Antipsychotics / Neuroleptics

“You’re crazier than ever!”

 ANTIPSYCHOTICS
– aka neuroleptics, major tranquilizers
– Schizophrenia / Psychosis
• Dopamine Hypothesis: ↑ dopamine
• delusion, hallucination, thought disorders, disorganized
speech, bizarre behavior, insomnia, combativeness
• e.g. amphetamine, levodopa
– MOA: block the following receptors:
• dopamine - Parkinson-like symptoms
• cholinergic - reverse of DUMBELS
• adrenergic (a1) - hypotension
• histamine - sedation
 Typical Antipsychotics
• Classic or old versions  “-azines”
– Phenothiazines
• Aliphatic  with “pro” except prochlorperazine
• Piperidine  with “rid”; piperacetazine
• Piperazine  with “phe”; prochlorperazine;
Trifluoperazine
– Thioxanthene  with “thixene”
– Butyrophenones  “ridol”
 Atypical Antipsychotics
• Newer versions
• With “-apine”; “-idone”; “-indole” suffixes
 Typical vs Atypical
Typical Atypical
Receptor blockade dopamine dopamine &
serotonin
Positive symptoms effective effective
Negative symptoms effective more effective
EPS more less
Tardive dyskinesia high low
Positive symptoms: delusions, hallucinations & thought disorders
Negative symptoms: withdrawal, blunted emotions & reduced ability to
relate to people
Extrapyramidal symptoms: involuntary movements, tremors & rigidity,
body restlessness, muscle contractions & changes in breathing & HR
Tardive dyskinesias: involuntary movements of the tongue, lips, face,
trunk, & extremities
Other uses:
– 1. Antiemetic - Prochlorperazine blocks
dopamine receptors
– 2. Intractable hiccups - Chlorpromazine
– 3. Pruritus – aliphatic typical antipsychotics
such as Promethazine (histamine blocker)
Effects
• Dopamine receptor blockade is the major effect that
correlates with therapeutic benefit for older antipsychotic
drugs.
• Dopaminergic tracts in the brain include the:
 mesocortical-mesolimbic pathways (regulating mentation and mood)
 nigrostriatal tract (extrapyramidal function)
 tuberoinfundibular pathways (control of prolactin release)
 chemoreceptor trigger zone (emesis).
 Mesocortical-mesolimbic dopamine receptor blockade presumably
underlies antipsychotic effects and a similar action on the chemoreceptor
trigger zone leads to the useful antiemetic properties of some antipsychotic
drugs.
• Note that almost all antipsychotic agents block both 1 and
histamine H1 receptors to some extent
Drug D2 D4 Alpha1 5-HT2 M H1
Block Block Block Block Block Block
Most phenothiazines and ++ – ++ + + +
thioxanthines
Thioridazine ++ – ++ + +++ +
Haloperidol +++ – + – – –
Clozapine – ++ ++ ++ ++ +
Molindone ++ – + – + +
Olanzapine + – + ++ + +
Quetiapine + – + ++ + +
Risperidone ++ – + ++ + +
Ziprasidone ++ – ++ ++ – +
Aripiprazole + + + ++ – +
 CLINICAL USES
• Treatment of Schizophrenia
– to reduce some of the positive symptoms of
schizophrenia, including hyperactivity, bizarre ideation,
hallucinations, and delusions.
– Beneficial effects may take several weeks to develop.
– Clozapine is effective in some schizophrenic patients
resistant to treatment with other antipsychotic drugs.
– Older drugs are still commonly used partly because of
their low cost compared with newer agents. Disadvantage:
no effect for negative symptoms
– Newer atypical drugs are reported to improve some of the
negative symptoms of schizophrenia, including emotional
blunting, social withdrawal, and lack of motivation.
 CLINICAL USES
• Other Psychiatric and Neurologic
Indications
– newer antipsychotic drugs (+ lithium)  initial treatment
of mania.
– Several second-generation drugs are approved for
treatment of acute mania; two of these (aripiprazole
and olanzapine) are approved for maintenance
treatment of bipolar disorder.
– The antipsychotic drugs are also used in the
management of psychotic symptoms of schizoaffective
disorders, in Gilles de la Tourette syndrome, and for
management of toxic psychoses caused by overdosage
of certain CNS stimulants.
– Molindone is used mainly in Tourette's syndrome; it is
rarely used in schizophrenia.
 CLINICAL USES
• Nonpsychiatric Indications
– With the exception of thioridazine, most
phenothiazines have antiemetic actions;
prochlorperazine is promoted solely for this
indication.
– H1-receptor blockade, most often present in
short side-chain phenothiazines, provides the
basis for their use as antipruritics and
sedatives and contributes to their antiemetic
effects.
 TOXICITY
• Reversible Neurologic Effects
– Dose-dependent extrapyramidal effects
include a Parkinson-like syndrome with
bradykinesia, rigidity, and tremor. This
toxicity may be reversed by a decrease in
dose and may be antagonized by concomitant
use of muscarinic blocking agents.
– Extrapyramidal toxicity occurs most frequently
with haloperidol and the more potent
piperazine side-chain phenothiazines (eg,
fluphenazine, trifluoperazine).
 TOXICITY
• Tardive Dyskinesias
– This important toxicity includes choreoathetoid movements of the
muscles of the lips and buccal cavity and may be irreversible.
– Tardive dyskinesias tend to develop after several years of
antipsychotic drug therapy but have appeared as early as 6 mo.
– Antimuscarinic drugs that usually ameliorate other
extrapyramidal effects generally increase the severity of tardive
dyskinesia symptoms.
– There is no effective drug treatment for tardive dyskinesia.
Switching to clozapine does not exacerbate the condition.
– Tardive dyskinesia may be attenuated temporarily by increasing
neuroleptic dosage; this suggests that tardive dyskinesia may be
caused by dopamine receptor sensitization.
 TOXICITY
• Autonomic Effects
– Autonomic effects result from blockade of peripheral muscarinic
receptors and adrenoceptors and are more difficult to manage in
elderly patients.
– Of the older antipsychotic agents, thioridazine has the strongest
autonomic effects and haloperidol the weakest. Clozapine and
most of the atypical drugs have intermediate autonomic effects.
– Regarding muscarinic receptor blockade, atropine-like effects
(dry mouth, constipation, urinary retention, and visual problems)
are often pronounced with the use of thioridazine and
phenothiazines with aliphatic side chains (eg, chlorpromazine).
– Regarding α-receptor blockade, postural hypotension caused by
blockade is a common manifestation of many of the older drugs,
especially phenothiazines. In the elderly, measures must be
taken to avoid falls resulting from postural fainting.
– Failure to ejaculate is common in men treated with the
phenothiazines.
 TOXICITY
• Endocrine and Metabolic Effects
– Endocrine and metabolic effects include
hyperprolactinemia, gynecomastia, the amenorrhea-
galactorrhea syndrome, and infertility.
– Most of these side effects are predictable
manifestations of dopamine D2 receptor blockade in
the pituitary
• dopamine is the normal inhibitory regulator of prolactin
secretion. Elevated prolactin is prominent with risperidone.
– Significant weight gain and hyperglycemia due to a
diabetogenic action occur with several of the atypical
agents, especially clozapine and olanzapine. These
effects may be especially problematic in pregnancy.
 TOXICITY
• Neuroleptic Malignant Syndrome
– Patients who are particularly sensitive to the
extrapyramidal effects of antipsychotic drugs may
develop a malignant hyperthermic syndrome.
– The symptoms include muscle rigidity, impairment of
sweating, hyperpyrexia, and autonomic instability,
which may be life threatening.
– Drug treatment involves the prompt use of
dantrolene, diazepam, and dopamine agonists.
 TOXICITY
• Sedation
– This is more marked with phenothiazines
(especially chlorpromazine) than with other
antipsychotics; this effect is usually perceived
as unpleasant by nonpsychotic persons.
– Fluphenazine and haloperidol are the least
sedating of the older drugs; aripiprazole
appears to be the least sedating of the newer
agents.
 TOXICITY
• Miscellaneous Toxicities
– Visual impairment caused by retinal deposits
has occurred with thioridazine ; at high
doses, this drug may also cause severe
conduction defects in the heart resulting in
fatal ventricular arrhythmias.
– Most of the atypicals, especially quetiapine
and ziprasidone, prolong the QT interval of
the electrocardiogram (ECG);
– Clozapine causes a small but important (1–
2%) incidence of agranulocytosis and at high
doses has caused seizures.
 TOXICITY
• Overdosage Toxicity
– Poisoning with antipsychotics other than thioridazine
is not usually fatal, although the FDA has warned of
an increased risk of death in elderly patients with
dementia.
– Hypotension often responds to fluid replacement.
– Most neuroleptics lower the convulsive threshold and
may cause seizures, which are usually managed
with diazepam or phenytoin.
– Thioridazine (and possibly ziprasidone) overdose,
because of cardiotoxicity, is more difficult to treat.