25. 12. 2022.

12:12 Antipsychotic Drugs - Pharmacology - An Illustrated Review

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

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.

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25. 12. 2022. 12:12 Antipsychotic Drugs - Pharmacology - An Illustrated Review

– 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.

Extrapyramidal system
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.
 
Pharmacokinetics
– 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.
Effects
– Neuroleptic:
— 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
Side effects
– 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).

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— 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
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

– Endocrine:
— 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)
– Other:
— Sedation
— 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.

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Drug interactions
– 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

Receptor Blocked Effects  

5-HT2 receptors in the CNS Antipsychotic  
D2 receptors in the mesolimbic- Antipsychotic
mesocortical pathway  

D2 receptors in the nigrostriatal Extrapyramidal (motor) side effects

pathway  

D2 receptors in the Hyperprolactinemia (increased blood prolactin)

tuberoinfundibular pathway  

D2 receptors in the chemoreceptor Antiemetic

trigger zone (CTZ)  

M1 muscarinic Anticholinergic effects: dry mouth, blurred vision, nasal

stuffiness, urinary retention, palpitations  
α1-adrenergic Orthostatic (postural) hypotension, impotence, failure to
ejaculate  
H1 histamine Sedation  
12.2 Typical Antipsychotics
Phenothiazines
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)
Uses
– Chlorpromazine has both antipsychotic and antiemetic efficacy, but adverse effects has made it
obsolete in treating schizophrenia.

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– 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.

Thioxanthenes
Thiothixene
Use. Borderline personality disorders (drug of choice)
Butyrophenones
Haloperidol

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.
Pimozide
Uses. This agent prevents the acute exacerbation of chronic schizophrenia and suppresses motor
and vocal tics in Tourette syndrome.
Loxapine
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
Uses
– 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.
Side effects
– 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

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