Antipsychotic Drugs Flashcards
THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA
The dopamine hypothesis for schizophrenia was the first neurotransmitter-based concept to be developed. Although it is no longer considered adequate to explain all aspects of schizophrenia, it is still highly relevant to understanding the major dimensions of schizophrenia, such as positive, negative, and cognitive symptoms. It is also essential for understanding the mechanism of action of antipsychotic drugs.
It is well known that drugs that increase dopaminergic activity increase or produce positive psychotic symptoms, whereas drugs that decrease dopaminergic activity decrease or stop positive symptoms. For example, (1) Drugs that increase dopaminergic activity, such as amphetamines, or cocaine, if given repeatedly, can cause a paranoid psychosis virtually indistinguishable from schizophrenia; (2) Antipsychotic drugs capable of treating positive psychotic symptoms are blockers of D2 dopamine receptors.
It is believed that hyperactivity of the mesolimbic dopamine pathway mediates the positive symptoms of schizophrenia. Additionally, there is evidence that hypoactivity of the mesocortical pathway may mediate the negative and cognitive symptoms.
Dopamine Pathways in the Brain
1. MESOLIMBIC PATHWAY
Projects from the midbrain to the limbic system.
This pathway is thought to have an important role in emotional behaviours.
Hyperactivity of this pathway is believed to account for positive psychotic symptoms.
Blockade of postsynaptic D2 receptors in this pathway is believed to mediate the antipsychotic efficacy of antipsychotic drugs and their ability to diminish positive symptoms.
2. NIGROSTRIATAL PATHWAY
Projects from the substantia nigra to the basal ganglia.
It controls motor movements.
When dopamine receptors are blocked in postsynaptic projections of this system disorders of movement can appear.
This pathway is part of the extrapyramidal nervous system. Therefore, motor adverse effects associated with blockade of D2 receptors in this system are called extrapyramidal reactions (EPRs). Extrapyramidal reactions include: acute dystonia (spastic retrocollis or torticollis), akathisia (uncontrollable restlessness) and Parkinsonian-like syndrome (tremors, bradykinesia, rigidity).
3. MESOCORTICAL PATHWAY
Projects from the midbrain to the prefrontal cortex.
Negative and cognitive symptoms may be due to reduced activity of this pathway.
Blockade of D2 receptors in the mesocortical pathway may cause or worsen negative and cognitive symptoms: It may cause emotional blunting and cognitive problems.
4. TUBEROINFUNDIBULAR PATHWAY
Projects from the hypothalamus to the anterior pituitary.
Dopamine released from these neurons physiologically inhibits prolactin secretion.
Blockade of D2 receptors in this pathway leads to an increase in prolactin levels, which may cause galactorrhea.
Chlorpromazine
CLASSICAL ANTIPSYCHOTICS
Low-potency drugs: Chlorpromazine and thioridazine. These drugs are less likely to produce extrapyramidal reactions and more likely to produce sedation and postural hypotension.
Fluphenazine
CLASSICAL ANTIPSYCHOTICS
High-potency drugs: Fluphenazine and haloperidol. These drugs are more likely to produce extrapyramidal reactions.
Haloperidol
CLASSICAL ANTIPSYCHOTICS
High-potency drugs: Fluphenazine and haloperidol. These drugs are more likely to produce extrapyramidal reactions.
Thioridazine
CLASSICAL ANTIPSYCHOTICS
Low-potency drugs: Chlorpromazine and thioridazine. These drugs are less likely to produce extrapyramidal reactions and more likely to produce sedation and postural hypotension.
Classical Antipsychotics Mechanism of Action
Block dopamine receptors in the brain and in the periphery. All dopamine receptors are G protein-coupled. Five different dopamine receptors have been described, consisting of two separate families, the D1-like and D2-like receptor groups.
D1-like dopamine receptors: D1 & D5: activate adenylyl cyclase
D2-like dopamine receptors: D2, D3, D4: inhibit adenylyl cyclase
The efficacy of the traditional neuroleptic drugs correlates closely with their ability to block D2 receptors in the mesolimbic pathway.
Clozapine
ATYPICAL ANTIPSYCHOTICS
Risperidone
ATYPICAL ANTIPSYCHOTICS
Olanzapine
ATYPICAL ANTIPSYCHOTICS
Quetiapine
ATYPICAL ANTIPSYCHOTICS
Aripiprazole
ATYPICAL ANTIPSYCHOTICS
The atypical antipsychotic drugs are currently the most widely used type of antipsychotic drugs.
Mechanism of Action of Atypical Antipsychotic Drugs
ATYPICAL ANTIPSYCHOTIC DRUGS
The term atypical antipsychotic entered into the Psychiatry vocabulary as a result of clinical experience with clozapine. The pharmacologic properties of this drug were found to differ substantially from those of conventional antipsychotics. Thus, clozapine is the prototype for atypical antipsychotics.
Since clozapine, several atypical antipsychotics have been released in the U.S. market: risperidone, olanzapine, quetiapine, aripiprazole.
Atypical antipsychotic drugs have higher affinities for other receptors than for the D2 receptor. For example:
Clozapine has high affinity for D1, D4, 5HT2, muscarinic and α−adrenergic receptors, but it is also a D2 blocker.
Risperidone blocks 5HT2 to a greater extent than it does D2.
COMMON PROPERTIES OF ATYPICAL ANTIPSYCHOTICS
Most atypical drugs exhibit dual antagonism at 5-HT2A and D2 receptors. They are sometimes referred to as serotonin-dopamine antagonists (SDA).
They appear to exert part of their action by blocking 5HT receptors.
They are much less likely to cause extrapyramidal reactions than classical agents.
They are less likely to cause tardive dyskinesia
They are less likely to cause increases in prolactin
They are more effective at treating negative symptoms.
They are effective in treatment of refractory populations.
PROPERTIES OF SOME ATYPICAL ANTIPSYCHOTIC AGENTS
Clozapine is the prototype of the atypical agents.
Risperidone has much more potent antidopaminergic and much less potent antimuscarinic activity than clozapine. Unlike clozapine, it can cause extrapyramidal reactions and hyperprolactinemia. However, risperidone can be considered an atypical antipsychotic because extrapyramidal reactions are rare at therapeutic doses. Risperidone is metabolized in the liver by CYP2D6 to an active metabolite, 9-hydroxyrisperidone. Since this metabolite and risperidone are nearly equipotent, the clinical efficacy of the drug reflects both compounds.
Clozapine and quetiapine are the agents least likely to induce EPR.
Aripiprazole is a partial agonist at D2 and 5HT1A receptors and an antagonist at 5HT2A receptors. Aripiprazole’s activity is due to the parent drug, and to a lesser extent, to its major metabolite, dehydroaripiprazole.
Actions of Antipsychotic Drugs
ACTIONS OF ANTIPSYCHOTIC DRUGS
The actions of antipsychotics reflect blockade of dopamine and/or serotonin receptors. But many block also muscarinic, α1-adrenergic receptors and H1 receptors, causing a variety of side effects.
ANTIPSYCHOTIC ACTIONS
Reduce hallucinations and agitation associated with schizophrenia by blocking dopamine receptors in mesolimbic system.
These drugs also have a calming effect and reduce spontaneous physical movement.
In contrast to the CNS depressants, such as barbiturates, the neuroleptics don’t depress intellectual function, and motor incoordination is minimal.
The onset of antipsychotic action is within the first 24 h of treatment and the magnitude of this action grows with time.
ANTIEMETIC EFFECTS
With the exception of aripiprazole and thioridazine, most neuroleptics have antiemetic effects mediated by blockade of D2 receptors of the chemoreceptor trigger zone of the medulla.
METABOLISM
Most antipsychotic drugs are almost completely metabolized, mainly by CYP2D6, CYP1A2 and CYP3A4. At typical clinical doses, antipsychotics do not usually interfere with the metabolism of other drugs.
Fluphenazine decanoate, haloperidol decanoate, and risperidone microspheres are slow-release (up to 2 to 4 weeks) formulations that are administered IM. These drugs are often used to treat outpatients and individuals who are noncompliant with oral medications. The risk of EPR is lower with these long-acting formulations compared to the oral formulations.
Adverse Effects of Antipsychotics
ADVERSE EFFECTS
Antipsychotics have a high therapeutic index and are generally safe agents.
NEUROLOGIC EFFECTS EXTRAPYRAMIDAL REACTIONS
The inhibitory effects of dopaminergic neurons are normally balanced by the excitatory actions of cholinergic neurons. Blocking dopamine receptors alters this balance, causing a relative excess of cholinergic influence and resulting in extrapyramidal motor effects.
Extrapyramidal reactions are associated with high D2 potency: Extrapyramidal effects are most likely to occur with high-potency conventional antipsychotic drugs, such as haloperidol and fluphenazine, that have a high affinity for D2-receptors in the basal ganglia.
Extrapyramidal effects are less likely to occur with low-potency conventional antipsychotic drugs such as chlorpromazine or thioridazine, which have lower affinity for dopamine D2-receptors.
Extrapyramidal effects are less likely to occur with conventional agents that exhibit strong anticholinergic activity, such as thioridazine and chlorpromazine, since the cholinergic activity is strongly dampened. This contrasts with haloperidol and fluphenazine, which have low anticholinergic activity and produce extrapyramidal effects.
Atypical antipsychotic drugs have in general low potential for causing extrapyramidal symptoms and also lower risk of tardive dyskinesia.
Extrapyramidal reactions include typical Parkinson’s syndrome, acute dystonic reactions, akathisia, and tardive dyskinesia.
PARKINSONISM
Parkinsonism can be treated with conventional antiparkinsonism drugs of the antimuscarinic type (benztropine or trihexyphenidyl), with diphenhydramine, or with amantadine. Levodopa should never be used in these patients.
ACUTE DYSTONIA
Acute dystonia can be controlled with benztropine, trihexyphenidyl, or diphenhydramine.
AKATHISIA
Management of akathisia typically requires reduction of dosage or a change of the antipsychotic drug. The drugs most commonly used to manage akathisia are clonazepam or propranolol.
TARDIVE DYSKINESIA
Late-occurring syndrome of abnormal choreoathetoid movements. It is the most important adverse effect of antipsychotic drugs. Patients display involuntary movements including lateral jaw movements and fly-catching motions of the tongue. Disfiguring and potentially irreversible disorder. Probably due to long-term dopamine receptor blockade, causing dopamine receptors to up-regulate.
When tardive dyskinesia is diagnosed the first step is to discontinue the antipsychotic drug or reduce the dose. A second step would be to eliminate all drugs with central anticholinergic action, particularly antiparkinsonian drugs and tricyclic antidepressants. Administration of diazepam may help. Tardive dyskinesia may worsen initially after antipsychotics are discontinued. Atypical antipsychotics may control psychosis while reducing the risk of tardive dyskinesia. In particular, clozapine has been recommended as treatment for patients with tardive dyskinesia who require antipsychotics.
NEUROLEPTIC MALIGNANT SYNDROME
Rare and potentially fatal reaction to antipsychotic drugs. Characterized by severe rigidity, tremor, hyperthermia, altered mental status, autonomic instability, elevated white cell count, elevated serum creatine kinase, and sometimes myoglobinemia with potential nephrotoxicity.
The syndrome is believed to result from an excessively rapid blockade of postsynaptic dopamine receptors. Treatment necessitates discontinuation of the neuroleptic, and supportive therapy. Dantrolene or bromocriptine may be helpful. Switching to an atypical drug after recovery is indicated.
SEDATION
Sedation is more likely with low-potency antipsychotics and with the atypical agents. It is due to blockade of central H1 receptors.
SEIZURES
Especially common with chlorpromazine and clozapine.
