Pharmacology - An Illustrated Review
12. Antipsychotic Drugs
Antipsychotic drugs (neuroleptics) ameliorate the symptoms of psychosis in disorders such as schizophrenia, acute mania, schizoaffective disorders, and borderline personality disorders. In addition, these agents are used as antiemetics and for a variety of other disorders, such as chronic multiple tics, neurogenic pain, Huntington disease (page 71), ballismus, infantile autism, and intractable hiccups. The two major groups of antipsychotic medications are the older typical antipsychotics and the newer atypical agents. They differ in the receptors that they block, the symptoms of schizophrenia that they alleviate, and their side effects.
Ballismus is a hyperkinetic disorder caused by damage, usually vascular, to the subthalamic nucleus, which is functionally related to the basal ganglia. This ultimately disinhibits neurons in the thalamus leading to excessive activity of the motor cortex. Ballismus is characterized by irregular, flinging movements of the limbs. Treatment, when necessary, involves the use of dopamine-blocking agents (e.g., pimozide, haloperidol, and chlorpromazine), despite the fact that dopamine has not been definitively linked to the disorder.
12.1 Features of Typical and Atypical Antipsychotic Agents
Mechanisms of action
– The primary therapeutic receptor mechanism of action for the typical antipsychotics is thought to be related to their ability to block the D2 subtype of dopamine receptor on post-synaptic neurons in the dopaminergic pathways in the brain (see page 67). Blockage of D2 receptors is also implicated in the extrapyrimidal (motor) side effects seen with antipsychotic agents.
– The atypical agents possess 5-HT2 as well as D2 antagonist properties.
– The atypical antipsychotic aripiprazole is unique in that it is a partial agonist at the D2 receptor.
– The antipsychotics also block M1 muscarinic, H1 histamine, and α1-adrenergic receptors to varying degrees, which accounts for some of their side effects.
The extrapyramidal system (EPS) is the collective name for the neurons, tracts, and pathways that regulate and coordinate movement. Tracts of the EPS mainly originate in the reticular formation of the pons and medulla and receive input from the cortex, basal ganglia, thalamus, and cerebellum. They then act upon cells of the ventral horn of the spinal cord. Because they do not directly innervate motor neurons, the EPS has a modulatory and regulatory function on movement, especially reflexes, postural control, and complex motor functions.
– Erratic and unpredictable absorption from the gastrointestinal (GI) tract
– Elimination half-life ranges from 20 to 40 hours.
– Very high therapeutic indices
– Flat dose–response cure
– Wide variations in plasma levels occur among individuals.
— Spontaneous movement and complex behavior are suppressed, but spinal reflexes remain intact.
— Reduced initiative, reduced interest in the environment, and reduced displays of emotion or affect.
— Patients are easily aroused and are capable of answering direct questions; intellectual function remains intact.
— Psychotic patients become less agitated.
— Withdrawn patients may become more responsive.
— Aggression and impulsive behavior are decreased.
— Hallucinations, delusions, and incoherent thoughts tend to decrease.
– Extrapyramidal (motor):
— No motor incoordination at usual doses.
— Spontaneous activity is diminished.
— Catatonic signs are relieved, or rigidity is induced.
– Antiemetic: prevent nausea and vomiting by blocking the effect of emetics that act on D2 receptors in the chemoreceptor trigger zone (CTZ), an area of the medulla that provides input to the vomiting control center (also in the medulla) to initiate vomiting
– Extrapyramidal (motor):
— Parkinsonism with bradykinesis, rigidity, and tremor may develop within 1 week to 1 month of initiation of antipsychotic drugs. It is treated with anticholinergics (e.g., benztropine) or amantadine (see pp. 113 and 114).
— Acute dystonia. This is sustained, often painful muscular spasms in which the patient adopts a twisted posture. It occurs rarely with antipsychotic therapy and is treated with anticholinergic antiparkinsonian agents (e.g., benztropine).
— Akathisia. This is a strong subjective feeling of distress or discomfort; compelling need to be in constant movement that may start within the first 2 weeks of antipsychotic therapy. It must be distinguished from anxiety or agitation, but if these are ruled out, then the dose of antipsychotic should be lowered or changed
— Tardive dyskinesia
Tardive dyskinesia is characterized by involuntary movements and appears only after months or years of treatment with antipsychotic agents. It is less common with atypical agents than typical agents. Stereotypically, the involuntary movements consist of sucking and smacking of the lips, lateral jaw movements, and fly-catching dartings of the tongue. These movements disappear during sleep. Symptoms may persist indefinitely or will sometimes disappear (in weeks to years), especially in younger patients. This condition worsens on withdrawal of antipsychotics and with concomitant use of anticholinergic drugs. There is no adequate drug therapy, so it must be prevented.
– Autonomic nervous system:
— Orthostatic (postural) hypotension, impotence, and failure to ejaculate
— Anticholinergic effects, including dry mouth, blurred vision, nasal stuffiness, urinary retention, palpitations, and toxic-confusional state at high doses
— Hyperprolactinemia (increased blood prolactin), which can result in amenorrhea (a bsence of a menstrual period), galactorrhea (spontaneous flow of milk from the breast, unassociated with lactation following childbirth), infertility, and impotence (inability to develop or maintain an erection)
— Weight gain
— Agranulocytosis (acute low white blood cell count)
— Pigmentary degeneration of the retina (rare)
— Neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome (NMS) is a neurologic disorder that occurs as a result of an idiosyncratic reaction to neuroleptic (antipsychotic) drugs. It usually appears within the first 2 weeks of therapy and presents with fever, muscular rigidity, altered mental status, and autonomic dysfunction (e.g., arrhythmias and fluctuating blood pressure). NMS tends to occur more frequently with typical antipsychotics. The drug management of NMS depends on the symptoms but includes discontinuing the neuroleptic medication, antipyretic drugs (e.g., acetaminophen), dopamine agonists (e.g., bromocriptine), and muscle relaxants (e.g., dantolene sodium). NMS can be fatal, but the prognosis improves with early detection and treatment.
Tolerance, dependence, and withdrawal
– Tolerance develops to sedative effects.
– Some signs of dependence may occur.
– Withdrawal may include muscular discomfort and difficulty sleeping.
– Antipsychotics may potentiate the sedative effects of central depressants and opioid analgesic s.
– Antiparkinsonian agents should not be used routinely in combination with antipsychotics, as they potentiate extrapyramidal side effects.
Table 12.1 summarizes of the effects of antipsychotic agents based on the receptors they block.
Table 12.1 Effects of Antipsychotic Agents Based on Receptors Blocked
5-HT2 receptors in the CNS
D2 receptors in the mesolimbic-mesocortical pathway
D2 receptors in the nigrostriatal pathway
Extrapyramidal (motor) side effects
D2 receptors in the tuberoinfundibular pathway
Hyperprolactinemia (increased blood prolactin)
D2 receptors in the chemoreceptor trigger zone (CTZ)
Anticholinergic effects: dry mouth, blurred vision, nasal stuffiness, urinary retention, palpitations
Orthostatic (postural) hypotension, impotence, failure to ejaculate
12.2 Typical Antipsychotics
Phenothiazine antipsychotics are divided into 3 chemical classes based on their side chain:
Perphenazine and fluphenazine (piperazine chain)
Uses. These agents are the most potent antipsychotics and antiemetics, but have the highest incidence of extrapyramidal side effects.
Note: typical antipsychotic agents alleviate some of the positive symptoms of schizophrenia (see box “Signs and symptoms of schizophrenia”).
Signs and symptoms of schizophrenia
Schizophrenia is characterized by positive, negative, and cognitive signs and symptoms. Positive: Delusions, hallucinations, agitation, disorganized speech, and disorganized behavior.
Negative: Flattened affect, alogia (lack of unprompted content in normal speech), avolition (lack of drive or motivation), anhedonia (inability to experience pleasure), catatonia, and social isolation.
Cognitive: Disorganized thinking, difficulty concentrating, and memory problems.
Chlorpromazine (aliphatic chain)
– Chlorpromazine has both antipsychotic and antiemetic efficacy, but adverse effects has made it obsolete in treating schizophrenia.
– Intractable hiccups (drug of choice)
Thioridazine (piperidine chain)
Uses. Thioridazine is the least potent antipsychotic agent and has the lowest incidence of extrapyramidal adverse effects.
Use. Borderline personality disorders (drug of choice)
Uses. Haloperidol is used extensively, especially for initial stabilization of the psychotic patient.
Side effects. It causes fewer adverse autonomic effects than phenothiazines, however, the induction of tardive dyskinesia and other extrapyramidal adverse effects limits its chronic use.
Uses. This agent prevents the acute exacerbation of chronic schizophrenia and suppresses motor and vocal tics in Tourette syndrome.
Uses. This drug is indicated for the treatment of schizoaffective disorders because its major metabolite, amoxapine, is an antidepressant.
12.3 Atypical Antipsychotics
Clozapine, Olanzapine, Quetiapine, Paliperidone, Risperidone, Ziprasidone, and Aripiprazole
– Psychotic disorders (olanzapine, quetiapine, paliperidone, risperidone, ziprasidone, aripiprazole). Clozapine is reserved for the treatment of refractory severe psychosis.
– Mania (olanzapine, ziprasidone)
— Bipolar disorder (quetiapine, risperidone, aripiprazole)
– Autism (risperidone, aripiprazole)
Note: Atypical antipsychotics improve positive, negative, and cognitive symptoms of schizophrenia.
– Atypical agents tend to produce less extrapyramidal reactions and anticholinergic side effects than the typical agents. However, they tend to produce weight gain, leading to type II diabetes and can cause cardiac QT interval prolongation leading to cardiac arrhythmias
– Clozapine may also cause agranulocytosis
Table 12.2 summarizes the differences between typical and atypical antipsychotic drugs.