help. The atypical antipsychotic clozapine has also been suggested as an alternative antipsychotic for patients experiencing tardive dyskinesia. Tardive dyskinesia may reverse upon discontinuation of the offending agent or it may be irreversible, withdrawal may also make tardive dyskinesia more severe.

Neuroleptic malignant syndrome, or NMS, is a rare, but potentially fatal side effect of antipsychotic treatment. NMS is characterized by fever, muscle rigidity, autonomic dysfunction, and altered mental status. Treatment includes discontinuation of the offending agent and supportive care.

The role of typical antipsychotics has come into question recently as studies have suggested that typical antipsychotics may increase the risk of death in elderly patients. A retrospective cohort study from the New England Journal of Medicine on 01 December 2005 showed an increase in risk of death with the use of typical antipsychotics that was on par with the increase shown with atypical antipsychotics. This has led some to question the common use of antipsychotics for the treatment of agitation in the elderly, particularly with the availability of alternatives such as mood stabilising and antiepileptic drugs.

Potency

Traditional antipsychotics are classified as high-potency, mid-potency, or low-potency based on their potency for the D2 receptor as noted in the table below.

PotencyExamplesAdverse Effect Profile
HighFluphenazine and HaloperidolMore extrapyramidal side effects (EPS) and less antihistaminic effects (e.g. sedation), alpha adrenergic antagonism (e.g. orthostatic hypotension), and anticholinergic effects (e.g. dry mouth).
MediumPerphenazine and LoxapineIntermediate D2 affinity, with more off-target effects than high-potency agents.
LowChlorpromazineLess risk of EPS but more antihistaminic effects, alpha adrenergic antagonism, and anticholinergic effects.

Prochlorperazine (Compazine, Buccastem, Stemetil) and Pimozide (Orap) are less commonly used to treat psychotic states, and so are sometimes excluded from this classification.

A related concept to D2 potency is the concept of “chlorpromazine equivalence”, which provides a measure of the relative effectiveness of antipsychotics. The measure specifies the amount (mass) in milligrams of a given drug that must be administered in order to achieve desired effects equivalent to those of 100 milligrams of chlorpromazine. Another method is “defined daily dose” (DDD), which is the assumed average dose of an antipsychotic that an adult would receive during long-term treatment. DDD is primarily used for comparing the utilization of antipsychotics (e.g. in an insurance claim database), rather than comparing therapeutic effects between antipsychotics. Maximum dose methods are sometimes used to compare between antipsychotics as well. It is important to note that these methods do not generally account for differences between the tolerability (i.e. the risk of side effects) or the safety between medications.

Below is list of typical antipsychotics organised by potency.

  • Low potency:
    • Chlorpromazine.
    • Chlorprothixene.
    • Levomepromazine.
    • Mesoridazine.
    • Periciazine.
    • Promazine.
    • Thioridazine (withdrawn by brand-name manufacturer and most countries, and since discontinued).
  • Medium potency:
    • Loxapine.
    • Molindone.
    • Perphenazine.
    • Thiothixene.
  • High potency:
    • Droperidol.
    • Flupentixol.
    • Fluphenazine.
    • Haloperidol.
    • Pimozide.
    • Prochlorperazine.
    • Thioproperazine.
    • Trifluoperazine.
    • Zuclopenthixol.

Long-Acting Injectables

Some typical antipsychotics have been formulated as a long-acting injectable (LAI), or “depot”, formulation. Depot injections are also used on persons under involuntary commitment to force compliance with a court treatment order when the person would refuse to take daily oral medication. This has the effect of dosing a person who doesn’t consent to take the drug. The United Nations Special Rapporteur On Torture has classified this as a human rights violation and cruel or inhuman treatment.

The first LAI antipsychotics (often referred to as simply “LAIs”) were the typical antipsychotics fluphenazine and haloperidol. Both fluphenazile and haloperidol are formulated as decanoates, referring to the attachment of a decanoic acid group to the antipsychotic molecule. These are then dissolved in an organic oil. Together, these modifications prevent the active medications from being released immediately upon injection, attaining a slow release of the active medications (note, though, that the fluphenazine decanoate product is unique for reaching peak fluphenazine blood levels within 24 hours after administration). Fluphenazine decanoate can be administered every 7 to 21 days (usually every 14 to 28 days), while haloperidol decanoate can be administered every 28 days, though some people receive more or less frequent injections. If a scheduled injection of either haloperidol decanoate or fluphenazine decanoate is missed, recommendations for administering make-up injectable dose(s) or providing antipsychotics to be taken by mouth vary by, e.g. how long ago the last injection was and how many previous injections the person has received (i.e. if steady state levels of the medication have been reached or not).

Both of the typical antipsychotic LAIs are inexpensive in comparison to the atypical LAIs. Doctors usually prefer atypical LAIs over typical LAIs due to the differences in adverse effects between typical and atypical antipsychotics in general.