Download ANTIPSYCHOTICS Objectives: After this lecture has been presented

ANTIPSYCHOTICS
Objectives: After this lecture has been presented, the student should be able to:
1. Describe some of the hallmark symptoms of schizophrenia and other psychotic disorders.
2. Describe the mechanism of action for the various types of antipsychotic medications.
3. Describe a potential rationale for the therapeutic choice of a particular antipsychotic.
4. Describe the similarities and differences in the side effects for the different
antipsychotics, and which medications are most likely to result in Tardive Dyskinesia or
Neuroleptic Malignant Syndrome.
I. Antipsychotics are prescribed specifically for several different types of psychoses, all of which
are described in detail in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
 schizophrenia (chemically-induced or organic in nature)
 mania
 organic mental disorder (OMD)
In general, the symptoms of the different types of psychoses are relatively wide-ranging and
include disorders of perception, thought patterns, consciousness, social interactions and affect
(cf. DSM-IV). Frequently, the symptoms of schizophrenia are divided into two major types,
positive and negative, and the type of symptoms can dictate the choice of antipsychotic.
II. The etiology of various psychoses has generally been deemed to be the result of excessive
dopamine (DA) activity in the central nervous system. This has been called the dopamine
hypothesis of schizophrenia (1963) and was largely determined from the knowledge that:
A. drugs that block dopamine receptors (i.e., dopamine antagonists) are therapeutically
effective in alleviating psychotic symptoms.
B. sympathomimetic drugs such as amphetamine, which release dopamine, can induce
psychosis.
III. As a class of drugs, the antipychotics are generally:
 orally administered (i.m. administration an option with certain drugs)
 95-98% bound to plasma proteins
 subject to extensive “first-pass” hepatic metabolism
 drugs with long “half-lives” (e.g., chlorpromazine - t½=30 hours)
 70% of patients respond to conventional drugs
IV. Administration of these drugs leads to characteristic physical and psychological effects
known as a “neuroleptic syndrome”. This syndrome includes effects such as:
 sedation
 emotional quieting
 psychomotor slowing
 affective indifference
V. There are at least eight classes of antipsychotic drugs, the five considered to be first
generation are:
A. Phenothiazines: these drugs are predominantly dopamine type-2 (D2) antagonists, with
varying degrees of selectivity
1. Aliphatics – low affinity D2 antagonists that pose an increased risk for autonomic side
effects
a. chlorpromazine (“Thorazine”)
b. promazine (“Sparine” - least effective of the aliphatics)
c. trifluopromazine (“Vesprin”)
2. Piperdines – have comparatively high affinity for the D2 receptor
a. mesoridazine (“Serentil”)
b. thioridazine (“Mellaril”)
3. Piperazines – high affinity D2 antagonists that pose an increased risk for
extrapyramidal side effects; least sedating
a. fluphenazine (“Prolixin” - decanoate formulation available)
b. perphenazine (“Trilafon”)
c. trifluoperazine (“Stelazine”)
B. Butyrophenone - haloperidol (“Haldol” – has high to intermediate affinity for the D2
receptor, and therefore, poses increased risk of extrapyramidal side effects; decanoate
formulation available)
C. Thioxanthenes – also have potent D2 antagonist properties:
1. chlorprothixene (“Taractan”)
2. thiothixene (“Navane”)
VI. The second generation antipsychotics are considered to be atypical and are only weakly
“antidopaminergic”. The absence of “antidopaminergic” effects substantially reduces the
potential for tardive dyskinesia and drug-induced parkinsonism.
A. Partial Dopamine Receptor Agonist – aripiprazole (Abilify) – theoretically, a partial
agonist should reduce incidence of neurolepsis, parkinsonism-like effects and potential
for tardive dyskinesia that can occur with the D2-receptor antagonists.
B. Dibenzodiazepines – heterocyclic compounds that have extraordinarily mixed receptorbinding profiles
1. clozapine (“Clozaril” – approved by the FDA in 1989, it seems to help those with
negative antipsychotic symptoms. This drug poses a risk for agranulocytosis, a
potentially life-threatening blood disorder. In addition, a recent retrospective
study revealed cardiovascular complications such as myocarditis and
cardiomyopathy resulting from chronic treatment with clozapine)
2. loxapine (“Loxitane”)
3. olanzapine (“Zyprexa” – approved within the last 5 years or so, it does not pose
the same risk of agranulocytosis as clozapine; case reports have described
incidents of olanzapine-induced sleepwalking)
C. Benzisoxazole – these drugs are relatively selective 5-HT2A receptor antagonist, but at
higher doses (>10 mg) has haloperidol-like effects)
1. risperidone (“Risperdal”)
2. paliperidone (“Invega” – primary active metabolite of risperidone; thought to
antagonize both D2 and 5-HT2A receptors)
3. ziprasidone (“Geodon”)
4.
D. Other heterocyclic antipsychotics
1. molindone (“Moban”)
2. pimozide (“Orap” – also indicated for the treatment of severe tics and involuntary
vocalizations that occur with Tourette’s syndrome)
3. quetiapine (“Seroquel”)
VIII.
The side effects that can result from taking antipsychotic medications are also wideranging and potentially lethal in the case of Neuroleptic Malignant Syndrome (NMS).
The broad spectrum of effects frequently associated with the antipsychotics results
from their relative selectivities as receptor antagonists.
A. Many antipsychotics can block peripheral muscarinic receptors, alpha-adrenergic
receptors, and histamine-1 receptors – frequently resulting in sedation and weight gain.
B. DA is a ubiquitous neurotransmitter that plays a substantial role in many brain areas
including the pituitary, hypothalamus, chemoreceptor trigger zone, and the
extrapyramidal system.
C. Some of the most common side effects:
1.
akathisias - unpleasant, subjective responses often characterized as “nervous
energy” (strongly contribute to noncompliance)
2.
Parkinsonism (drug-induced or “pseudoparkinsonism”)
3.
dystonias, dyskinesias and akinesias - disorders of muscle tonicity and movement,
with the distinct absence of movement (akinesias) also being a problem.
4.
tardive dyskinesias - probably the most serious of the drug-induced
extrapyramidal side effects; the symptoms develop late during antipsychotic drug
therapy.
5.
Neuroleptic Malignant Syndrome - occurs in 1% of the patients taking
antipsychotic drug therapy. However, 20-30% of these may die from it. This
syndrome is particularly problematic since:
a. can occur at therapeutic doses
b. can be seen within hours of starting treatment, or after months of treatment
c. the symptoms include:
1. muscular rigidity
2. impaired breathing or ventilation
3. autonomic hyperactivity
4. extremely high temperatures
6.
blood abnormalities - a host of hematological problems can arise during
antipsychotic therapy, including a fatal agranulocytosis.
7.
endocrine abnormalities - leads to increased serum prolactin, which can lead to
amenorrhea, gynecomastia and false-positive pregnancy tests.
8.
cardiovascular effects - orthostatic hypotension
D. Drug interactions can also be a problem during antipsychotic therapy. Two of the most
common examples are:
1. the potentiation of other CNS depressants such as alcohol
2. an interaction with OTC medications such as antihistamines.
IX. Examples of contraindications for “typical” antipsychotic therapy:
1. blood dyscrasias
2. Parkinsonism
3. chronic alcoholism
4. liver disease